Bicyclic heterocyclic derivatives and related uses

Abstract

# imgabs0 # The disclosure relates to compounds of Formula (T): and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods of making. The compounds disclosed herein are useful for modulating orexin receptor activity and can be used to treat disorders in which orexin receptor activity is involved, such as narcolepsy, hyperactivity disorders, neurodegenerative disorders, symptoms of rare genetic disorders, mental health disorders, metabolic syndromes, osteoporosis, heart failure, coma or complications of reviving from anesthesia.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 315,436, filed on March 1, 2022, the entire contents 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. One in every 2,000 people worldwide suffers from narcolepsy. Onset can occur in adolescence, lasts throughout life, and has a debilitating impact on quality of life. Narcolepsy type 1 (NT1) is caused by the loss of neurons in the brain that produce orexin neuropeptides. There is no known cure, and currently approved treatments are symptomatic. Therefore, the development of drug therapies to restore lost orexin signaling is critical 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 of the boundaries of 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 nighttime sleep, and inappropriately timed rapid eye movement (REM) sleep, as well as sleep paralysis and half-awake / half-asleep hallucinations. Cataplexy is a sudden, reversible loss of muscle tone (lack of tone in REM sleep) that intrudes into the wakeful state in response to emotional stimuli, and is a diagnostic sign of NT1.

[0005] The two main symptoms of narcolepsy type 1 (excessive daytime sleepiness and cataplexy) can be reduced by reactivation of orexin neurotransmission at OX2R in mouse models. 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 time and reduce cataplexy-like behavior in orexin-neuron-ablated mice. The selective OX2R agonist YNT-185 administered intraperitoneally or ICV modestly increases wakefulness in wild-type (WT) and orexin ligand-deficient mice, and reduces sleep onset REM stage and cataplexy-like events in the NT1 mouse model. Subcutaneous administration of the selective OX2R agonist TAK-925 modestly increases 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. In fact, preliminary clinical studies reported on TAK-925 showed significantly increased levels of arousal and a trend toward 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 OX2R stimulation promotes wakefulness in intact orexin animals, orexin receptor agonists can treat excessive daytime sleepiness in patients with normal orexin levels, including type 2 narcolepsy, idiopathic hypersomnia or sleep apnea. Similarly, orexin receptor agonists can provide benefits of 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 disorders and jet lag disorders). 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) may be alleviated with orexin receptor agonists. Other indications for which orexin receptor agonists are thought to have benefit include attention deficit hyperactivity disorder, age-related cognitive dysfunction, metabolic syndrome and obesity, osteoporosis, heart failure, coma, and emergence from anesthesia.

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

[0012] X is -C(R X1 )3 or -N(R X2 )2;

[0013] Each R X1 are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl,

[0014] or two R X1 Together with the atoms to which they are attached, they form a C3-C4 cycloalkyl or a 4-membered heterocycloalkyl;

[0015] Each R X2 are independently H, C1-C6 alkyl or C1-C6 haloalkyl;

[0016] Ar1 is a C6 aryl group substituted by one or more R3;

[0017] R3 is halogen;

[0018] R1 is C1-C6 alkyl or C1-C6 haloalkyl;

[0019] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0020] Each R 2S are independently halogen;

[0021] R 4a is H; and

[0022] R 4b It's H.

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

[0024]

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

[0026] Z is -NH-;

[0027] X is -C(R X1 )3 or -N(R X2 )2;

[0028] Each R X1 is independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy,

[0029] or two R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted with one or more halogens;

[0030] Each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl or -(CH2) n-C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens,

[0031] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0032] Ar1 is a C6 aryl group substituted by one or more R3;

[0033] R3 is halogen;

[0034] R1 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0035] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0036] Each R 2S are independently halogen;

[0037] R 4a It is H;

[0038] R 4b is H; and

[0039] n is 0, 1 or 2.

[0040] In some aspects, the present disclosure provides a compound of formula (I"):

[0041]

[0042] or a pharmaceutically acceptable salt thereof, wherein:

[0043] Z is -NH-;

[0044] X is -C(R X1 )3 or -N(R X2 )2;

[0045] Each R X1 is independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy,

[0046] or two R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted with one or more halogens;

[0047] Each R X2are independently H, C1-C6 alkyl, C1-C6 haloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens,

[0048] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0049] Ar1 is a C6 aryl group substituted by one or more R3;

[0050] R3 is halogen;

[0051] R1 is C3-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0052] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0053] Each R 2S are independently halogen;

[0054] R 4a It is H;

[0055] R 4b is H; and

[0056] n is 0, 1 or 2.

[0057] In some aspects, the present disclosure provides a compound of formula (I'"):

[0058]

[0059] or a pharmaceutically acceptable salt thereof, wherein:

[0060] Z is -NH-;

[0061] X is -C(R X1 )3 or -N(R X2 )2;

[0062] Each R X1 are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the alkyl is optionally substituted with one or more -OH or C1-C6 alkoxy groups,

[0063] or two R X1 Together with the atoms to which they are attached, they form a C3-C4 cycloalkyl group or a 4-membered or 5-membered heterocycloalkyl group;

[0064] Each R X2are independently H, C1-C6 alkyl or C1-C6 haloalkyl,

[0065] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0066] Ar1 is a C6 aryl group substituted by one or more R3;

[0067] R3 is halogen or C1-C6 alkoxy;

[0068] R1 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0069] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0070] Each R 2S are independently halogen or C1-C6 alkyl;

[0071] R 4a is H; and

[0072] R 4b It's H.

[0073] In some aspects, the present disclosure provides a compound of formula (II):

[0074]

[0075] or a pharmaceutically acceptable salt thereof, wherein:

[0076] Z is -NH-;

[0077] X is -C(R X1 )3 or -N(R X2 )2;

[0078] Each R X1 is independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy,

[0079] or two R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted with one or more halogens;

[0080] Each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, -(CH(C1-C6 alkyl))n -C3-C6 cycloalkyl, -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more CN, halogen or C1-C6 alkoxy,

[0081] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0082] Ar1 is a C6 aryl group substituted by one or more R3;

[0083] R3 is halogen;

[0084] R1 is C3-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0085] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0086] Each R 2S are independently halogen;

[0087] R 4a It is H;

[0088] R 4b is H; and

[0089] n is 0, 1 or 2.

[0090] In some aspects, the present disclosure provides a compound of formula (II'):

[0091]

[0092] or a pharmaceutically acceptable salt thereof, wherein:

[0093] Z is -NH-;

[0094] X is -C(R X1 )3 or -N(R X2 )2;

[0095] Each R X1 is independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy,

[0096] or two R X1Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted with one or more halogens;

[0097] Each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, -(CH(C1-C6 alkyl)) n -C3-C6 cycloalkyl, -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more CN, halogen or C1-C6 alkoxy,

[0098] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0099] Ar1 is a C6 aryl group substituted by one or more R3;

[0100] R3 is halogen;

[0101] R1 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0102] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0103] Each R 2S are independently halogen;

[0104] R 4a It is H;

[0105] R 4b is H; and

[0106] n is 0, 1 or 2.

[0107] In some aspects, the present disclosure provides a compound of formula (II"):

[0108]

[0109] or a pharmaceutically acceptable salt thereof, wherein:

[0110] Z is -NH-;

[0111] X is -C(R X1 )3 or -N(R X2 )2;

[0112] Each R X1is independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy,

[0113] or two R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more oxo, -CN, halogen, C1-C6 haloalkyl or C1-C6 alkoxy;

[0114] Each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, -(CH(C1-C6 alkyl)) n -C3-C6 cycloalkyl, -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more CN, halogen or C1-C6 alkoxy,

[0115] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0116] Ar1 is a C6 aryl group substituted by one or more R3;

[0117] R3 is halogen;

[0118] R1 is C3-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0119] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0120] Each R 2S are independently halogen;

[0121] R 4a It is H;

[0122] R 4b is H; and

[0123] n is 0, 1 or 2.

[0124] In some aspects, the present disclosure provides a compound of formula (II'"):

[0125]

[0126] or a pharmaceutically acceptable salt thereof, wherein:

[0127] Z is -NH-;

[0128] X is -C(R X1 )3 or -N(R X2 )2;

[0129] Each R X1 is independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy,

[0130] or two R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more oxo, -CN, halogen, C1-C6 haloalkyl or C1-C6 alkoxy;

[0131] Each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, -(CH(C1-C6 alkyl)) n -C3-C6 cycloalkyl, -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more CN, halogen or C1-C6 alkoxy,

[0132] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0133] Ar1 is a C6 aryl group substituted by one or more R3;

[0134] R3 is halogen;

[0135] R1 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0136] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0137] Each R 2S are independently halogen;

[0138] R 4a It is H;

[0139] R 4b is H; and

[0140] n is 0, 1 or 2.

[0141] 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 Scheme 1).

[0142] 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.

[0143] 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 1-91).

[0144] In some aspects, the disclosure provides a method of modulating orexin receptor activity (eg, in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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).

[0149] 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).

[0150] 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.

[0151] 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.

[0152] 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 receptor activity (eg, in vitro or in vivo).

[0153] 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).

[0154] 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.

[0155] 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.

[0156] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0157] In some aspects, the present disclosure provides a method of preparing a compound comprising one or more of the steps described herein.

[0158] Unless otherwise defined, all technical and scientific terms used in this article have the same meanings as those of ordinary skill in the art to which the present 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 in 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.

[0159] Other features and advantages of the disclosure will be apparent from the following detailed description, and from the claims. DETAILED DESCRIPTION

[0160] The present disclosure relates to spiroheterocyclic derivatives, prodrugs and pharmaceutically acceptable salts thereof, which can modulate orexin-2 receptor activity and are therefore used in methods for treating the human or animal body. The present disclosure also relates to methods for preparing these compounds, pharmaceutical compositions comprising them, and their use in treating disorders in which orexin-2 receptors are involved (such as neurodegenerative disorders, neurological disorders, symptoms of rare genetic disorders, mental disorders, mental health disorders, circadian rhythm disorders, metabolic syndrome, osteoporosis, heart failure, complications of coma or awakening from anesthesia).

[0161] definition

[0162] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0163] As used herein, "alkyl", "C1, C2, C3, C4, C5 or C6 alkyl" or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl 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 chain alkyl 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 chain alkyl has four or fewer carbon atoms.

[0164] As used herein, the term "optionally substituted alkyl" refers to unsubstituted alkyl groups or alkyl groups 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 ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety.

[0165] As used herein, the term "alkenyl" is included in the unsaturated aliphatic group similar to the above-mentioned alkyl in terms of length and possible substitution, but containing 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 main chain. The term "C2-C6" includes alkenyl containing 2-6 carbon atoms. The term "C3-C6" includes alkenyl containing 3-6 carbon atoms.

[0166] 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 ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate ion, sulfamoyl, sulfonylamino, nitro, trifluoromethyl, cyano, heterocyclic, alkylaryl or aromatic or heteroaromatic moieties.

[0167] As used herein, the term "alkynyl" includes unsaturated aliphatic groups similar to the above-mentioned alkyl 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 (e.g., C2-C6 for straight chain, C3-C6 for branched chain) in its main chain. The term "C2-C6" includes alkynyl containing 2-6 carbon atoms. The term "C3-C6" includes alkynyl containing 3-6 carbon atoms. As used herein, "C2-C6 alkenylene joints" or "C2-C6 alkynylene joints" are 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.

[0168] 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 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.

[0169] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl) include unsubstituted moieties and moieties having one or more specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0170] As used herein, the term "cycloalkyl" refers to a cycloalkyl group having 3 to 30 carbon atoms (e.g., C3-C 12 、C3-C 10 The saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused ring, bridged ring or spiro) system of C3-C8 (C3-C8). 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 cycloalkyl, only one ring in the cycloalkyl needs to be non-aromatic.

[0171] 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), for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example, 1, 2, 3, 4, 5 or 6 heteroatoms, unless otherwise specified, the heteroatoms are independently selected from nitrogen, oxygen and sulfur. Examples of heterocycloalkyl include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolyl, indolyl, 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, only one ring in the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0172] As used herein, the term "aryl" includes groups having aromaticity, including "conjugated" or polycyclic systems having one or more aromatic rings and not containing any heteroatoms in the ring structure. The term aryl includes monovalent species and divalent species. Examples of aryl include, but are not limited to, phenyl, biphenyl, naphthyl, etc. Conveniently, aryl is phenyl.

[0173] As used herein, the term "heteroaryl" is intended to include a stable 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocycle 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.

[0174] In addition, the terms "aryl" and "heteroaryl" include polycyclic aromatic and heteroaryl groups, for example, tricyclic, bicyclic, for example, naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0175] The cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings may be substituted at one or more ring positions (e.g., a carbon or heteroatom such as N forming the ring) with substituents as described above, such as alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkyl The term "alkyl" refers to any of a alkylthiocarbonyl group, a phosphate group, a phosphonate group, a phosphinate group, an amino group (including an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group and an alkylarylamino group), an acylamino group (including an alkylcarbonylamino group, an arylcarbonylamino group, a carbamoyl group and an urea group), an amidino group, an imino group, a sulfhydryl group, an alkylthio group, an arylthio group, a thiocarboxylate group, a sulfate group, an alkylsulfinyl group, a sulfonate group, a sulfamoyl group, a sulfonamido group, a nitro group, a trifluoromethyl group, a cyano group, an azido group, a heterocyclic group, an alkylaryl group, or an aromatic or heteroaromatic moiety. The aryl and heteroaryl groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic rings to form a polycyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0176] As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom are replaced by an option in a designated group, provided that the normal valence of the designated atom is not exceeded and the substitution produces a stable compound. When the substituent is an oxo or keto (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 represent a compound that is robust enough to withstand separation from RM to a useful purity and formulated into an effective therapeutic agent.

[0177] When a bond to a substituent is shown to cross the 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, but only if such combinations result in stable compounds.

[0178] 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 the group may be optionally substituted with up to two R moieties, and R at each occurrence is independently selected from the definition of R. In addition, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0179] As used herein, the term "hydroxy" or "hydroxyl" includes a group having -OH or -O - The group.

[0180] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0181] The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogen atoms.

[0182] 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 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.

[0183] 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 halogenated alkoxy. 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 group, phosphinate ion group, amino group (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino group (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate ion group, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic group, alkylaryl or aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0184] 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, that is, one or more A, one or more B, one or more C, or any combination thereof, unless otherwise specified.

[0185] 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 as well as those shown in the examples.

[0186] It should be understood that throughout the 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 a particular process step, the process also consists essentially of or consists of the enumerated process steps. Further, it should be understood that the order of steps or 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.

[0187] 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 its pharmaceutically acceptable salt in some cases.

[0188] 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 prepared from readily prepared intermediates by employing standard synthetic methods and procedures that are known to those skilled in the art or that will be apparent to 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 art. Although not limited to any one or a few 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.

[0189] Those of ordinary skill in the art will note that in reaction sequence and synthesis scheme as described herein, 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 refer to Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, the 3rd edition, John Wiley & Sons: New York, 1999.

[0190] 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 of humans or non-human animals, including rodents and other disease models.

[0191] 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 used herein.

[0192] 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.

[0193] As used herein, the term "subject in need" refers to both, both of which refer to an object suffering from a disease or an object with an increased risk of developing a disease. "Subject" includes mammals. 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 object can also be a bird or poultry. In one embodiment, the mammal is a human. The object in need can be an object that has been previously diagnosed or identified as suffering from a disease or disorder disclosed herein. The object in need can also be an object suffering from a disease or disorder disclosed herein. Alternatively, the object in need can 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). The object in need can suffer from a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that has not responded or has not yet responded to treatment). The object can be resistant at the beginning of treatment, or can become resistant during treatment. In some embodiments, the object in need has received all known effective therapies for diseases or disorders disclosed herein and failed. In some embodiments, the subject in need thereof has received at least one prior therapy.

[0194] 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 the disease, condition, or disorder. The term "treatment" may also include treatment of in vitro cells or animal models. It should be understood that references to "treatment" include alleviation of existing symptoms of a condition. Thus, "treatment" of a state, disorder or condition includes: (1) preventing the onset of clinical symptoms of a state or delaying the onset of clinical symptoms of a state in a human who may have or is susceptible to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or ameliorating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0195] 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.

[0196] As used herein, the terms "prevent," "preventing," or "protecting against" describe the reduction or elimination of the onset of symptoms or complications of such disease, condition, or disorder.

[0197] It should be understood that for detailed descriptions of known techniques 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 referenced when making or using an aspect of the present disclosure.

[0198] 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.

[0199] 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 vial on a capsule, IV bag, tablet, 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 appreciated 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. A variety of routes are considered, 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 the compounds 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 preservatives, buffers or propellants required.

[0200] 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.

[0201] 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. "Pharmaceutically acceptable excipient" as used in this specification and claims includes one and more than one such excipient.

[0202] It should be understood that the pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, for example, intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical) and transmucosal administration. Solutions or suspensions for parenteral, intradermal or subcutaneous applications may include the following components: sterile diluents such as water for injection, saline solutions, fixed oils, polyethylene glycols, 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 such as sodium chloride or dextrose for adjusting tonicity. pH can be adjusted with an acid or alkali (such as hydrochloric acid or sodium hydroxide). Parenteral preparations can be contained in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0203] It should be understood that the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject by many well-known methods currently used for chemotherapeutic treatments. For example, the compounds of the present disclosure can be injected into the bloodstream or body cavity or orally administered 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., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during treatment and within a reasonable period of time after treatment.

[0204] As used herein, the term "therapeutically effective amount" refers to the 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.

[0205] As used herein, the term "therapeutically effective amount" refers to the 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.

[0206] 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 (usually 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 for 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 that is 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.

[0207] 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, the time and frequency of administration, drug combinations, 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.

[0208] 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 prepared 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 usable products. Of course, the appropriate formulation depends on the route of administration selected.

[0209] 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 of easy injection. 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 a dispersion medium, which contains, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size (in the case of dispersions) 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 extended by including an agent (for example, aluminum monostearate and gelatin) that delays absorption in the composition.

[0210] Sterile injectable solutions can be prepared as follows: the required amount of the active compound is mixed with one or a combination of ingredients listed above as needed in an appropriate solvent, followed by filtration sterilization. Typically, dispersions are prepared as follows: the active compound is mixed with a sterile vehicle containing a basic dispersion medium and other ingredients required from those listed above. For sterile powders for the preparation of sterile injectable solutions, the preparation methods are vacuum drying and freeze drying, which produce a powder of the active ingredient plus any additional desired ingredients from its previously sterile filtered solution.

[0211] Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They can be encapsulated in a gelatin capsule or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be mixed with an excipient 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 applied orally and gargled and spit out or swallowed. Pharmaceutically compatible binders and / or excipients can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth 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.

[0212] 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.

[0213] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant suitable for the barrier to be penetrated is 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 or suppositories. For transdermal administration, the active compound is formulated into an ointment, salves, gel, or cream generally known in the art.

[0214] The active compound can be prepared 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. The method for preparing such a preparation is obvious to those skilled in the art. The material can also be commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to 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.

[0215] It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unit dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in combination 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.

[0216] 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 medicament, the age, weight and clinical condition of the patient receiving the treatment, and the experience and judgment of the clinician or practitioner administering the therapy. Generally, the dosage should be sufficient to cause a slowdown and preferably a regression of the symptoms of the disease or disorder disclosed herein, and also preferably a complete regression 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 are regression. As used herein, the term "dosage effective manner" refers to the amount of an active compound that produces a desired biological effect in an object or cell.

[0217] It will be appreciated that the pharmaceutical compositions may be included in a container, pack, or dispenser together with instructions for administration.

[0218] It should be understood that for compounds of the present disclosure that are capable of further forming salts, all such forms are also contemplated within the scope of the claimed disclosure.

[0219] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure in which the parent compound is modified by preparing an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues such as inorganic or organic acid salts of amines, acidic residues such as alkaline or organic salts of carboxylic acids, and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed by non-toxic inorganic or 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, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolylaminophenylarsanilic acid, hexylresorcinic acid, hexabasic acid, hydroxyacetic ... 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, acetic, succinic, sulfamic, para-aminobenzenesulfonic, sulfuric, tannic, tartaric, toluenesulfonic, and common amino acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0220] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, dibenzylethylenediamine salt, tromethamine salt, ammonium salt, arginine salt, or lysine salt.

[0221] 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 acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth metal ions, or aluminum ions); or salts formed when coordinated with organic bases 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.

[0222] 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.

[0223] 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.

[0224] The dosing regimen utilizing 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. An ordinary skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, combat, or arrest the progression of the condition. An ordinary skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to combat or arrest the progression of the condition.

[0225] Techniques for preparing and administering the disclosed compounds of the present disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and pharmaceutically acceptable salts thereof are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical preparation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such a pharmaceutical composition in an amount sufficient to provide the desired dose within the range described herein.

[0226] Unless otherwise noted, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure are apparent from different examples. The examples provided explain different components and methods for practicing the present disclosure. The examples do not limit the disclosure claimed. Based on the present disclosure, a skilled person can identify and adopt other components and methods for practicing the present disclosure.

[0227] In the synthetic schemes described herein, compounds may be drawn in one particular configuration for simplicity. Such a particular configuration should not be interpreted 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.

[0228] 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 is relevant prior art, nor does it constitute any admission about its content or date. Now that the invention has been described 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 for illustrative purposes rather than limiting the claims that follow.

[0229] As used herein, the phrase "compounds of the present disclosure" refers to those compounds disclosed both generically and specifically herein.

[0230] Compounds of the Disclosure

[0231] In some aspects, the present disclosure provides a compound of formula (I):

[0232]

[0233] or a pharmaceutically acceptable salt thereof, wherein:

[0234] Z is -NH-;

[0235] X is -C(R X1 )3 or -N(R X2 )2;

[0236] Each R X1 are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl,

[0237] or two R X1 Together with the atoms to which they are attached, they form a C3-C4 cycloalkyl or a 4-membered heterocycloalkyl;

[0238] Each R X2 are independently H, C1-C6 alkyl or C1-C6 haloalkyl;

[0239] Ar1 is a C6 aryl group substituted by one or more R3;

[0240] R3 is halogen;

[0241] R1 is C1-C6 alkyl or C1-C6 haloalkyl;

[0242] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0243] Each R 2S are independently halogen;

[0244] R 4a is H; and

[0245] R 4b It's H.

[0246] In some aspects, the present disclosure provides a compound of formula (I'):

[0247]

[0248] or a pharmaceutically acceptable salt thereof, wherein:

[0249] Z is -NH-;

[0250] X is -C(R X1 )3 or -N(R X2 )2;

[0251] Each R X1are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy,

[0252] or two R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted with one or more halogens;

[0253] Each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens,

[0254] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0255] Ar1 is a C6 aryl group substituted by one or more R3;

[0256] R3 is halogen;

[0257] R1 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0258] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0259] Each R 2S are independently halogen;

[0260] R 4a It is H;

[0261] R 4b is H; and

[0262] n is 0, 1 or 2.

[0263] In some aspects, the present disclosure provides a compound of formula (I"):

[0264]

[0265] or a pharmaceutically acceptable salt thereof, wherein:

[0266] Z is -NH-;

[0267] X is -C(R X1 )3 or -N(R X2 )2;

[0268] Each R X1 are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy,

[0269] or two R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted with one or more halogens;

[0270] Each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens,

[0271] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0272] Ar1 is a C6 aryl group substituted by one or more R3;

[0273] R3 is halogen;

[0274] R1 is C3-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0275] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0276] Each R 2S are independently halogen;

[0277] R 4a It is H;

[0278] R 4b is H; and

[0279] n is 0, 1 or 2.

[0280] In some aspects, the present disclosure provides a compound of formula (I'"):

[0281]

[0282] or a pharmaceutically acceptable salt thereof, wherein:

[0283] Z is -NH-;

[0284] X is -C(R X1 )3 or -N(R X2 )2;

[0285] Each R X1 is independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the alkyl is optionally substituted with one or more -OH or C1-C6 alkoxy groups,

[0286] or two R X1 Together with the atoms to which they are attached, they form a C3-C4 cycloalkyl group or a 4-membered or 5-membered heterocycloalkyl group;

[0287] Each R X2 are independently H, C1-C6 alkyl or C1-C6 haloalkyl,

[0288] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0289] Ar1 is a C6 aryl group substituted by one or more R3;

[0290] R3 is halogen or C1-C6 alkoxy;

[0291] R1 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0292] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0293] Each R 2S are independently halogen or C1-C6 alkyl;

[0294] R 4a is H; and

[0295] R 4b It's H.

[0296] In some aspects, the present disclosure provides a compound of formula (II):

[0297]

[0298] or a pharmaceutically acceptable salt thereof, wherein:

[0299] Z is -NH-;

[0300] X is -C(R X1 )3 or -N(R X2 )2;

[0301] Each R X1are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy,

[0302] or two R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted with one or more halogens;

[0303] Each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, -(CH(C1-C6 alkyl)) n -C3-C6 cycloalkyl, -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more CN, halogen or C1-C6 alkoxy,

[0304] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0305] Ar1 is a C6 aryl group substituted by one or more R3;

[0306] R3 is halogen;

[0307] R1 is C3-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0308] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0309] Each R 2S are independently halogen;

[0310] R 4a It is H;

[0311] R 4b is H; and

[0312] n is 0, 1 or 2.

[0313] In some aspects, the present disclosure provides a compound of formula (II"):

[0314]

[0315] or a pharmaceutically acceptable salt thereof, wherein:

[0316] Z is -NH-;

[0317] X is -C(R X1 )3 or -N(R X2 )2;

[0318] Each R X1 are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy,

[0319] or two R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more oxo, -CN, halogen, C1-C6 haloalkyl or C1-C6 alkoxy;

[0320] Each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, -(CH(C1-C6 alkyl)) n -C3-C6 cycloalkyl, -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more CN, halogen or C1-C6 alkoxy,

[0321] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0322] Ar1 is a C6 aryl group substituted by one or more R3;

[0323] R3 is halogen;

[0324] R1 is C3-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0325] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0326] Each R 2S are independently halogen;

[0327] R 4a It is H;

[0328] R 4b is H; and

[0329] n is 0, 1 or 2.

[0330] In some aspects, the present disclosure provides a compound of formula (II'"):

[0331]

[0332] or a pharmaceutically acceptable salt thereof, wherein:

[0333] Z is -NH-;

[0334] X is -C(R X1 )3 or -N(R X2 )2;

[0335] Each R X1 are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy,

[0336] or two R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more oxo, -CN, halogen, C1-C6 haloalkyl or C1-C6 alkoxy;

[0337] Each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, -(CH(C1-C6 alkyl)) n -C3-C6 cycloalkyl, -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more CN, halogen or C1-C6 alkoxy,

[0338] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0339] Ar1 is a C6 aryl group substituted by one or more R3;

[0340] R3 is halogen;

[0341] R1 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0342] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0343] Each R 2S are independently halogen;

[0344] R 4a It is H;

[0345] R 4b is H; and

[0346] n is 0, 1 or 2.

[0347] It should be understood that for compounds of Formula (I), (I'), (I"), (I'"), (II), (II") or (II'"), X, Z, R X1 , R X2 、Ar1、R1、R2、R 2S , R3, R 4a , R 4b or n may each (where applicable) be selected from the groups described herein, and the X1 , R X2 、Ar1、R1、R2、R 2S , R3, R 4a , R 4b Any group described in any of or n may be (where applicable) the same as those described herein for X, Z, R X1 , R X2 、Ar1、R1、R2、R 2S , R3, R 4a , R 4b or any combination of the remaining one or more of n.

[0348] In some embodiments, X is -C(R X1 )3 or -N(R X2 )2.

[0349] In some embodiments, X is -C(R X1 )3. In some embodiments, X is -N(R X2 )2.

[0350] In some embodiments, Z is -NH-.

[0351] In some embodiments, each R X1 are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl,

[0352] or two R X1 Together with the atoms to which they are attached they form a C3-C4 cycloalkyl or a 4-membered heterocycloalkyl.

[0353] In some embodiments, each R X1are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted with one or more C1-C6 alkoxy groups,

[0354] or two R X1 Together with the atoms to which they are attached they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted with one or more halogens.

[0355] In some embodiments, each R X1 are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted with one or more -OH or C1-C6 alkoxy groups,

[0356] or two R X1 Together with the atoms to which they are attached they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted with one or more halogens.

[0357] In some embodiments, each R X1 are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted with one or more -OH or C1-C6 alkoxy groups.

[0358] In some embodiments, each R X1 independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted with one or more C1-C6 alkoxy groups.

[0359] In some embodiments, each R X1 are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl.

[0360] In some embodiments, each R X1 Independently H.

[0361] In some embodiments, each R X1 are independently -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl.

[0362] In some embodiments, each R X1 are independently halogen.

[0363] In some embodiments, each R X1 is independently F, Cl, Br or I. In some embodiments, each R X1 is independently F, Cl or Br. In some embodiments, each R X1 is independently F or Cl.

[0364] In some embodiments, each R X1 is independently F. In some embodiments, each R X1 is independently Cl. In some embodiments, each R X1 is independently Br. In some embodiments, each R X1 Independently is I.

[0365] In some embodiments, each R X1 is independently -CN.

[0366] In some embodiments, each R X1 is independently -OH.

[0367] In some embodiments, each R X1 are independently C1-C6 alkyl.

[0368] In some embodiments, each R X1 is independently methyl. In some embodiments, each R X1 In some embodiments, each R X1 In some embodiments, each R X1 In some embodiments, each R X1 In some embodiments, each R X1 In some embodiments, each R X1 is independently isopropyl. In some embodiments, each R X1 is independently isobutyl. X1 is independently isopentyl. In some embodiments, each R X1 In some embodiments, each R X1 In some embodiments, each R X1 In some embodiments, each R X1 In some embodiments, each R X1 is independently tert-butyl.

[0369] In some embodiments, each R X1is independently C1-C6 alkyl, which is optionally substituted with one or more -OH or C1-C6 alkoxy groups.

[0370] In some embodiments, each R X1 is independently a C1-C6 alkyl group substituted with one or more -OH or C1-C6 alkoxy groups.

[0371] In some embodiments, each R X1 is independently C1-C6 alkyl, optionally substituted with one or more -OH.

[0372] In some embodiments, each R X1 is independently a C1-C6 alkyl group substituted with one or more -OH groups.

[0373] In some embodiments, each R X1 is independently a C1-C6 alkyl group, which is optionally substituted with one or more C1-C6 alkoxy groups.

[0374] In some embodiments, each R X1 is independently a C1-C6 alkyl group substituted with one or more C1-C6 alkoxy groups.

[0375] In some embodiments, each R X1 are independently C1-C6 alkoxy.

[0376] In some embodiments, each R X1 is independently methoxy. X1 In some embodiments, each R X1 In some embodiments, each R X1 In some embodiments, each R X1 In some embodiments, each R X1 is independently hexyloxy.

[0377] In some embodiments, each R X1 are independently C1-C6 haloalkyl.

[0378] In some embodiments, each R X1 is independently halomethyl. X1 is independently haloethyl. In some embodiments, each R X1 In some embodiments, each R X1 In some embodiments, each R X1In some embodiments, each R X1 is independently a halohexyl group.

[0379] In some embodiments, each R X1 are independently C3-C6 cycloalkyl.

[0380] In some embodiments, each R X1 is independently C3 cycloalkyl. X1 is independently C4 cycloalkyl. X1 is independently C5 cycloalkyl. X1 are independently C6 cycloalkyl.

[0381] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C3-C4 cycloalkyl or a 4-membered heterocycloalkyl.

[0382] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more oxo, -CN, halogen, C1-C6 haloalkyl or C1-C6 alkoxy.

[0383] In some embodiments, both R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl.

[0384] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted with one or more halogens.

[0385] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C3-C5 cycloalkyl group which is optionally substituted with one or more oxo, -CN, halogen, C1-C6 haloalkyl or C1-C6 alkoxy.

[0386] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C3-C5 cycloalkyl group which is substituted by one or more oxo, -CN, halogen, C1-C6 haloalkyl or C1-C6 alkoxy groups.

[0387] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C3-C5 cycloalkyl group.

[0388] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C3-C4 cycloalkyl group.

[0389] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C3 cycloalkyl.

[0390] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C3 cycloalkyl group which is optionally substituted with one or more halogens.

[0391] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C3 cycloalkyl group which is substituted by one or more halogens.

[0392] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C4 cycloalkyl.

[0393] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C4 cycloalkyl group which is optionally substituted by one or more halogens.

[0394] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C4 cycloalkyl group which is substituted by one or more halogens.

[0395] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C5 cycloalkyl.

[0396] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C5 cycloalkyl group which is optionally substituted with one or more halogens.

[0397] In some embodiments, both R X1 Together with the atoms to which they are attached they form a C5 cycloalkyl which is substituted by one or more halogens.

[0398] In some embodiments, both R X1 Together with the atoms to which they are attached they form a 4- or 5-membered heterocycloalkyl group which is optionally substituted with one or more oxo, -CN, halogen, C1-C6 haloalkyl or C1-C6 alkoxy.

[0399] In some embodiments, both R X1 Together with the atoms to which they are attached they form a 4- or 5-membered heterocycloalkyl group which is substituted by one or more oxo, -CN, halogen, C1-C6 haloalkyl or C1-C6 alkoxy.

[0400] In some embodiments, both R X1 Together with the atoms to which they are attached, they form a 4- or 5-membered heterocycloalkyl group.

[0401] In some embodiments, both R X1 Together with the atoms to which they are attached they form a 4-membered heterocycloalkyl.

[0402] In some embodiments, both R X1 Together with the atoms to which they are attached they form a 5-membered heterocycloalkyl.

[0403] In some embodiments, each R X2 are independently H, C1-C6 alkyl or C1-C6 haloalkyl.

[0404] In some embodiments, each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens,

[0405] or two R X2 Together with the atoms to which they are attached they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group.

[0406] In some embodiments, each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, -(CH(C1-C6 alkyl)) n -C3-C6 cycloalkyl, -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more CN, halogen or C1-C6 alkoxy.

[0407] In some embodiments, each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens.

[0408] In some embodiments, both R X2 Together with the atoms to which they are attached they form a 4-membered heterocycloalkyl.

[0409] In some embodiments, both R X2 Together with the atoms to which they are attached they form a 4-membered heterocycloalkyl group which is optionally substituted with a C1-C6 alkoxy group.

[0410] In some embodiments, both R X2 Together with the atoms to which they are attached they form a 4-membered heterocycloalkyl group which is substituted by a C1-C6 alkoxy group.

[0411] In some embodiments, each R X2 Independently H.

[0412] In some embodiments, each R X2 are independently C1-C6 alkyl, C1-C6 haloalkyl, -(CH(C1-C6 alkyl)) n -C3-C6 cycloalkyl, -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more CN, halogen or C1-C6 alkoxy.

[0413] In some embodiments, each R X2 are independently C1-C6 alkyl or C1-C6 haloalkyl.

[0414] In some embodiments, each R X2 are independently C1-C6 alkyl, C1-C6 haloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens.

[0415] In some embodiments, each R X2 are independently C1-C6 alkyl.

[0416] In some embodiments, each R X2 is independently methyl. In some embodiments, each R X2 In some embodiments, each R X2 In some embodiments, each R X2 In some embodiments, each R X2 In some embodiments, each R X2 In some embodiments, each R X2 is independently isopropyl. In some embodiments, each R X2 is independently isobutyl. X2 is independently isopentyl. In some embodiments, each R X2 In some embodiments, each R X2 In some embodiments, each R X2In some embodiments, each R X2 In some embodiments, each R X2 is independently tert-butyl.

[0417] In some embodiments, each R X2 are independently C1-C6 haloalkyl.

[0418] In some embodiments, each R X2 is independently halomethyl. X2 is independently haloethyl. In some embodiments, each R X2 In some embodiments, each R X2 In some embodiments, each R X2 In some embodiments, each R X2 is independently a halohexyl group.

[0419] In some embodiments, each R X2 is independently -(CH(C1-C6 alkyl)) n -C3-C6 cycloalkyl, -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl or -(CH2) n -C3-C6 cycloalkyl.

[0420] In some embodiments, each R X2 is independently -(CH(C1-C6 alkyl)) n -C3-C6 cycloalkyl, -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more CN, halogen or C1-C6 alkoxy.

[0421] In some embodiments, each R X2 is independently -(CH(C1-C6 alkyl)) n -C3-C6 cycloalkyl, -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is substituted by one or more CN, halogen or C1-C6 alkoxy.

[0422] In some embodiments, each R X2 is independently -(CH(C1-C6 alkyl)) n-C3-C6 cycloalkyl.

[0423] In some embodiments, each R X2 is independently -(CH(C1-C6 alkyl)) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more CN, halogen or C1-C6 alkoxy.

[0424] In some embodiments, each R X2 is independently -(CH(C1-C6 alkyl)) n -C3-C6 cycloalkyl, wherein the cycloalkyl is substituted by one or more CN, halogen or C1-C6 alkoxy.

[0425] In some embodiments, each R X2 is independently -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl.

[0426] In some embodiments, each R X2 is independently -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more CN, halogen or C1-C6 alkoxy.

[0427] In some embodiments, each R X2 is independently -(CH(C1-C6 haloalkyl)) n -C3-C6 cycloalkyl, wherein the cycloalkyl is substituted by one or more CN, halogen or C1-C6 alkoxy.

[0428] In some embodiments, each R X2 independently -(CH2) n -C3-C6 cycloalkyl.

[0429] In some embodiments, each R X2 independently -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more CN, halogen or C1-C6 alkoxy.

[0430] In some embodiments, each R X2 independently -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is substituted by one or more CN, halogen or C1-C6 alkoxy.

[0431] In some embodiments, each R X2 independently -(CH2) n-C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens.

[0432] In some embodiments, each R X2 independently -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is substituted by one or more halogens.

[0433] In some embodiments, each R X2 independently -(CH2) n -C3 cycloalkyl.

[0434] In some embodiments, each R X2 independently -(CH2) n -C3 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens.

[0435] In some embodiments, each R X2 independently -(CH2) n -C3 cycloalkyl, wherein the cycloalkyl is substituted by one or more halogens.

[0436] In some embodiments, each R X2 independently -(CH2) n -C4 cycloalkyl.

[0437] In some embodiments, each R X2 independently -(CH2) n -C4 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens.

[0438] In some embodiments, each R X2 independently -(CH2) n -C4 cycloalkyl, wherein the cycloalkyl is substituted by one or more halogens.

[0439] In some embodiments, each R X2 independently -(CH2) n -C5 cycloalkyl.

[0440] In some embodiments, each R X2 independently -(CH2) n -C5 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens.

[0441] In some embodiments, each R X2 independently -(CH2) n -C5 cycloalkyl, wherein the cycloalkyl is substituted by one or more halogens.

[0442] In some embodiments, each R X2 independently -(CH2) n -C6 cycloalkyl.

[0443] In some embodiments, each R X2 independently -(CH2) n -C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens.

[0444] In some embodiments, each R X2 independently -(CH2) n -C6 cycloalkyl, wherein the cycloalkyl is substituted by one or more halogens.

[0445] In some embodiments, Ar1 is C6 aryl (eg, phenyl).

[0446] In some embodiments, Ar1 is C6 aryl (eg, phenyl) substituted with one or more R3.

[0447] In some embodiments, Ar1 is C6 aryl (eg, phenyl) substituted with one R3.

[0448] In some embodiments, Ar1 is C6 aryl (eg, phenyl) substituted with two R3.

[0449] In some embodiments, Ar1 is C6 aryl (eg, phenyl) substituted with three R3.

[0450] In some embodiments, Ar1 is C6 aryl (eg, phenyl) substituted with four R3.

[0451] In some embodiments, R1 is C1-C6 alkyl or C1-C6 haloalkyl.

[0452] In some embodiments, R1 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C7 cycloalkyl, optionally substituted with one or more halogens.

[0453] In some embodiments, R1 is C3-C6 alkyl, C1-C6 haloalkyl, or C3-C7 cycloalkyl, optionally substituted with one or more halogens.

[0454] In some embodiments, R1 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C7 cycloalkyl optionally substituted with one halogen.

[0455] In some embodiments, R1 is C3-C6 alkyl, C1-C6 haloalkyl, or C3-C7 cycloalkyl optionally substituted with one halogen.

[0456] In some embodiments, R1 is C1-C6 alkyl.

[0457] In some embodiments, R1 is C3-C6 alkyl.

[0458] 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.

[0459] In some embodiments, R1 is C1-C6 haloalkyl.

[0460] 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.

[0461] In some embodiments, R1 is C3-C7 cycloalkyl.

[0462] In some embodiments, R1 is cyclopropyl. In some embodiments, R1 is cyclobutyl. In some embodiments, R1 is cyclopentyl. In some embodiments, R1 is cyclohexyl. In some embodiments, R1 is cycloheptyl.

[0463] In some embodiments, R1 is C3-C7 cycloalkyl, optionally substituted with one or more halogens.

[0464] In some embodiments, R1 is C3-C7 cycloalkyl, optionally substituted with one halogen.

[0465] In some embodiments, R2 is C6 aryl (eg, phenyl).

[0466] In some embodiments, R2 is C6 aryl (eg, phenyl), which is optionally substituted with one or more R 2S replace.

[0467] In some embodiments, R2 is C6 aryl (eg, phenyl) replaced by one or more R 2S replace.

[0468] In some embodiments, each R2S are independently halogen or C1-C6 alkyl.

[0469] In some embodiments, each R 2S are independently halogen.

[0470] In some embodiments, each R 2S is independently F, Cl, Br or I. In some embodiments, each R 2S is independently F, Cl or Br. In some embodiments, each R 2S is independently F or Cl.

[0471] In some embodiments, each R 2S is independently F. In some embodiments, each R 2S is independently Cl. In some embodiments, each R 2S is independently Br. In some embodiments, each R 2S Independently is I.

[0472] In some embodiments, each R 2S are independently C1-C6 alkyl.

[0473] In some embodiments, each R 2S In some embodiments, each R 2S In some embodiments, each R 2S In some embodiments, each R 2S In some embodiments, each R 2S In some embodiments, each R 2S In some embodiments, each R 2S is independently isopropyl. In some embodiments, each R 2S is independently isobutyl. 2S is independently isopentyl. In some embodiments, each R 2S In some embodiments, each R 2S In some embodiments, each R 1S In some embodiments, each R 2S In some embodiments, each R 2S is independently tert-butyl.

[0474] In some embodiments, each R3 is independently halogen or C 1-6 Alkoxy.

[0475] In some embodiments, each R3 is independently halogen.

[0476] In some embodiments, each R3 is independently F, Cl, Br, or I. In some embodiments, each R3 is independently F, Cl, or Br. In some embodiments, each R3 is independently F or Cl.

[0477] In some embodiments, each R3 is independently F. In some embodiments, each R3 is independently Cl. In some embodiments, each R3 is independently Br. In some embodiments, each R3 is independently I.

[0478] In some embodiments, each R3 is independently C 1-6 Alkoxy.

[0479] In some embodiments, each R3 is independently methoxy. In some embodiments, each R3 is independently ethoxy. In some embodiments, each R3 is independently propoxy. In some embodiments, each R3 is independently butoxy. In some embodiments, each R3 is independently pentoxy. In some embodiments, each R3 is independently hexoxy.

[0480] In some embodiments, R 4a It's H.

[0481] In some embodiments, R 4b It's H.

[0482] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1.

[0483] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0484] In some embodiments, the compound has formula (I-1a) or (I-1b):

[0485]

[0486] or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4 and q is 0, 1, 2, 3, 4 or 5.

[0487] In some embodiments, the compound has formula (I-1a) or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0488] In some embodiments, the compound has formula (I-1b) or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0489] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0490] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0491] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0492] In some embodiments, the compound is selected from the compounds described in Table 1.

[0493] In some embodiments, the compound is selected from the compounds described in Table 2 and prodrugs and pharmaceutically acceptable salts thereof.

[0494] In some embodiments, the compound is selected from the compounds described in Table 2 and pharmaceutically acceptable salts thereof.

[0495] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 2 and pharmaceutically acceptable salts thereof.

[0496] In some embodiments, the compound is selected from the compounds described in Table 2.

[0497] In some embodiments, the compound is selected from the compounds described in Table 3 and prodrugs and pharmaceutically acceptable salts thereof.

[0498] In some embodiments, the compound is selected from the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[0499] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[0500] In some embodiments, the compound is selected from the compounds described in Table 3.

[0501] In some embodiments, the compound is selected from the compounds described in Table 4 and prodrugs and pharmaceutically acceptable salts thereof.

[0502] In some embodiments, the compound is selected from the compounds described in Table 4 and pharmaceutically acceptable salts thereof.

[0503] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 4 and pharmaceutically acceptable salts thereof.

[0504] In some embodiments, the compound is selected from the compounds described in Table 4.

[0505] Table 1

[0506]

[0507]

[0508]

[0509] Table 2

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525] Table 3

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533] Table 4

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542] In some embodiments, the compound is not disclosed in PCT / US2021 / 049021.

[0543] In some embodiments, the compound is not selected from the compounds described in Table 5.

[0544] Table 5

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0572] 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.

[0573] 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.

[0574] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0575] 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.

[0576] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0577] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 2.

[0578] 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.

[0579] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2 and pharmaceutically acceptable salts thereof.

[0580] 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.

[0581] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2.

[0582] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 3.

[0583] 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.

[0584] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[0585] 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.

[0586] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3.

[0587] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 4.

[0588] 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.

[0589] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 4 and pharmaceutically acceptable salts thereof.

[0590] 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.

[0591] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 4.

[0592] It should be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, by performing the procedures disclosed in the schemes described herein and / or in the examples, isotopic derivatives can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents.

[0593] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0594] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any of the compounds of the formulae disclosed herein.

[0595] 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'), Formula (I), Formula (II), or Formula (III) is isotopically enriched with respect to one or more isotopes or labeled with one or more isotopes compared to the corresponding compound of Formula (I'), Formula (I), Formula (II), or Formula (III). In some embodiments, the isotopic derivative is enriched with respect to one or more atoms or labeled with one or more atoms selected from 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 are deuterated with 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.

[0596] 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 36 For 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.

[0597] 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 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.

[0598] For the avoidance of doubt, it should be understood that where a group is defined in this specification using "described herein," the group encompasses the first occurring and broadest definition as well as each and all of the specific definitions for that group.

[0599] The various functional groups and substituents constituting the compounds of formula (I'), formula (I), formula (II) or formula (III) are generally 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. More conveniently, the molecular weight is less than 600, for example 550 daltons or less.

[0600] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, sufficiently basic acid addition salts of the compounds of the present disclosure, 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 the compounds of the present disclosure that are sufficiently acidic 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.

[0601] It should be understood that the compounds of any of the formulae disclosed herein and any pharmaceutically acceptable salts thereof include stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of the compounds.

[0602] As used herein, the term "isomerism" refers to compounds that have the same molecular formula but differ in the bonding sequence 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 each enantiomeric form of opposite chirality is termed a "racemic mixture".

[0603] As used herein, the term "chiral center" refers to a carbon atom to which are bonded four different substituents.

[0604] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having more than one chiral center may exist as individual diastereomers or as a mixture of diastereomers, referred to as a "diastereomeric mixture". When there is one chiral center, the stereoisomers may be characterized by the absolute configuration (R or S) of the chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are 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).

[0605] 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). According to the Cahn-Ingold-Prelog rules, 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.

[0606] 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 isomers or geometric isomers, 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, and it should be understood that not all isomers may have the same level of activity.

[0607] 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.

[0608] As used herein, the term "atropisomer" is a class of stereoisomers in which the atoms of the two isomers are arranged differently in space. The existence of atropisomers is due to restricted rotation caused by hindered rotation of large groups around a central bond. Such atropisomers usually exist as a mixture, but due to recent advances in chromatographic techniques, it has become possible to separate a mixture of two atropisomers in certain circumstances.

[0609] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium, and it is easily converted 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 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. In possible various types of tautomerism, two types 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.

[0610] 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 some tautomers can have a higher level of activity than other tautomers.

[0611] Compounds with the same molecular formula but different bonding properties or order of their atoms or the arrangement of their atoms in space are called "isomers". Isomers whose atoms are arranged differently in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, 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-handed 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 called a "racemic mixture".

[0612] 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 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. 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), such as by synthesis 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 having orexin modulating activity.

[0613] The present disclosure also encompasses compounds of the present disclosure as defined herein, comprising one or more isotopic substitutions.

[0614] It should be understood that 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, mesylate, trifluoroacetate, glutamate, glucuronide, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthylidenesulfonate and acetate (e.g., trifluoroacetate).

[0615] 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.

[0616] 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.

[0617] As used herein, the term "solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the 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. Hydrates are formed by the combination of one or more water molecules with a molecule of a substance, wherein the water remains in its molecular state as H2O.

[0618] As used herein, the term "analog" refers to a compound that is similar in structure to another but has a slightly different composition (such as the replacement of one atom by an atom of a different element, or the presence of a particular functional group, or the replacement of one functional group by another). Thus, an analog is a compound that is similar or equivalent in function and appearance, but different in structure or origin from a reference compound.

[0619] As used herein, the term "derivative" refers to compounds having a common core structure and being substituted with various groups as described herein.

[0620] As used herein, the term "bioisostere" refers to a compound produced by the exchange of one atom or one group of atoms with another roughly similar atom or group of atoms. The purpose of bioisosteric replacement is to create a new compound with similar biological properties to 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.

[0621] It is also to 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 is to be understood that the present disclosure encompasses all such solvated forms having orexin modulating activity.

[0622] It is also 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 orexin modulating 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.

[0623] Compounds of any of the formulae disclosed herein may exist in a number of different tautomeric forms, and reference to a compound of Formula (I), (I'), (I") or (I'") includes all such forms. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all other forms are still encompassed by Formula (I), (I'), (I") or (I'") . Examples of tautomeric forms include keto-, enol- and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (exemplified below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thione / enethiol and nitro / acid nitro.

[0624]

[0625] Compounds of any of the formulae disclosed herein containing an amine functional group may also form N-oxides. Reference herein to compounds of formula (I), formula (I'), formula (I") or formula (I'") containing an amine functional group also includes N-oxides. In the case where the compound contains several amine functional groups, one or more than one nitrogen atom may be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Jerry March's Advanced Organic Chemistry, 4th edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with meta-chloroperbenzoic acid (mCPBA), for example in an inert solvent such as dichloromethane.

[0626] Any of the compounds of the formula disclosed herein can be administered in the form of a prodrug, which 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 can be cleaved in vivo at any of the esters or amide groups of the formula disclosed herein.

[0627] 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 the human or animal body by cleavage of its prodrug. Thus, the present disclosure includes those compounds of any of the formulae disclosed herein generated by organic synthesis, as well as such compounds generated in the human or animal body by metabolism of a precursor compound, i.e., the compounds of any of the formulae disclosed herein may be synthetically generated compounds or metabolically generated compounds.

[0628] Suitable pharmaceutically acceptable prodrugs of the compounds of any of the formulae disclosed herein are prodrugs that are suitable, based on sound medical judgment, for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity. Various forms of prodrugs have been described, for example in the following literature: a) Methods in Enzymology, Volume 42, pages 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", H. Bundgaard, pages 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.

[0629] 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 phosphoramide 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 10 Alkoxycarbonyl (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, piperazine-1-ylmethyl and 4-(C1-C4 alkyl) piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups of hydroxyl include α-acyloxyalkyl (such as acetoxymethyl and pivaloyloxymethyl).

[0630] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein having a carboxyl group are, for example, amides thereof which are cleavable in vivo, for example with amines (such as ammonia), C 1-4 Amides formed by 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.

[0631] 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, 10 Amides formed by alkanoyl (such as acetyl), benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4alkyl)piperazin-1-ylmethyl.

[0632] The in vivo effects of any of the compounds of the formula disclosed herein can be partially exerted by one or more metabolites formed in the human or animal body after administration of any of the compounds of the formula disclosed herein. As described above, the in vivo effects of any of the compounds of the formula disclosed herein can also be exerted by the metabolism of the precursor compound (prodrug).

[0633] Suitably, the present disclosure excludes any individual compound that does not possess a biological activity as defined herein.

[0634] Synthesis method

[0635] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0636] In some aspects, the present disclosure provides a method of producing a compound comprising one or more steps as described herein.

[0637] In some aspects, the present disclosure provides compounds obtainable or obtained or directly obtained by a process for preparing a compound as described herein.

[0638] In some aspects, the disclosure provides intermediates as described herein, which are suitable for use in methods of preparing compounds as described herein.

[0639] The compounds of the present disclosure may be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying examples.

[0640] 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.

[0641] Those skilled in the art of organic synthesis will understand that the functionality present on the various portions of the molecule must be compatible with the reagents and reaction conditions utilized.

[0642] It should be understood that in the process of synthesizing the disclosed compound in the method defined herein, or in the synthesis process of some starting materials, it may be desirable to protect some substituents to prevent their undesirable reactions. A skilled chemist will understand when such protection is needed, and how such blocking groups can be placed and removed later. For example, referring to one of a plurality of general texts on this theme, such as " Protective Groups in Organic Synthesis " (publisher: John Wiley & Sons) by Theodora Green. The blocking group can be removed by any convenient method described in the document or known to a skilled chemist to be suitable for removing the blocking group in question, and such a method is selected to realize the removal of the blocking group, and the group elsewhere in the molecule is produced with minimum interference. Therefore, if reactant includes, for example, a group such as amino, carboxyl or hydroxyl, it may be desirable to protect the group in some reactions mentioned herein.

[0643] For example, suitable protecting groups for amino or alkylamino are, for example, acyl (e.g., alkanoyl (such as acetyl)), alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), arylmethoxycarbonyl (e.g., benzyloxycarbonyl) or aroyl (e.g., benzoyl). The deprotection conditions for the above-mentioned protecting groups necessarily vary with the selection of the protecting groups. Thus, for example, by, for example, hydrolysis with a suitable base (such as an alkali metal hydroxide, such as 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 treatment with a suitable acid (such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid), and arylmethoxycarbonyl such as benzyloxycarbonyl can be removed, for example, by hydrogenation with a catalyst (such as palladium on carbon), or by treatment with a Lewis acid such as tris(trifluoroacetic acid) boron. 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.

[0644] Suitable protecting groups for hydroxyl groups are, for example, acyl groups (e.g., alkanoyl groups (such as acetyl)), aroyl groups (e.g., benzoyl groups), or arylmethyl groups (e.g., benzyl groups). The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting groups. Thus, for example, acyl groups such as alkanoyl groups or aroyl groups may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide) or ammonia. Alternatively, arylmethyl groups such as benzyl groups may be removed by, for example, hydrogenation over a catalyst (e.g., palladium on carbon).

[0645] A suitable protecting group for a carboxyl group is, for example, an esterifying group, for example methyl or ethyl, which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example tert-butyl, which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example benzyl, which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0646] Once a compound of Formula (I), Formula (I'), Formula (I") or Formula (I'") has been synthesized by any of the methods defined herein, the method may further include the following additional steps: (i) removing any protecting groups present; (ii) converting the compound of Formula (I), Formula (I'), Formula (I") or Formula (I'"); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0647] The resulting compounds of Formula (I), Formula (I'), Formula (I") or Formula (I'") may be isolated and purified using techniques well known in the art.

[0648] 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.

[0649] The reaction temperature is suitably between about -100°C and 300°C, depending on the reaction step and conditions used.

[0650] Reaction times is normally 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, it is easy to determine suitable reaction times.Based on the temperature of reaction given above, suitable reaction times is normally in the scope of between 10 minutes and 48 hours.

[0651] In addition, by utilizing the procedures described herein, in combination 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.

[0652] 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 technician 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 easily synthesized by: reacting other compounds of the present disclosure under suitable conditions, for example, by applying standard synthetic methods such as reduction, oxidation, addition or substitution reactions, a specific functional group present in the compounds of the present disclosure or its suitable precursor molecules is converted to another; these methods are well known to technicians. Similarly, the technician will apply (whenever necessary or useful) the protection (or protective) groups synthesized; suitable protection 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).

[0653] A general route for preparing compounds of the present application is described in Scheme 1 herein.

[0654] Compound I, which is a compound of formula I wherein Z═NH, can be generated from commercially available and known compound A according to the process shown in reaction scheme 1 below.

[0655] Reaction Scheme 1

[0656]

[0657] Examples of amino protecting groups P1 include, but are not limited to, carbamate protecting groups such as tert-butyl carbamate, etc. Examples of leaving groups X include halogens, particularly bromine or iodine, or sulfonates such as methanesulfonate.

[0658] Compound C can be generated by subjecting Compound A to a nucleophilic substitution reaction with Compound B in the presence of a base. Examples of the base include lithium amide, etc. Alternatively, Compound C can also be generated by converting to a corresponding enamine and then reacting the enamine with Compound B. Examples of amines that can be used for enamine formation include, but are not limited to, pyrrolidine.

[0659] Compound D can be produced by subjecting compound C to a reductive amination reaction. Examples of the amine used include ammonium salts such as ammonium formate. Examples of reducing agents include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen and formic acid. In addition, a metal catalyst can be added to the reaction system. Examples of the catalyst used include iridium catalysts.

[0660] Compound F can be produced by sulfonamidation reaction of compound D and compound E in the presence of a base. Compound E may be commercially available or may be produced by a known method. Examples of the base used include organic bases such as tertiary alkylamines such as N,N-diisopropylethylamine and the like.

[0661] Compound G can be prepared by subjecting Compound F to a deprotection reaction to remove the protecting group P1. The specific deprotection reaction will depend on the choice of protecting group. In the case where P1 is tert-butyl carbamate, deprotection can be achieved by treatment with an acid such as hydrochloric acid or trifluoroacetic acid.

[0662] Compound I can be prepared by subjecting Compound G and Compound H to a condensation reaction. Examples of Compound H include acyl halides such as acyl chlorides, alkyl chloroformates, carbamoyl chlorides, etc.; activated carboxylic acids such as anhydrides, activated esters, etc. Examples of activators for carboxylic acids include carbodiimide condensation agents, carbonate condensation agents such as 1,1-carbonyldiimidazole (CDI), etc.; benzotriazol-1-yloxy-tris dimethylaminophosphonium salts (BOP reagents), alkyl chloroformates; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), etc.). When a condensation agent is used, an additive such as 1-hydroxybenzotriazole (HOBt) or dimethylaminopyridine (DMAP) may be added to the reaction system.

[0663] The compound I obtained by the above method can be isolated and purified by known means (such as solvent extraction, phase transfer, crystallization, chromatography, etc.).

[0664] When Compound 1 contains optical isomers, stereoisomers, and rotational isomers, these compounds are also included in Compound 1, and each compound can be obtained by a synthesis method or a separation method. For example, when optical isomers exist in Compound 1, the optical isomers separated from the compound are also included in Compound 1.

[0665] Bioassay

[0666] Once the compounds designed, selected and / or optimized by the above methods are produced, 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 by conventional assays, including but not limited to those described below.

[0667] 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 quickly 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.

[0668] Various in vitro or in vivo bioassays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo bioassays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0669] Despite the loss of orexin cells and reduced orexin in the cerebrospinal fluid in NT1, orexin receptors on postsynaptic neurons remain intact and are suitable targets for pharmacological therapeutic intervention. Orexins A and B (OXA and OXB) can be cleaved from a single precursor molecule (prepro-orexin) that is produced exclusively in the lateral hypothalamus. Both orexins bind to OX2R with similar high affinity, but the orexin-1 receptor (OX1R) can be 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.

[0670] In some embodiments, the biological assays are described in the Examples herein.

[0671] The biological activity of the compounds of the present disclosure can be determined in cells that stably express orexin type 2 or orexin type 1 receptors. Activity can be measured in cells (e.g., Chinese hamster ovary (CHO) cells expressing human orexin type 2 receptor (hOX2R) or human orexin type 2 receptor (hOX1R)) administered with the compounds of the present disclosure. The agonist activity of the compounds of the present disclosure can be determined by fluorescence values.

[0672] The wake-promoting efficacy of the compounds of the present disclosure can be evaluated in a model (e.g., a B6.Cg-Tg (HCRT-MJD) 1 Stak / J (Atax) mouse model of NT1 and wild-type (WT) colony mates). Following administration of the compounds of the present disclosure (e.g., oral administration), the model (e.g., a mouse model) can be monitored by rapid, non-invasive sleep and wake classification of physiologically relevant readouts (such as body movement and breathing rate) using unsupervised machine learning.

[0673] Pharmaceutical composition

[0674] 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 formulas described herein or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 2. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 3.

[0675] 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.

[0676] 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.

[0677] 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.

[0678] Any suitable solubilizing agent can be used. The example of solubilizing agent includes cyclodextrin, such as those selected from the following: 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-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, random methylated-γ-cyclodextrin and trimethyl-γ-cyclodextrin and mixtures thereof.

[0679] 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.

[0680] 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.

[0681] 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.

[0682] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from 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 (Carbopol-such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0683] 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 adjusting agent. The pH adjusting agent 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 adjusting agents 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.

[0684] The aqueous vehicle may also contain a buffer to stabilize the pH. When used, the buffer is selected from the following: phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts, including disodium tetraborate), citrate buffers (such as citric acid or its salts, including sodium citrate) and ε-aminocaproic acid and mixtures thereof.

[0685] 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), stearic acid polyoxyl 40 esters, fatty acid glycol esters, fatty acid glycerides, sucrose fatty esters, and polyoxyethylene fatty esters and mixtures thereof.

[0686] 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 an excipient 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 spit out or swallowed. Pharmaceutically compatible binders and / or excipients can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth 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.

[0687] 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.

[0688] The compositions of the present disclosure may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as 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).

[0689] 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.

[0690] 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 orexin-related condition mentioned herein.

[0691] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat the orexin-related conditions mentioned herein, slow the progression thereof, and / or alleviate the symptoms associated with the conditions.

[0692] The dose size of the compound of formula (I'), formula (I), formula (II) or formula (III) 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.

[0693] How to use

[0694] In some aspects, the 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 disclosure, or a pharmaceutically acceptable salt thereof.

[0695] In some aspects, the 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 disclosure, or a pharmaceutically acceptable salt thereof.

[0696] In some aspects, the 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 disclosure, or a pharmaceutically acceptable salt thereof.

[0697] In some aspects, the 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 disclosure, or a pharmaceutically acceptable salt thereof.

[0698] 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.

[0699] 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.

[0700] 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.

[0701] 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.

[0702] In some embodiments, the disease or disorder is associated with orexin receptor activity. In some embodiments, the disease or disorder is a disease or disorder in which orexin receptor activity is involved.

[0703] In some embodiments, the disease or disorder is associated with orexin-2 receptor activity. In some embodiments, the disease or disorder is a disease or disorder in which orexin-2 receptor activity is involved.

[0704] 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.

[0705] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0706] 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.

[0707] 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.

[0708] 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.

[0709] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0710] In some aspects, the present disclosure provides a method of treating or preventing hypersomnia 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.

[0711] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0712] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0713] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0714] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0715] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0716] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0717] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0718] 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.

[0719] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0720] In some aspects, the present disclosure provides a method of treating hypersomnia 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.

[0721] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0722] 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.

[0723] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0724] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0725] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0726] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0727] 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 therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0728] 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.

[0729] 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.

[0730] In some aspects, the present disclosure provides a method of treating or preventing 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.

[0731] 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.

[0732] 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.

[0733] 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.

[0734] 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.

[0735] 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.

[0736] 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.

[0737] 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.

[0738] 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.

[0739] 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.

[0740] In some aspects, the present disclosure provides a method of treating hypersomnia 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.

[0741] 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.

[0742] 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.

[0743] 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.

[0744] 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.

[0745] 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.

[0746] 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.

[0747] 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.

[0748] 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.

[0749] 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).

[0750] 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).

[0751] 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.

[0752] 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.

[0753] 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.

[0754] 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.

[0755] 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.

[0756] 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.

[0757] 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.

[0758] 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.

[0759] 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.

[0760] 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.

[0761] 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.

[0762] 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.

[0763] 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.

[0764] 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.

[0765] 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.

[0766] 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.

[0767] 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.

[0768] 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.

[0769] 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.

[0770] 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.

[0771] 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.

[0772] 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.

[0773] 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.

[0774] 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.

[0775] 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).

[0776] 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).

[0777] 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.

[0778] 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.

[0779] 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.

[0780] 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.

[0781] 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 hypersomnia disorder in a subject in need thereof.

[0782] 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.

[0783] 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.

[0784] 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.

[0785] 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.

[0786] 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.

[0787] 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.

[0788] 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.

[0789] 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.

[0790] 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, 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.

[0791] 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.

[0792] 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 hypersomnia disorder in a subject in need thereof.

[0793] 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.

[0794] 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.

[0795] 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.

[0796] 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.

[0797] 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.

[0798] 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.

[0799] 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.

[0800] 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.

[0801] The present disclosure provides compounds that act as modulators of orexin receptor activity.

[0802] In some embodiments, the compounds of the present disclosure are agonists of the orexin receptor.

[0803] The present disclosure provides compounds that act as modulators of orexin-2 receptor activity.

[0804] In some embodiments, the compounds of the present disclosure are agonists of the orexin-2 receptor.

[0805] In some embodiments, modulation of an orexin receptor is activation of the orexin receptor.

[0806] 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.

[0807] 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, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0808] 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, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0809] 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, the method comprising administering to the patient a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0810] 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, the method comprising administering to the patient a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0811] 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.

[0812] In some embodiments, the present disclosure also provides a method of treating a disease or disorder by reducing excessive sleepiness.

[0813] In some embodiments, the present disclosure also provides a method of treating a disease or disorder by reducing excessive daytime sleepiness.

[0814] In some embodiments, the disease or disorder is associated with excessive sleepiness and / or excessive daytime sleepiness.

[0815] In some embodiments, the disease or disorder is primary hypersomnia, a neurodegenerative disorder, a symptom of a hypersomnia / neurodegenerative disorder, a symptom of a rare genetic disorder, a mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or emergence from anesthesia.

[0816] In some embodiments, the disease or disorder is a 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.

[0817] In some embodiments, the excessive daytime sleepiness is associated with a neurodegenerative disorder.

[0818] In some embodiments, the neurodegenerative disorder associated with excessive daytime sleepiness is Parkinson's disease, Alzheimer's disease, Huntington's disease, or multiple sclerosis.

[0819] In some embodiments, the disease or disorder is recurring hypersomnia.

[0820] In some embodiments, the recurrence of hypersomnia is narcolepsy type 1, narcolepsy type 2, or idiopathic hypersomnia.

[0821] In some embodiments, the disease or disorder is sleep apnea, traumatic brain injury, age-related cognitive dysfunction, or excessive daytime sleepiness.

[0822] In some embodiments, excessive daytime sleepiness is associated with sleep apnea, traumatic brain injury, or age-related cognitive dysfunction.

[0823] 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.

[0824] In some embodiments, the excessive sleep is a symptom of narcolepsy.

[0825] In some embodiments, the disease or disorder is a symptom of narcolepsy.

[0826] In some embodiments, the symptoms of narcolepsy are excessive daytime sleepiness, cataplexy, sleep paralysis, half-awake and half-asleep hallucinations, nocturnal sleep disturbances, or inappropriately timed rapid eye movement (REM) sleep.

[0827] In some embodiments, the symptom of narcolepsy is excessive daytime sleepiness.

[0828] In some embodiments, the symptom of narcolepsy is cataplexy. In some embodiments, cataplexy is a diagnostic condition of narcolepsy (eg, narcolepsy type 1).

[0829] In some embodiments, the symptom of narcolepsy is sleep paralysis.

[0830] In some embodiments, the symptoms of narcolepsy are semi-awake and semi-asleep hallucinations.

[0831] In some embodiments, the symptom of narcolepsy is disturbed nocturnal sleep.

[0832] In some embodiments, a symptom of narcolepsy is inappropriately timed rapid eye movement (REM) sleep.

[0833] In some embodiments, the neurodegenerative disorder is characterized by cataplexy.

[0834] In some embodiments, the neurodegenerative disorder is characterized by excessive daytime sleepiness.

[0835] In some embodiments, the neurodegenerative disorder is Parkinson's disease.

[0836] In some embodiments, the neurodegenerative disorder is Alzheimer's disease.

[0837] In some embodiments, the neurodegenerative disorder is Huntington's disease.

[0838] In some embodiments, the neurodegenerative disorder is multiple sclerosis.

[0839] In some embodiments, the neurodegenerative disorder is traumatic brain injury.

[0840] In some embodiments, the neurodegenerative disorder is sleep apnea.

[0841] In some embodiments, the neurodegenerative disorder is age-related cognitive dysfunction.

[0842] In some embodiments, the neurodegenerative disorder is recurrent hypersomnia disorder.

[0843] In some embodiments, the recurrent excessive sleep disorder is Klein-Levin syndrome, inappropriately timed sleep (eg, delayed or advanced sleep phase disorder), shift work disorder, and jet lag disorder.

[0844] In some embodiments, the disease or disorder is a symptom of a rare genetic disorder.

[0845] In some embodiments, the symptom of the rare genetic disorder is abnormal daytime sleepiness.

[0846] In some embodiments, the symptom of the rare genetic disorder is excessive daytime sleepiness.

[0847] In some embodiments, the symptom of the rare genetic disorder is REM stage sleep onset.

[0848] In some embodiments, the symptoms of the rare genetic disorder are characterized by cataplexy-like symptoms.

[0849] 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.

[0850] In some embodiments, the disease or disorder is a mental health disorder.

[0851] In some embodiments, the mental health disorder is attention deficit hyperactivity disorder.

[0852] In some embodiments, the mental health disorder is attention deficit disorder.

[0853] In some embodiments, the disease or disorder is metabolic syndrome.

[0854] In some embodiments, the metabolic syndrome is obesity.

[0855] In some embodiments, the disease or disorder is osteoporosis.

[0856] In some embodiments, the disease or disorder is heart failure.

[0857] In some embodiments, the disease or disorder is coma.

[0858] In some embodiments, the disease or disorder is emergence from anesthesia.

[0859] In some embodiments, the disease or disorder is a complication of emergence from anesthesia.

[0860] 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.

[0861] In some embodiments, the disease or disorder is narcolepsy, idiopathic hypersomnia, or sleep apnea.

[0862] Route of administration

[0863] 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.

[0864] 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 (I), Formula (I'), Formula (I"), or Formula (I'") with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit, the benefit experienced by the individual may be increased.

[0865] 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 dosage, mode of administration, and number of administrations.

[0866] 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 disclosure, there is provided a combination for the treatment of a disease in which orexin activity is involved, the combination comprising a compound of the disclosure as defined above or a pharmaceutically acceptable salt thereof and another suitable agent.

[0867] 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.

[0868] In addition to their use in therapeutic drugs, the compounds of Formula (I), Formula (I'), Formula (I") or Formula (I'") and their pharmaceutically acceptable salts 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, rats and mice) as part of the search for new therapeutic agents.

[0869] 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.

[0870] The compounds of the present disclosure, or pharmaceutical compositions comprising these compounds, may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (ie, at the desired site of action).

[0871] 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, for example, 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, for example, subcutaneous or intramuscular.

[0872] Exemplary embodiments

[0873] Exemplary embodiment No. 1. A compound of formula (I):

[0874]

[0875] or a pharmaceutically acceptable salt thereof, wherein:

[0876] Z is -NH-;

[0877] X is -C(R X1 )3 or -N(R X2 )2;

[0878] Each R X1 are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl,

[0879] or two R X1 Together with the atoms to which they are attached, they form a C3-C4 cycloalkyl or a 4-membered heterocycloalkyl;

[0880] Each R X2 are independently H, C1-C6 alkyl or C1-C6 haloalkyl;

[0881] Ar1 is a C6 aryl group substituted by one or more R3;

[0882] R3 is halogen;

[0883] R1 is C1-C6 alkyl or C1-C6 haloalkyl;

[0884] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0885] Each R 2S are independently halogen;

[0886] R 4a is H; and

[0887] R 4b It's H.

[0888] Exemplary embodiment No. 2. A compound of formula (I'):

[0889]

[0890] or a pharmaceutically acceptable salt thereof, wherein:

[0891] Z is -NH-;

[0892] X is -C(R X1 )3 or -N(R X2 )2;

[0893] Each R X1 is independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy,

[0894] or two R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted with one or more halogens;

[0895] Each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens,

[0896] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0897] Ar1 is a C6 aryl group substituted by one or more R3;

[0898] R3 is halogen;

[0899] R1 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0900] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0901] Each R 2S are independently halogen;

[0902] R4a It is H;

[0903] R 4b is H; and

[0904] n is 0, 1 or 2.

[0905] Exemplary embodiment No. 3. A compound of formula (I"):

[0906]

[0907] or a pharmaceutically acceptable salt thereof, wherein:

[0908] Z is -NH-;

[0909] X is -C(R X1 )3 or -N(R X2 )2;

[0910] Each R X1 is independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy,

[0911] or two R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted with one or more halogens;

[0912] Each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens,

[0913] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0914] Ar1 is a C6 aryl group substituted by one or more R3;

[0915] R3 is halogen;

[0916] R1 is C3-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0917] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0918] Each R 2S are independently halogen;

[0919] R 4a It is H;

[0920] R 4b is H; and

[0921] n is 0, 1 or 2.

[0922] Exemplary embodiment No. 4. A compound of formula (I''):

[0923]

[0924] or a pharmaceutically acceptable salt thereof, wherein:

[0925] Z is -NH-;

[0926] X is -C(R X1 )3 or -N(R X2 )2;

[0927] Each R X1 are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the alkyl is optionally substituted with one or more -OH or C1-C6 alkoxy groups,

[0928] or two R X1 Together with the atoms to which they are attached, they form a C3-C4 cycloalkyl group or a 4-membered or 5-membered heterocycloalkyl group;

[0929] Each R X2 are independently H, C1-C6 alkyl or C1-C6 haloalkyl,

[0930] or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group;

[0931] Ar1 is a C6 aryl group substituted by one or more R3;

[0932] R3 is halogen or C1-C6 alkoxy;

[0933] R1 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen;

[0934] R2 is optionally replaced by one or more R 2S Substituted C6 aryl;

[0935] Each R 2S are independently halogen or C1-C6 alkyl;

[0936] R 4a is H; and

[0937] R 4b It's H.

[0938] Exemplary embodiment No. 5. A compound as described in any of the preceding exemplary embodiments, wherein X is -C(R X1 )3.

[0939] Exemplary embodiment No. 6. A compound as described in any one of exemplary embodiments 1-4, wherein X is -N(R X2 )2.

[0940] Exemplary embodiment number 7. A compound as described in any of the preceding exemplary embodiments, wherein each R X1 Independently H.

[0941] Exemplary embodiment number 8. A compound as described in any one of exemplary embodiments 1-6, wherein each R X1 are independently -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl.

[0942] Exemplary embodiment number 9. A compound as described in any of the preceding exemplary embodiments, wherein each R X2 Independently H.

[0943] Exemplary embodiment number 10. A compound as described in any one of exemplary embodiments 1-8, wherein each R X2 are independently C1-C6 alkyl or C1-C6 haloalkyl.

[0944] Exemplary Embodiment No. 11. The compound as described in any of the preceding exemplary embodiments, wherein Ar1 is C6-aryl substituted with one R3.

[0945] Exemplary Embodiment No. 12. The compound as described in any of the preceding exemplary embodiments, wherein Ar1 is C6-aryl substituted with two R3.

[0946] Exemplary embodiment No. 13. A compound as described in any of the preceding exemplary embodiments, wherein R1 is C1-C6 alkyl or C1-C6 haloalkyl

[0947] Exemplary embodiment No. 14. The compound as described in any of the preceding exemplary embodiments, wherein R2 is C6 aryl.

[0948] Example 15. A compound as described in any of the preceding example embodiments, wherein R2 is replaced by one or more R 2S Substituted phenyl.

[0949] Exemplary embodiment number 16. A compound as described in any of the preceding exemplary embodiments, wherein each R 2S are independently halogen.

[0950] Exemplary Embodiment No. 17. The compound as described in any of the preceding exemplary embodiments, wherein each R3 is independently halogen.

[0951] Exemplary embodiment No. 18. The compound as described in any of the preceding exemplary embodiments, wherein the compound has formula (I-1a) or (I-1b):

[0952]

[0953] or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4 and q is 0, 1, 2, 3, 4 or 5.

[0954] Exemplary Embodiment No. 19. The compound as described in any of the preceding exemplary embodiments, which is selected from the compounds described in Table 1, Table 2, Table 3 or Table 4, and prodrugs and pharmaceutically acceptable salts thereof.

[0955] Exemplary embodiment No. 20. 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.

[0956] Exemplary embodiment No. 21. The pharmaceutical composition according to Exemplary embodiment 20, wherein the compound is selected from the compounds described in Table 1, Table 2, Table 3 or Table 4.

[0957] Exemplary embodiment No. 22. A method of modulating orexin-2 receptor activity, comprising contacting a cell with a compound of any one of exemplary embodiments 1-19 or a pharmaceutically acceptable salt thereof; optionally the activity is in vitro or in vivo.

[0958] Exemplary embodiment No. 23. A method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound or pharmaceutically acceptable salt thereof as described in any one of Exemplary Embodiments 1-19, or a pharmaceutical composition as described in Exemplary Embodiment 20 or Exemplary Embodiment 21.

[0959] Exemplary embodiment number 24. A compound or a pharmaceutically acceptable salt thereof as described in any one of exemplary embodiments 1-19, or a pharmaceutical composition as described in exemplary embodiment 20 or exemplary embodiment 21, for use in modulating orexin-2 receptor activity; optionally the activity is in vitro or in vivo.

[0960] Exemplary embodiment No. 25. The compound or pharmaceutically acceptable salt thereof as described in any one of Exemplary Embodiments 1-19, or the pharmaceutical composition as described in Exemplary Embodiment 20 or Exemplary Embodiment 21, for use in treating or preventing a disease or disorder.

[0961] Exemplary embodiment No. 26. Use of a compound according to any one of exemplary embodiments 1 to 19 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for modulating orexin-2 receptor activity; optionally the activity is in vitro or in vivo.

[0962] Exemplary embodiment No. 27. Use of the compound or pharmaceutically acceptable salt thereof according to any one of Exemplary embodiments 1-19 in the preparation of a medicament for treating or preventing a disease or disorder.

[0963] Exemplary embodiment number 28. The method, compound, pharmaceutical composition or use of any one of exemplary embodiments 22-27, wherein the disease or disorder is associated with an orexin receptor involved.

[0964] Exemplary embodiment number 29. A method, compound, pharmaceutical composition or use as described in any of exemplary embodiments 22-28, wherein the disease or disorder is narcolepsy, hypersomnia, neurodegenerative disorder, neurological disorder, symptoms of a rare genetic disorder, mental disorder, mental health disorder, circadian rhythm disorder, metabolic syndrome, osteoporosis, heart failure, coma or promoting awakening from anesthesia.

[0965] Exemplary embodiment No. 30. The method, compound, pharmaceutical composition or use of any one of exemplary embodiments 22-28, wherein the disease or disorder is narcolepsy, idiopathic hypersomnia or sleep apnea.

[0966] Example

[0967] For illustrative purposes, neutral compounds of Formula (I), Formula (I'), Formula (I") or Formula (I'") were synthesized and tested in the Examples. It should be understood that the neutral compounds of Formula (I), Formula (I'), Formula (I") or Formula (I'") can be converted into the corresponding pharmaceutically acceptable salts of the compounds using conventional techniques in the art (e.g., by saponification of esters to carboxylates, or by hydrolysis of amides to form the corresponding carboxylic acids, and then converting the carboxylic acids to carboxylates).

[0968] abbreviation:

[0969]

[0970]

[0971]

[0972] NMR spectra were recorded on a Bruker Avance III HD UltraShield 400 MHz with a 5 mm PABBO probe, a Bruker AVANCE NEO 400 MHz equipped with a 5 mm Iprobe, a Bruker AVANCE III HD400 MHz with a 5 mm BBO probe, a Varian 400MR equipped with a 5 mm 4NUCPFG. Samples were recorded at 25 °C using DMSO-d6, MeOH-d4 or MeOH-d4 as solvent.

[0973] LCMS conditions

[0974] Method A: LC / MS (gradient was 5-95% B in 0.7 min, 95-95% B in 0.45 min, 95-5% B in 0.01 min, and then held at 0% B for 0.44 min (1.5 mL / min flow rate). Mobile phase A was 0.0375% CF3CO2H in water and mobile phase B was 0.018% CF3CO2H in CH3CN. The column used for chromatography was a ChromolithFlash RP-18e 25-2 mm column. Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection and positive electrospray ionization (MS).

[0975] Method B: 5_95AB_6min-220-254: LC / MS (gradient was 5% B in 0.40 min and 5-95% B in 2.60 min, held at 95% B in 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 Kinetex C18 2.1*50 mm, 5μm. Detection methods were diode array (DAD) and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.

[0976] Method C: 5_95CD_6min-220-254-ELSD: LC / MS (gradient was 5% B in 0.40 min and 5-95% B in 0.40-3.40 min, kept at 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 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 methods were diode array (DAD) and evaporative light scattering (ELSD) detection with positive electrospray ionization. The MS range was 100-1000.

[0977] Method D: 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 0.037% trifluoroacetic acid in water, mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50×2.1 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.

[0978] Method E: LC / MS (column used for chromatography was Kinetex 5 μm 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. 5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95-100% B (1.00 -1.80 min), 5% B in 1.81 min, and hold at 5% B for 0.39 min. The flow rate was 1.0 mL / min (0.01-1.80), 1.2 mL (1.81-2.20). )

[0979] Method F: 5-95CD_2min: LC / MS (column used for chromatography was Xbridge C18 2.1*50mm, 5μm. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 10mM ammonium bicarbonate in water, and mobile phase B was HPLC grade acetonitrile. The gradient was 5-95% B in 1.50min. 5% B in 0.01min, 5-95% B (0.01-0.70min), 95% B (0.70-1.16min), 95-5% B (1.16-1.50min). The flow rate was 1.5mL / min.

[0980] Method G: 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, 30x2 mm. Column oven temperature of 45°C. Hewlett Packard G1315A diode array detector and Waters micromass ZQ mass spectrometer with UV detection from 230 to 400 nm. Gradients were written in the following format: [time (min) / %C:%D], long runs: [0.00 / 98:2], [0.1 / 98:2], [8.4 / 5:95], [10.0 / 5:95].

[0981] Method H: 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, 30x2 mm. Column oven temperature of 45°C. Hewlett Packard G1315A diode array detector and Waters micromass ZQ mass spectrometer with UV detection from 230 to 400 nm. 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].

[0982] Method I: 5-95CD_2min: LC / MS (column used for chromatography was Xbridge C18 2.1*50mm, 5μm. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 10mM ammonium bicarbonate in water, and mobile phase B was HPLC grade acetonitrile. The gradient was 5-95% B in 1.50min. 5% B in 0.01min, 5-95% B (0.01-0.70min), 95% B (0.70-1.16min), 95-5% B (1.16-1.50min). The flow rate was 1.5mL / min.

[0983] Method J: 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). The detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection with positive electrospray ionization. The MS range was 100-1000.

[0984] Method K: LC / MS (gradient was 5% B in 0.40 min and 5-95% B in 0.40-3.40 min, held at 95% B for 0.45 min, and then 95-5% B in 0.01 min, flow rate was 0.8 mL / min. Mobile phase A was H2O+10 mM NH4HCO3, mobile phase B was acetonitrile. The column used for chromatography was an Xbridge-C18 2.1*50 mm column (5 μm particles). The detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection with positive electrospray ionization. The MS range was 100-1000.

[0985] Method L: LC / MS (column used for chromatography was Xbridge Shield RP18 2.1*50 mm, (5 μm particles). Detection method was diode array (DAD). MS mode was negative electrospray ionization. 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 4.5 min, 0.5% B in 0.01 min, 5-95% B (0.01-3.00 min), 95% B (3.00-3.50 min), 95-5% B (3.50-4.00 min) and held at 5% B for 0.3 min. The flow rate was 1.0 mL / min.

[0986] Method M: LC / MS (column used for chromatography was Kinetex 5 μm EVO C18 100A. Detection method was diode array (DAD). MS mode was positive electrospray ionization. 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. Gradient was 5-95% B in 1.50 min. 5% B in 0.01 min, 5-95% B (0.01-0.70 min), hold at 95% B for 0.46 min. 95-5% B (1.61 -1.50 min), and hold at 5% B for 0.11 min. Flow rate was 1.5 mL / min.

[0987] Method N: LC / MS (column used for chromatography was Xbridge-C18 2.1*50 mm, (5 μm particles). Detection method was diode array (DAD). MS mode was positive electrospray ionization. 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, 0.5% B in 0.01 min, 5-95% B (0.01-3.00 min) and held at 95% B in 0.5 min, 95-5% 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).

[0988] Method O: LC / MS (column used for chromatography was Kinetex 5 μm EVO C18 100A 2.1*30 mm. Detection method was diode array (DAD). MS mode was positive electrospray ionization. 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. 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 for 0.5 min, 95-5% B (3.50 -3.51 min), and held at 5% B for 0.79 min. Flow rate was 1.0 mL / min.

[0989] Procedure for the preparation of intermediate 1

[0990] Step-1: tert-Butyl 6-(3-bromobenzyl)-7-oxo-5-azaspiro[2.4]heptane-5-carboxylate

[0991]

[0992] Under nitrogen, at -70 ° C, over 5 minutes, to a solution of 7-oxo-5-azaspiro [2.4] heptane-5-formic acid tert-butyl ester (0.9 g, 4.26 mmol, 1 equivalent) in tetrahydrofuran (1.0 mL), a solution of bis (trimethylsilyl) amine lithium in tetrahydrofuran (1 M, 4.26 mL, 1 equivalent) was added dropwise, during which the temperature was maintained at below -70 ° C. The reaction mixture was warmed to 25 ° C over 5 minutes and stirred at 25 ° C for 0.5 hours. Then 1-bromo-3-(bromomethyl) benzene (1.12 g, 4.47 mmol, 1.05 equivalents) in tetrahydrofuran (1 mL) was added at -70 ° C in 5 min. The reaction mixture was stirred for another 2 h at 25 ° C. The reaction mixture was quenched by MeOH and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0 to 95 / 5) to give the title compound (0.42 g, 23% yield) as a colorless oil. LCMS (Method A) (ESI+): m / z 324.0 (M+H-55) + ,RT:0.876min.

[0993] Step-2: tert-Butyl 7-amino-6-(3-bromobenzyl)spiro[2.4]heptane-5-carboxylate_cis racemic

[0994]

[0995] A mixture of tert-butyl 6-(3-bromobenzyl)-7-oxo-5-azaspiro[2.4]heptane-5-carboxylate (0.42 g, 1.10 mmol, 1 eq.), ammonium formate (244 mg, 3.87 mmol, 3.5 eq.) in methanol (1.0 mL) was degassed and purged with nitrogen 3 times, followed by the addition of bis[2-(2-pyridyl)phenyl]iridium(1+); 2-(2-pyridyl)pyridine; hexafluorophosphate (18 mg, 22.1 μmol, 0.02 eq.). Under a nitrogen atmosphere, the mixture was stirred at 80 °C for 3 h. The reaction mixture was quenched with water (5.0 mL) and then extracted with ethyl acetate (5.0 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the subject compound (420 mg, crude), which was used directly in the next step. LCMS (Method A) (ESI+): m / z 325.2 (M+H-55) + ,RT:0.670min.

[0996] Step-3: tert-Butyl 6-(3-bromobenzyl)-7-(methylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate_cis racemic (Intermediate 1)

[0997]

[0998] To a solution of tert-butyl 7-amino-6-(3-bromobenzyl)spiro[2.4]heptane-5-carboxylate-cis racemic (0.15 g, 393 μmol, 1 eq.) in dichloromethane (4.0 mL) was added methanesulfonyl chloride (37 μL, 472 μmol, 1.2 eq.) and triethylamine (110 μL, 787 μmol, 2 eq.). The mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give the subject compound (0.13 g, 65% yield) as a brown oil, which was used directly in the next step. LCMS (Method A) (ESI+): m / z 361.2 (M+H-55) + ,RT:0.809min.

[0999] Procedure for the preparation of intermediate 2

[1000] Step-1: tert-Butyl 6-(3-bromo-2-fluorobenzyl)-7-oxo-5-azaspiro[2.4]heptane-5-carboxylate

[1001]

[1002] At -78 ° C, to a solution of 7-oxo-5-azaspiro [2.4] heptane-5-tert-butyl formate (2.0 g, 9.47 mmol) in tetrahydrofuran (4.0 mL), a solution of bis (trimethylsilyl) amine lithium in tetrahydrofuran (14.2 mL, 1 M, 14.2 mmol) was added. The reaction mixture was stirred at -78 ° C for 5 min, then warmed to 0 ° C and stirred at this temperature for 30 min, then stirred at room temperature for another 30 min. Then 1-bromo-3-(bromomethyl)-2-fluoro-benzene (2.66 g, 9.94 mmol) was added at room temperature. Then the reaction mixture was allowed to warm to room temperature and stirred for another 90 min. The reaction mixture was quenched with water, diluted with EtOAc and washed with 1M HCl aqueous solution and brine, filtered through a hydrophobic glass frit and evaporated in vacuo. The residue was purified by flash column chromatography [Gradient: 0% to 20% ethyl acetate in isohexane] to give the title compound as a yellow oil (1.25 g, 33% yield). LCMS (Method E) (ESI+): m / z 342.2 (M+H-56) + ,RT:1.71min.

[1003] Step-2: tert-Butyl 7-amino-6-(3-bromo-2-fluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylate_cis racemic

[1004]

[1005] A solution of tert-butyl 6-(3-bromo-2-fluorobenzyl)-7-oxo-5-azaspiro[2.4]heptane-5-carboxylate (1.25 g, 3.14 mmol) in methanol (10 mL) was degassed and ammonium formate (2.97 g, 47.1 mmol) and chloro[N-[4-(dimethylamino)phenyl]-2-pyridinecarboxamidato](pentamethylcyclopentadienyl)iridium(III) (189 mg, 0.31 mmol) were added. The reaction was heated at 70 °C for 7 h. The reaction mixture was diluted with 1 M NaOH, brine and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered through a hydrophobic frit and evaporated in vacuo. The residue was purified by flash column chromatography [Gradient: 10% to 100% ethyl acetate in isohexane, then gradient: 0% to 100% MeOH in dichloromethane] to give the title compound as a yellow\orange oil (964 mg, 77% yield). LCMS (Method E) (ESI+): m / z 343.1 (M+H-56) + ,RT:1.52min.

[1006] Step-3: tert-Butyl 6-(3-bromo-2-fluorobenzyl)-7-(methylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate_cis racemic (Intermediate 2)

[1007]

[1008] To a solution of tert-butyl 7-amino-6-(3-bromo-2-fluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylate-cis racemic (964 mg, 2.41 mmol) and triethylamine (0.47 mL, 3.38 mmol) in dichloromethane (12 mL) was added methanesulfonyl chloride (0.22 mL, 2.9 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc and washed with 1M aqueous HCl, saturated aqueous NaHCO, brine, dried over MgSO, passed through a hydrophobic glass frit and evaporated in vacuo. The residue was purified by flash column chromatography [gradient: 0% to 100% ethyl acetate in isohexane] to give the subject compound (1.05 g, 91% yield) as a white solid. LCMS (Method E) (ESI+): m / z 421.3 (M+H-56) + ,RT:1.52min.

[1009] Procedure for the preparation of intermediate 3

[1010] Step-1: tert-Butyl 6-([1,1'-biphenyl]-3-ylmethyl)-7-oxo-5-azaspiro[2.4]heptane-5-carboxylate

[1011]

[1012] Under nitrogen, at -70 ° C, a solution of lithium bis(trimethylsilyl)amine (1M in tetrahydrofuran, 19 mL, 1 eq.) was added dropwise to a solution of tert-butyl 7-oxo-5-azaspiro[2.4]heptane-5-carboxylate (4.0 g, 18.9 mmol, 1 eq.) in tetrahydrofuran (40 mL) over a period of 5 min. The temperature was maintained below -70 ° C. The reaction mixture was warmed to 25 ° C over a period of 5 minutes and stirred at 25 ° C for 0.5 hours. Then 3-(bromomethyl)-1,1'-biphenyl (4.45 g, 18 mmol, 0.95 eq.) in tetrahydrofuran (40 mL) was added at -70 ° C over 5 min. The reaction mixture was stirred for another 6 h at 25 ° C. The reaction mixture was quenched by adding water (10 mL), and then diluted with ethyl acetate and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0 to 95 / 5) to give the title compound (5.0 g, 33% yield) as a brown oil. LCMS (Method A) (ESI+): m / z 322.3 (M+H-55) + ,RT:0.910min. Step-2: 6-([1,1'-biphenyl]-3-ylmethyl)-7-amino-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester_cis racemic

[1013]

[1014] A mixture of tert-butyl 6-([1,1'-biphenyl]-3-ylmethyl)-7-oxo-5-azaspiro[2.4]heptane-5-carboxylate (4.40 g, 12 mmol, 1 eq), ammonium formate (2.28 g, 36 mmol, 3.1 eq), bis[2-(2-pyridyl)phenyl]iridium(1+); 2-(2-pyridyl)pyridine; hexafluorophosphate (94 mg, 117 μmol, 0.02 eq) in methanol (40 mL) was degassed and purged with nitrogen 3 times, and then stirred at 80 ° C for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 0 to 50 / 50) to give the subject compound (0.65 g, 28% yield) as a yellow solid. LCMS (Method A) (ESI+): m / z 323.3 (M+H-55) + ,RT:0.689min.

[1015] Step-3: tert-Butyl 6-([1,1'-biphenyl]-3-ylmethyl)-7-(methylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate_cis racemic

[1016]

[1017] Methanesulfonyl chloride (196 μL, 2.54 mmol, 1.2 equiv) and triethylamine (735 μL, 5.28 mmol, 2.5 equiv) were added to a solution of 6-([1,1'-biphenyl]-3-ylmethyl)-7-amino-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester_cis racemic (0.8 g, 2.11 mmol, 1 equiv) in dichloromethane (5.0 mL). The reaction mixture was stirred at 20 ° C for 2 h. The reaction mixture was quenched by water (10 mL), and then diluted with ethyl acetate and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the subject compound (0.8 g, 78% yield) as a brown oil, which was used directly in the next step. LCMS (Method B) (ESI+): m / z 401.0 (M+H-55) + ,RT:0.816min.

[1018] Step-4: N-(6-([1,1'-biphenyl]-3-ylmethyl)-5-azaspiro[2.4]heptane-7-yl)methanesulfonamide hydrochloride_cis racemic (Intermediate 3)

[1019]

[1020] A solution of tert-butyl 6-([1,1'-biphenyl]-3-ylmethyl)-7-(methylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate_cis racemic (0.8 g, 1.75 mmol, 1 eq) in HCl / ethyl acetate (4M, 18 mL, 40 eq). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to give the subject compound (0.55 g, 82% yield) as a white solid, which was used directly in the next step. LCMS (Method C) (ESI+): m / z 357.2 (M+H) + ,RT:0.635min.

[1021] Procedure for the preparation of intermediate 4

[1022] Step-1: cis-racemization of tert-butyl 6-([1,1'-biphenyl]-3-ylmethyl)-7-(ethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate

[1023]

[1024] To a solution of 6-([1,1'-biphenyl]-3-ylmethyl)-7-amino-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester-cis racemic (0.5 g, 1.32 mmol, 1 eq) and ethanesulfonyl chloride (150 μL, 1.59 mmol, 1.2 eq) in dichloromethane (5.0 mL) was added pyridine (266 μL, 3.30 mmol, 2.5 eq). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the subject compound (0.42 g, 66% yield) as a yellow oil, which was used directly in the next step. LCMS (Method B) (ESI+): m / z 415.2 (M+H-55) + ,RT:0.835min.

[1025] Step-2: N-(6-([1,1'-biphenyl]-3-ylmethyl)-5-azaspiro[2.4]heptane-7-yl)ethanesulfonamide hydrochloride_cis racemic (Intermediate 4)

[1026]

[1027] A solution of tert-butyl 6-([1,1'-biphenyl]-3-ylmethyl)-7-(ethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate_cis racemic (0.42 g, 892 μmol, 1 eq) in HCl / dioxane (4 M, 8.92 mL, 40 eq) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (250 mg, 74% yield), which was used directly in the next step. LCMS (Method C) (ESI+): m / z 371.3 (M+H) + ,RT:0.672min.

[1028] Procedure for the preparation of intermediate 8

[1029] Step-1: tert-Butyl 6-(3-bromo-2-fluorobenzyl)-7-oxo-5-azaspiro[2.4]heptane-5-carboxylate

[1030]

[1031] Under nitrogen, tetrahydrofuran (1.4 L) was loaded into the reactor and LiHMDS (4.0 L, 1 M in THF, 1.2 eq.) was added. The reaction mixture was cooled to -70°C to -65°C. A solution of tert-butyl 7-oxo-5-azaspiro[2.4]heptane-5-carboxylate (700 g, 1.0 eq.) in THF (1.4 L) was added dropwise to the reactor and stirred for 3 hours at -70°C to -65°C. Then, Et2Zn (3.3 L, 1 M in toluene, 1.0 eq.) was added dropwise to the reactor at -70°C to -65°C, followed by DMPU (552 g, 1.3 eq.) being added dropwise to the reactor 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.

[1032] LCMS (Method O) (ESI+): m / z 341.9 (M+H-55) +, RT: 1.97 min Step-2: (E / Z)-tert-butyl 6-(3-bromo-2-fluorobenzyl)-7-(((R)-tert-butylsulfinyl)imino)-5-azaspiro[2.4]heptane-5-carboxylate

[1033]

[1034] To a solution of tert-butyl 6-(3-bromo-2-fluorobenzyl)-7-oxo-5-azaspiro[2.4]heptane-5-carboxylate (100 g, 1.0 eq.) in toluene (2.4 L) was added Ti(OEt)4 (171.8 g, 3 eq.) and (R)-2-methylpropane-2-sulfinamide (70 g, 2.3 eq.). 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.

[1035] Step-3: (6S,7S)-tert-butyl 6-(3-bromo-2-fluorobenzyl)-7-(((R)-tert-butylsulfinyl)amino)-5-azaspiro[2.4]heptane-5-carboxylate

[1036]

[1037] A solution of (E / Z)-tert-butyl 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 H2O (30 mL, 0.2 V) was cooled to -50°C. Under nitrogen, NaBH4 (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 (SiO2, eluted with petroleum ether:ethyl acetate = 10: 1 to 1: 1) to obtain 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.

[1038] Step-4: (6S,7S)-7-amino-6-(3-bromo-2-fluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (Intermediate 8)

[1039]

[1040] 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 eq) in MeOH (2.2 L) was cooled to 0 °C. Acetyl chloride (18.9 g, 1.1 eq) 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 aqueous NaHCO3 (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 phases were concentrated in vacuo at less than 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 under vacuum at <40 °C for 8 h to give the title compound as a yellow solid (178 g, 68.2% yield).

[1041] 1H 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).

[1042] Procedure for the preparation of Intermediate 9 (6S,7S)-tert-butyl 6-(3-bromo-2-fluorobenzyl)-7-(methylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate (Intermediate 9)

[1043]

[1044] To a solution of (6S,7S)-7-amino-6-(3-bromo-2-fluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester, intermediate 8 (1 g, 2.50 mmol, 1 eq.) in dichloromethane (20 mL) was added triethylamine (1.05 mL, 7.51 mmol, 3 eq.) and MsCl (250 μL, 3.23 mmol, 1.29 eq.) at 0 °C. The mixture was stirred at 20 °C for 3 hours. MsCl (331 μL, 4.28 mmol, 1.71 eq.) was further added at 0 °C. The resulting reaction mixture was stirred at 20 °C for another 5 hours. After quenching by adding 20 mL of water, the organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluted with petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give the title compound (0.98 g, 73.8% yield) as a white solid.

[1045] 1 H NMR (400MHz, chloroform-d) δ0.44(br s,1H),0.60-0.76(m,3H),1.20-1.45(m,9H),2.66-2.97(m,3H),3.01-3.12(m,2H),3.50-3.78(m,1H),4.20(br d,1H),4.36-4.54(m,2H),6.94-7.02(m,1H),7.11(br s,1H),7.44(br t,1H).

[1046] Procedure for the Preparation of Intermediate 10 (6S,7S)-tert-butyl 6-(3-bromo-2-fluorobenzyl)-7-(ethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate (Intermediate 10)

[1047]

[1048] To a solution of (6S,7S)-7-amino-6-(3-bromo-2-fluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester, intermediate 8 (6 g, 15 mmol, 1 eq) in pyridine (66 mL) was added ethanesulfonyl chloride (2.90 g, 22.54 mmol, 2.13 mL, 1.5 eq) dropwise at 25 °C. The mixture was stirred at 90 °C for 12 hours. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL). The organic phase was washed with 0.5N HCl (2×30 mL), saturated NaHCO3 solution (2×20 mL), brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give the title compound (3 g, 5.72 mmol, 38.1% yield) as a yellow solid.

[1049] 1 H NMR (400 MHz, chloroform-d) δ 0.34-0.46 (m, 1H), 0.63-0.72 (m, 3H), 1.26-1.47 (m, 11H), 2.67-3.10 (m, 6H), 3.64-3.73 (m, 1H), 4.12-4.19 (m, 2H), 4.34-4.44 (m, 1H), 6.93-7.02 (m, 1H), 7.06-7.15 (m, 1H), 7.39-7.47 (m, 1H)

[1050] Procedure for the Preparation of Intermediate 11 (6S,7S)-tert-butyl 6-(3-bromo-2-fluorobenzyl)-7-((fluoromethyl)sulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate (Intermediate 11)

[1051]

[1052] To a solution of (6S,7S)-7-amino-6-(3-bromo-2-fluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester, intermediate 8 (0.75 g, 1.88 mmol, 1 eq) in acetonitrile (35 mL) was added pyridine (758 μL, 9.39 mmol, 5 eq) and fluoromethanesulfonyl chloride (1.37 M in acetonitrile, 1.65 mL, 1.2 eq) at 0°C. The reaction mixture was warmed to 20°C and stirred at 20°C for 3 hours. Another reaction was set up as described above and the two batches were combined. The reaction mixture was concentrated under reduced pressure and the residue was poured into water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica (eluted with petroleum ether / ethyl acetate = 100 / 1 to 7 / 1) to give the title compound (1.5 g, 2.73 mmol, 67.8% yield) as a white solid.

[1053] 1 H NMR(400MHz, chloroform-d)δppm 0.38-0.76(m,4H)1.25-1.50(m,9H)2.72-3.12(m,3H)3.68(br s,1H)4.21(br dd,1H)4.39(br s,1H)4.76(br d,J=10.26Hz,1H)4.83-5.16(m,2H)6.94-7.02(m,1H)7.12(br s,1H)7.44(br t,1H).

[1054] Procedure for the Preparation of Intermediate 12 Tert-butyl (6S,7S)-6-(3-bromo-2-fluorobenzyl)-7-((difluoromethyl)sulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate (Intermediate 12)

[1055]

[1056] At 0 ° C, pyridine (505 μL, 6.26 mmol, 5 equivalents) and difluoromethanesulfonyl chloride (226 mg, 1.50 mmol, 1.2 equivalents) were added to a solution of (6S, 7S)-7-amino-6-(3-bromo-2-fluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester, intermediate 8 (0.5 g, 1.25 mmol, 1 equivalent) in acetonitrile (12 mL) at 0 ° C. The reaction mixture was stirred at 25 ° C for 12 hours. Another four reactions were set up as above, and the five reaction mixtures were combined and quenched by adding 60 mL of water and extracted with ethyl acetate (2 × 60 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluted with petroleum ether / ethyl acetate=100 / 0 to 10 / 1) to obtain the subject compound (1.9 g, 56.2% yield) as a white solid.

[1057] 1 H NMR (400MHz, methanol-d4) δ0.58-0.76(m,3H),1.00-1.29(m,10H),2.65-2.92(m,1H),3.08(br d,1H),3.20(br d,1H),3.68(br d,1H),4.20(br d,1H),4.34(br d,1H),6.49-6.82(m,1H),7.03(br t,1H),7.16(br t,1H),7.36-7.55(m,1H).

[1058] Procedure for the preparation of intermediate 13

[1059] Step 1: 3-Bromo-2,5-difluorobenzaldehyde

[1060]

[1061] At 0 ° C, i-PrMgCl (2M in THF, 4.41 L, 1 equivalent) was added dropwise to a solution of 1,3-dibromo-2,5-difluorobenzene (2.4 kg, 8.83 mol, 1 equivalent) in diethyl ether (24 L), the mixture was stirred at 0 ° C for 2 h, and then N, N-dimethylformamide (645 g, 8.83 mol, 1 equivalent) was added dropwise at 0 ° C. The resulting mixture was stirred for 10 h at 25 ° C. The mixture was poured into a saturated NH4Cl aqueous solution (15 L) and extracted with petroleum ether (3×10 L). The organic layer was washed with brine (10 L), dried over Na2SO4, and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 20 / 1) to give the subject compound (1.3 kg, 62% yield) as a colorless oil.

[1062] 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.63 (ddd, 1H) 8.09 (ddd, 1H) 10.12 (d, 1H).

[1063] Step 2: (3-Bromo-2,5-difluorophenyl)methanol

[1064]

[1065] At 0 ° C, NaBH4 (289 g, 7.65 mol, 1.3 eq.) was added to a solution of 3-bromo-2,5-difluorobenzaldehyde (1.3 kg, 5.88 mol, 1 eq.) in methanol (13 L). The reaction mixture was then warmed to 25 ° C and stirred for 12 h. The mixture was poured into a saturated NH4Cl aqueous solution (10 L) and extracted with ethyl acetate (3×5 L). The organic layer was washed with brine (5 L), dried over Na2SO4 and concentrated under reduced pressure to give the subject compound (1.4 Kg, 77.8% yield) as a white solid, which was used in the next step without further purification.

[1066] 1 H NMR (400MHz, CDCl3) δ1.98 (br s, 1H), 4.78 (s, 2H), 7.19 (dddd, 2H).

[1067] Step 3: 1-Bromo-3-(bromomethyl)-2,5-difluorobenzene

[1068]

[1069] Phosphate tribromide (728 g, 2.69 mol, 0.5 eq.) was added to a solution of (3-bromo-2,5-difluorophenyl)methanol (1.2 kg, 5.38 mol, 1 eq.) in dichloromethane (12 L) at 0 °C. The mixture was stirred at 25 °C for 12 h. The organic layer was poured into a saturated aqueous NaHCO solution (10 L) and extracted with petroleum ether (3 × 5 L). The organic layer was washed with brine (5 L), dried over Na2SO4 and concentrated under reduced pressure to give the subject compound (1.2 kg, 74.1% yield) as a white solid, which was used in the next step without further purification.

[1070] 1 H NMR (400MHz, DMSO-d6) δ4.67(d,2H),7.49(ddd,1H),7.66(ddd,1H).

[1071] Step 4: tert-Butyl 6-(3-bromo-2,5-difluorobenzyl)-7-oxo-5-azaspiro[2.4]heptane-5-carboxylate

[1072]

[1073] A mixture of tetrahydrofuran (200 mL) and [bis(trimethylsilyl)amide]lithium (1 M in tetrahydrofuran, 1.14 L, 1.2 eq) was cooled to -70°C, and then a solution of tert-butyl 7-oxo-5-azaspiro[2.4]heptane-5-carboxylate (200 g, 947 mmol, 1 eq) in tetrahydrofuran (400 mL) was added dropwise at -70°C. The resulting mixture was stirred at -70°C. After 2h, diethylzinc (1M in toluene, 947mL, 1 equivalent), 1,3-dimethylhexahydropyrimidin-2-one (149mL, 1.23mol, 1.3 equivalents) and 1-bromo-3-(bromomethyl)-2,5-difluoro-benzene (325g, 1.14mol, 1.2 equivalents) in tetrahydrofuran (400mL) were added dropwise at -70°C. The mixture was stirred for 2h at -70°C. Three more batches were set up as described above. All four reaction mixtures were combined. The reaction mixture was quenched at 0°C by ice water (10L). The precipitate was filtered, the filter cake was washed with ethyl acetate (5L) and the filtrate was extracted three times with ethyl acetate (5L). The combined organic layer was washed with NaCl aqueous solution (saturated, 2L), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (elution gradient 0-100% ethyl acetate in petroleum ether) to give the title compound (1.2 kg, 65% yield) as a white solid.

[1074] 1 H NMR(400MHz,DMSO-d6)δppm 0.84-1.21(m,4H)1.27-1.47(m,9H)2.89-3.19(m,2H)3.21-3.31(m,1H)3.60-3.87(m,1H)4.36(br 1H)6.85-7.23(m,1H),7.63(br s,1H).

[1075] Step 5: (E / Z)-tert-butyl 6-(3-bromo-2,5-difluorobenzyl)-7-(((R)-tert-butylsulfinyl)imino)-5-azaspiro[2.4]heptane-5-carboxylate

[1076]

[1077] The mixture of 6-(3-bromo-2,5-difluorobenzyl)-7-oxo-5-azaspiro[2.4]heptane-5-formic acid tert-butyl ester (200g, 480mmol, 1 equivalent), (R)-2-methylpropane-2-sulfinamide (116.5g, 961mmol, 2 equivalents), tetraethoxytitanium (548g, 2.40mol, 498mL, 5 equivalents) is degassed, purged three times with N2 and then stirred at 60 ℃ for 24h under N2 atmosphere. Five more batches are set as described above. All six reaction mixtures are merged. The combined reaction is diluted with tetrahydrofuran (1.1L) and poured into ice water (2.2L). The collected reaction mixture is filtered through diatomite and washed by tetrahydrofuran (5L), and the filtrate is extracted three times with ethyl acetate (2L). The combined organic layers were washed with aqueous NaCl (saturated, 3 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (elution gradient of 0-100% ethyl acetate / petroleum ether) to give the subject compound (1.1 kg, 70% yield) as a yellow oil.

[1078] 1 H NMR(400MHz,DMSO-d6)δppm 0.81-1.07(m,2H)1.10-1.25(m,16H)1.27-1.41(m,4H)2.87-3.24(m,2H) 3.35-3.78(m,2H)5.10-5.59(m,1H)6.84-7.28(m,1H)7.52-7.74(m,1H).

[1079] Step 6: (6S,7S)-tert-butyl 6-(3-bromo-2,5-difluorobenzyl)-7-(((R)tert-butylsulfinyl)amino)-5-azaspiro[2.4]heptane-5-carboxylate

[1080]

[1081] To a solution of (E / Z)-6-(3-bromo-2,5-difluorobenzyl)-7-(((R)-tert-butylsulfinyl)imino)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (220 g, 424 mmol, 1 eq) in tetrahydrofuran (2 L) and H2O (40 mL) was slowly added sodium borohydride (24 g, 635 mmol, 1.5 eq) at -50 °C. The mixture was stirred at 20 °C for 2 h. Four additional batches were set up as described above. All five reaction mixtures were combined. The combined reaction mixture was quenched at 0 °C by adding ice water (1 L), and then diluted with ethyl acetate (500 mL), and extracted three times with ethyl acetate (2 L). The combined organic layers were washed with aqueous NaCl solution (saturated, 2 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography (elution gradient of 0-100% ethyl acetate / petroleum ether) to give the title compound (380 g, 34.5% yield) as a white solid.

[1082] 1 H NMR(400MHz,DMSO-d6)δppm 0.46-0.80(m,3H)0.96-1.18(m,16H)1.24(br d,3H)2.55-2.75(m,1H)2.84-3.25(m,2H)3.56(br d,1H)3.97(br s,2H)4.87(br d,1H)7.11-7.70(m,2H).

[1083] Step 7: (6S,7S)-tert-butyl 7-amino-6-(3-bromo-2,5-difluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylate (Intermediate 13)

[1084]

[1085] A mixture of methanol (7.6 L) and tert-butyl (6S,7S)-6-(3-bromo-2,5-difluorobenzyl)-7-(((R)-tert-butylsulfinyl)amino)-5-azaspiro[2.4]heptane-5-carboxylate (380 g, 729 mmol, 1 eq) was cooled to 0 °C, and then acetyl chloride (60.06 g, 765 mmol, 1.05 eq) was added dropwise and purged with N2 three times at 0 °C. Under N2 atmosphere, the mixture was stirred at 20 °C for 12 h. At 0 °C, the reaction mixture was poured into ethyl acetate / saturated sodium bicarbonate solution (1 / 1, 10 L) and extracted three times with ethyl acetate (2 L). The combined organic layers were washed with aqueous NaCl solution (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (elution gradient of 0-100% ethyl acetate / petroleum ether) to give the title compound (185 g, 60% yield) as a white solid. LCMS (Method J) (ESI+): m / z=361 (M-56) + ,RT:2.130min.

[1086] Procedure for the preparation of intermediate 14

[1087] Step 1: (6S,7S)-tert-butyl 6-(3-bromo-2,5-difluorobenzyl)-7-(methylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate (Intermediate 14)

[1088]

[1089] To a mixture of (6S,7S)-7-amino-6-(3-bromo-2,5-difluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester, intermediate 13 (2.5 g, 5.99 mmol, 1 eq.) and triethylamine (2.50 mL, 17.97 mmol, 3 eq.) in dichloromethane (25 mL) was added methanesulfonyl chloride (1.64 mL, 21.21 mmol, 3.54 eq.) at 0 °C under nitrogen. The mixture was stirred at 25 °C for 12 h. The mixture was poured into saturated sodium bicarbonate (50 mL) and stirred for 3 minutes. The aqueous phase was extracted with triethylamine (3×25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The mixture was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give the title compound (2.8 g, yield 90.5%) as a white solid. LCMS (Method M) (ESI+): m / z 439.1 (M-56) + ,RT:0.802min.

[1090] Procedure for the Preparation of Intermediate 15 Tert-butyl (6S,7S)-7-amino-6-((2,5-difluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-5-carboxylate (Intermediate 15)

[1091]

[1092] XPhos-Pd-G3 (391 mg, 462 umol, 0.1 eq.), potassium phosphate (2.95 g, 13.9 mmol, 3 eq.) and phenylboronic acid (1.13 g, 9.25 mmol, 2 eq.) were added to a solution of (6S,7S)-7-amino-6-(3-bromo-2,5-difluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester, intermediate 13 (1.93 g, 4.63 mmol, 1 eq.) in tetrahydrofuran (20 mL). The mixture was stirred at 80 °C for 12 h. The mixture was poured into water (50 mL) and extracted with dichloromethane (3 x 40 mL). The organic layer was washed with brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 3: 1 to 2: 1) to give the title compound (1.87 g, 97.6% yield) as a yellow oil. LCMS (Method M) (ESI+): m / z 359.0 (M-56 + ),RT:0.670min.

[1093] Procedure for the preparation of intermediate 16

[1094] Step 1: N-((6S,7S)-6-((2,5-difluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-7-yl)-1-fluoromethanesulfonamide

[1095]

[1096] To a solution of (6S,7S)-7-amino-6-((2,5-difluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (1.87 g, 4.51 mmol, 1 eq) in acetonitrile (20 mL) was added pyridine (1.82 mL, 22.56 mmol, 5 eq) and fluoromethanesulfonyl chloride (777 mg, 5.87 mmol, 1.2 eq). The mixture was stirred at 90 °C for 12 hours. The mixture was poured into saturated aqueous ammonium chloride solution (80 mL) and extracted with dichloromethane (3×50 mL). The organic layer was washed with brine (100 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 4: 1 to 3: 1) to give the title compound (1.75 g, 76% yield) as a yellow oil. LCMS (Method M) (ESI+): m / z 411.1 (M + H-100) + ,RT:1.145min.

[1097] Step 2: N-((6S,7S)-6-((2,5-difluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-7-yl)-1-fluoromethanesulfonamide hydrochloride (Intermediate 16)

[1098]

[1099] A solution of N-((6S,7S)-6-((2,5-difluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-7-yl)-1-fluoromethanesulfonamide (1.75 g, 3.52 mmol, 1 eq) in HCl / dioxane (20 mL) was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow oil (1.3 g, 93.1% yield), which was used in the next step without further purification. LCMS (Method M) (ESI+): m / z 411.1 (M+H) + ,RT:0.810min

[1100] Procedure for the Preparation of Intermediate 17 Tert-butyl (6S,7S)-6-(3-bromo-2,5-difluorobenzyl)-7-((difluoromethyl)sulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate (Intermediate 17)

[1101]

[1102] At 0 ° C, difluoromethanesulfonyl chloride (902 mg, 5.99 mmol, 2 equivalents) and pyridine (1.21 mL, 14.98 mmol, 5 equivalents) were added to a solution of (6S, 7S)-7-amino-6-(3-bromo-2,5-difluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester, intermediate 13 (1.25 g, 3.00 mmol, 1 equivalent) in acetonitrile (50 mL). The reaction mixture was stirred at 20 ° C for 12 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate=3 / 1) to obtain the subject compound (0.98 g, 55.4% yield) as a white solid.

[1103] 1 H NMR (400MHz, chloroform-d) δ0.29-0.77(m,4H),1.25-1.46(m,9H),2.71-3.20(m,3H),3.70(br s,1H),4.26-4.34(m,1H),4.40(br s,1H),4.63(br s,1H),5.95-6.32(m,1H),6.90(br s,1H),7.20(br s,1H)

[1104] Example 1

[1105] Step 1: (6S,7S)-7-amino-6-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester

[1106]

[1107] At 20 ° C, to a solution of (6S, 7S)-7-amino-6-(3-bromo-2-fluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester, intermediate 8 (0.1 g, 250 μmol, 1 eq) in THF (2 mL), (3,5-difluorophenyl)boronic acid (99 mg, 626 μmol, 2.5 eq), Xphos G3 Pd (11 mg, 12 μmol, 0.05 eq) and K3PO4 (106 mg, 501 μmol, 2 eq) were added. The resulting reaction mixture was stirred at 80 ° C under N2 atmosphere for 8 hours. Four more batches were set up as above and all five reaction mixtures were combined and diluted with 30 mL of ethyl acetate and then washed with 10 mL of water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [water(NH 4 HCO 3 )-ACN]; B%: 40%-70%, 8 min) to give the title compound (190 mg, 33.3% yield) as a light yellow solid.

[1108] 1 H NMR (400MHz, methanol-d4) δ0.40-0.70(m,3H),0.88-1.02(m,1H),1.03-1.31(m,9H),2.80-2.97(m,1H),3.04(br d,1H),3.17(d,1H),3.52(br d,1H),3.56-3.71(m,1H),4.23-4.42(m,1H),6.97(br t,1H),7.09-7.25(m,3H),7.26-7.31(m,1H),7.40(br t,1H).

[1109] Step 2: (6S,7S)-7-(difluoromethylsulfonylamino)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester

[1110]

[1111] To a solution of tert-butyl (6S,7S)-7-amino-6-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-5-carboxylate (0.2 g, 460 μmol, 1 eq), 3,5-lutidine (250 mg, 2.30 mmol, 260 μL, 5 eq) in acetonitrile (2 mL) at 0°C was added difluoromethanesulfonyl chloride (118 mg, 790 μmol, 1.7 eq). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched by the addition of water (10 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1 / 1) to give (6S,7S)-tert-butyl 7-(difluoromethylsulfonylamino)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-5-carboxylate (0.2 g, yield 79%) as a white solid. LCMS method E: (ESI+): m / z 491 (M-tBu) + ,RT:0.95min.

[1112] Step 3: N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-7-yl]-1,1-difluoromethanesulfonamide

[1113]

[1114] A solution of (6S,7S)-7-(difluoromethylsulfonylamino)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (0.2 g, 366 μmol, 1 eq.) in HCl / dioxane (4 M, 5 mL) was stirred at 20° C. for 3 h. The mixture was concentrated under reduced pressure to give N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-7-yl]-1,1-difluoromethanesulfonamide (0.15 g, 92% yield) as a white solid. LCMS, Method E: (ESI+): m / z 447 (M+H) + ,RT:0.70min.

[1115] Step 4: N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-(3-fluoro-2-hydroxy-2-methyl-propionyl)-5-azaspiro[2.4]heptane-7-yl]-1,1-difluoromethanesulfonamide

[1116]

[1117] To a solution of N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-7-yl]-1,1-difluoromethanesulfonamide (120 mg, 270 μmol, 1 eq) in DMF (0.2 mL) was added 3-fluoro-2-hydroxy-2-methyl-propionic acid (39 mg, 320 μmol, 1.2 eq), DIEA (104 mg, 810 μmol, 140 μL, 3 eq) and HATU (153 mg, 400 μmol, 1.2 eq). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was treated with water (10 mL) and extracted with ethyl acetate (3×5 mL). The organic layers were combined and washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1 / 1) to give N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-(3-fluoro-2-hydroxy-2-methyl-propionyl)-5-azaspiro[2.4]heptane-7-yl]-1,1-difluoro-methanesulfonamide (80 mg, yield 54%) as a white solid. LCMS method I: (ESI+): m / z 551 (M+H) + ,RT:0.87min

[1118] Step 5: N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-[(2R)-3-fluoro-2-hydroxy-2-methyl-propionyl]-5-azaspiro[2.4]heptane-7-yl]-1,1-difluoro-methanesulfonamide

[1119]

[1120] 80 mg of N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-(3-fluoro-2-hydroxy-2-methyl-propionyl)-5-azaspiro[2.4]heptane-7-yl]-1,1-difluoro-methanesulfonamide was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O EtOH]]; B%: 20%-20%, 8 min) to give N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-[(2R)-3-fluoro-2-hydroxy-2-methyl-propionyl]-5-azaspiro[2.4]heptan-7-yl]-1,1-difluoro-methanesulfonamide (19.5 mg) as a white solid.

[1121] Example 2

[1122] Step 1: N-[(6S,7S)-5-(2-cyclopropyl-2-hydroxy-propionyl)-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptane-7-yl]-1-fluoro-methanesulfonamide

[1123]

[1124] To a mixture of the HCl salt of N-[(6S,7S)-5-H-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptane-7-yl]-1-fluoro-methanesulfonamide (120 mg, 280 μmol, 1 eq) and 2-cyclopropyl-2-hydroxy-propionic acid (91 mg, 699 μmol, 2.5 eq) in DMF (1.2 mL) at 0°C was added HATU (213 mg, 560 μmol, 2 eq) and DIEA (181 mg, 1.40 mmol, 244 μL, 5 eq). The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (3×10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, then filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 5 / 1) to give N-[(6S,7S)-5-(2-cyclopropyl-2-hydroxy-propionyl)-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptan-7-yl]-1-fluoro-methanesulfonamide (0.09 g, yield 63%) as a white solid.

[1125] LCMS method F: (ESI+): m / z 505 (M+H) + ,RT:0.89min.1 H NMR (400MHz, methanol-d4) δ0.11-0.43(m,4H),0.59-0.74(m,3H),0.98-1.13(m,3.6H),1.1 7-1.23(m,1.4H),2.84-3.04(m,1H),3.11-3.22(m,1H),3.68-3.87(m,1H),4.05-4.0 9(m,1H),4.14-4.35(m,1H),4.95-5.08(m,1H),5.12(s,1H),5.23(s,1H),7.07-7.17 (m,1H),7.22-7.30(m,2H),7.31-7.37(m,1H),7.38-7.45(m,2H),7.50-7.57(m,2H).

[1126] Step 2: N-[(6S,7S)-5-[(2R)-2-cyclopropyl-2-hydroxy-propionyl]-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptan-7-yl]-1-fluoro-methanesulfonamide and N-[(6S,7S)-5-[(2S)-2-cyclopropyl-2-hydroxy-propionyl]-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptan-7-yl]-1-fluoro-methanesulfonamide

[1127]

[1128] N-[(6S,7S)-5-(2-cyclopropyl-2-hydroxy-propionyl)-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptane-7-yl]-1-fluoro-methanesulfonamide (90 mg, mixture of diastereomers) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O MeOH]; B%: 30%-30%, 14 min) to give N-[(6S,7S)-5-[(2R)-2-cyclopropyl-2-hydroxy-propionyl]-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]hept-7-yl]-1-fluoro-methanesulfonamide (28 mg, RT=2.23 min in SFC) and N-[(6S,7S)-5-[(2S)-2-cyclopropyl-2-hydroxy-propionyl]-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]hept-7-yl]-1-fluoro-methanesulfonamide (31 mg, RT=2.49 min in SFC), both as white solids.

[1129] Example 3

[1130] Step 1: (6S,7S)-7-amino-6-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester

[1131]

[1132] To a solution of (6S,7S)-7-amino-6-(3-bromo-2-fluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester, intermediate 8 (600 mg, 1.50 mmol, 1 eq.) and 2-(3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (541 mg, 2.25 mmol, 1.5 eq.) in toluene (3 mL) and H2O (0.9 mL) at 20°C was added Pd(dppf)Cl2 (36 mg, 150 μmol, 0.1 eq.) and potassium carbonate (415 mg, 3.0 mmol, 2 eq.). The resulting mixture was stirred at 80°C for 2 h. The resulting mixture was treated with H2O (5 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were combined, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by chromatography on silica gel (eluted with petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to give (6S,7S)-7-amino-6-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (600 mg, yield 92%) as a white solid. LCMS method E: (ESI+): m / z 377 (M-55) + ,RT:0.64min.

[1133] Step 2: (6S,7S)-tert-butyl 7-(fluoromethylsulfonylamino)-6-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-5-carboxylate

[1134]

[1135] To a solution of (6S,7S)-7-amino-6-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (500 mg, 1.16 mmol, 1 eq) and 1-methyl-1H-imidazole (285 mg, 3.47 mmol, 3 eq) in tetrahydrofuran (2.5 mL) at 0°C was added fluoromethanesulfonyl chloride (230 mg, 1.73 mmol, 1.5 eq). The resulting mixture was stirred at 25°C for 2 h. The resulting mixture was treated with H2O (5 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were combined, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography on silica gel (eluted with petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give tert-butyl (6S,7S)-7-(fluoromethylsulfonylamino)-6-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-5-carboxylate (400 mg, yield 65%) as a white solid. LCMS method E: (ESI+): m / z 473 (M-55) + ,RT:0.75min.

[1136] Step 3: 1-Fluoro-N-((6S,7S)-6-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-7-yl)methanesulfonamide

[1137]

[1138] A solution of tert-butyl (6S,7S)-7-(fluoromethylsulfonylamino)-6-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-5-carboxylate (500 mg, 0.95 mmol, 1 eq) in hydrochloric acid / dioxane (3 mL, 4M) was stirred at 20°C for 3 h. The resulting mixture was concentrated under reduced pressure to give 1-fluoro-N-((6S,7S)-6-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-7-yl)methanesulfonamide (400 mg, 99% yield) as a white solid, which was used directly in the next step without further purification. LCMS, Method E: (ESI+): m / z 429.1 (M+H) + ,RT:0.657min.

[1139] Step 4: N-((6S,7S)-5-((S)-2-cyclopropyl-2-hydroxyacetyl)-6-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-7-yl)-1-fluoromethanesulfonamide

[1140]

[1141] To a mixture of 1-fluoro-N-((6S,7S)-6-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptan-7-yl)methanesulfonamide (140 mg, 0.33 mmol, 1 eq) and 2-cyclopropyl-2-hydroxyacetic acid (57 mg, 0.49 mmol, 1.5 eq) in dimethylformamide (1.4 mL) was added diisopropylethylamine (211 mg, 1.58 mmol, 270 μL, 5 eq) and HATU (186 mg, 0.490 mmol, 1.5 eq) at 0° C. The mixture was stirred at 20° C. for 12 h. The reaction mixture was purified by preparative HPLC (NH4HCO3 conditions) to give a white solid, which was further separated by SFC (column: REGIS(S,S)WHELK-O1 (250 mm×25 mm, 10 μm); mobile phase: [0.1% NH3·H2O ethanol]; B%: 60%-60%, 8 min) to give N-((6S,7S)-5-((S)-2-cyclopropyl-2-hydroxyacetyl)-6-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptan-7-yl)-1-fluoromethanesulfonamide (30 mg, 17% yield) as a white solid.

[1142] Example 4

[1143] Step 1: (6S,7S)-7-amino-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester

[1144]

[1145] To a solution of (6S,7S)-7-amino-6-(3-bromo-2-fluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester, intermediate 8 (2 g, 5.00 mmol, 1 eq.) and (3,5-difluorophenyl)boronic acid (1.19 g, 7.50 mmol, 1.5 eq.) in H2O (4 mL) and dioxane (20 mL) was added cesium carbonate (4.90 g, 15.0 mmol, 3 eq.) and cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (367 mg, 500 μmol, 0.1 eq.). The mixture was stirred at 80°C for 2 h. The reaction solution was evaporated and silica gel powder was mixed in. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 0.7 / 1) to give (6S, 7S) -7-amino-6- [ [3- (3, 5-difluorophenyl) -2-fluoro-phenyl] methyl] -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester (1.51 g, 70% yield) as a yellow solid. LCMS method E (ESI +): m / z 377 (M + 1-56) + ,RT:0.89min.

[1146] Step 2: (6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-7-(fluoromethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester

[1147]

[1148] To a solution of (6S,7S)-7-amino-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (938 mg, 2.17 mmol, 1 eq) in acetonitrile (10 mL) was added pyridine (860 mg, 11.0 mmol, 875 μL, 5 eq) and fluoromethanesulfonyl chloride (373 mg, 2.82 mmol, 1.3 eq). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give (6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-7-(fluoromethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate (1.0 g, 87% yield) as a yellow solid, which was used directly in the next step. LCMS method E: (ESI+): m / z 429 (M+1-100) + ,RT:1.11min.

[1149] Step 3: N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-7-yl]-1-fluoro-methanesulfonamide

[1150]

[1151] To a solution of (6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-7-(fluoromethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (1 g, 2.02 mmol, 1 eq) in HCl / dioxane (20 mL). The mixture was stirred at 20 °C for 3 h. The mixture was concentrated under reduced pressure to give N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-7-yl]-1-fluoro-methanesulfonamide (0.85 g, 81% yield as HCl salt) as a yellow solid, which was used directly in the next step. LCMS method E: (ESI+): m / z 429 (M+1) + ,RT:0.87min.

[1152] Step 4: (6S,7S)-N-[(1R)-2,2-difluoro-1-methyl-ethyl]-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-7-(fluoromethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxamide

[1153]

[1154] A mixture of N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-7-yl]-1-fluoro-methanesulfonamide (100 mg, 233 μmol, 1 eq), DIEA (91 mg, 700 μmol, 3 eq) and triphosgene (35 mg, 117 μmol, 0.5 eq) in acetonitrile (1 mL) was stirred at 25 °C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure and a solution of (2R)-1,1-difluoropropane-2-amine (89 mg, 934 μmol, 4 eq), triethylamine (71 mg, 700 μmol, 97.46 μL, 3 eq) and dichloromethane (1 mL) was added. The mixture was stirred at 25 °C for 14 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the product. The residue was purified by preparative HPLC (neutral conditions), column: Waters XbridgeBEH C18 100*30mm*10μm: mobile phase: [water(NH4HCO3)-acetonitrile]; B%: 50%-70%, 8 min to give (6S,7S)-N-[(1R)-2,2-difluoro-1-methyl-ethyl]-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-7-(fluoromethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxamide (20 mg, 16% yield) as a yellow solid.

[1155] Example 5

[1156] Step 1: (6S,7S)-7-amino-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester

[1157]

[1158] To a solution of (6S,7S)-7-amino-6-[(2-fluoro-3-bromo-phenyl)methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (5 g, 12.5 mmol, 1 eq) and phenylboronic acid (3.05 g, 25.0 mmol, 2 eq) in tetrahydrofuran (50 mL) was added Xphos-Pd-G3 (530 mg, 626 μmol, 0.05 eq) and K3PO4 (7.97 g, 37.60 mmol, 3 eq) at 25°C. The mixture was stirred at 80°C for 12 h. The mixture was poured into water (50 mL) and the two phases were separated. The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether / ethyl acetate = 100 / 1 to 2 / 1) to give (6S,7S)-7-amino-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (4 g, yield 81%) as a white solid. LCMS method E (ESI+): m / z 341 (M-55) + ,RT:0.68min.

[1159] Step 2: (6S,7S)-tert-butyl 7-(fluoromethylsulfonylamino)-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptane-5-carboxylate

[1160]

[1161] Fluoromethanesulfonyl chloride (535 mg, 4.04 mmol, 2 eq.) was added to a solution of (6S, 7S)-7-amino-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (0.8 g, 2.02 mmol, 1 eq.) in pyridine (8 mL) at 25 °C. The mixture was stirred at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (eluted with petroleum ether / ethyl acetate=100 / 1 to 1 / 1) to give (6S, 7S)-7-(fluoromethylsulfonylamino)-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (0.8 g, 80% yield) as a white solid. LCMS method E: (ESI+): m / z 437 (M-55) + ,RT:0.84min.

[1162] Step 3: 1-Fluoro-N-[(6S,7S)-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptane-7-yl]methanesulfonamide

[1163]

[1164] A solution of (6S,7S)-tert-butyl 7-(fluoromethylsulfonylamino)-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptane-5-carboxylate (0.7 g, 1.42 mmol, 1 eq.) in HCl / dioxane (4 M, 10.5 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give 1-fluoro-N-[(6S,7S)-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptane-7-yl]methanesulfonamide (0.7 g, crude) as a white solid, which was used in the next step without further purification. LCMS Method E: (ESI+): m / z 393 (M+H) + ,RT:0.66min.

[1165] Step 4: N-[(6S,7S)-5-(1-cyanocyclopropanecarbonyl)-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptane-7-yl]-1-fluoro-methanesulfonamide

[1166]

[1167] To a solution of 1-fluoro-N-[(6S,7S)-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptane-7-yl]methanesulfonamide (70 mg, 178 μmol, 1 eq) in N,N-dimethylformamide (0.7 mL) at 25° C., 1-cyanocyclopropanecarboxylic acid (26 mg, 232 μmol, 1.3 eq), triethylamine (72 mg, 713 μmol, 99 μL, 4 eq) and propylphosphonic anhydride (114 mg, 357 μmol, 106 μL, 2 eq) were added. The resulting mixture was stirred at 25° C. for 12 h. The reaction mixture was purified by preparative HPLC (NH4HCO3 conditions) (column: Phenomenex C18 75*30mm*3μm; mobile phase: [water(NH4HCO3)-CH3CN]; B%: %-%, 8min) to give N-[(6S,7S)-5-(1-cyanocyclopropanecarbonyl)-6-[(2-fluoro-3-phenyl-phenyl)methyl]-5-azaspiro[2.4]heptane-7-yl]-1-fluoro-methanesulfonamide (24.7 mg, yield 28%) as a white solid.

[1168] Example 6

[1169] Step 1: (6S,7S)-7-amino-6-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester

[1170]

[1171] To a solution of (6S,7S)-7-amino-6-[[2-fluoro-3-bromo-phenyl]methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (300 mg, 750 μmol, 1 eq) in dioxane (2.5 mL) and H2O (0.5 mL) was added (3-fluorophenyl)boronic acid (315 mg, 2.25 mmol, 1.5 eq), Cs2CO3 (734 mg, 2.25 mmol, 2 eq) and Pd(dppf)Cl2 (27 mg, 38 μmol, 0.1 eq). The mixture was stirred at 90 °C for 12 h under N2 atmosphere. The reaction was poured into water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic phases were combined and washed with brine (10 mL). The organic phase was dried over magnesium sulfate and concentrated to give a residue, and purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 8:2 to 1:1) to give (6S,7S)-7-amino-6-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (280 mg, yield 90%) as a yellow solid.

[1172] LCMS method E (ESI+): m / z 359 (M-55) + ,RT:1.28min. 1 H NMR: (400MHz, CDCl3) δppm0.32-0.65(m,3H)0.70-0.81(m,1H)1.19-1.38(m,9H)2.66-2.92(m,1H)2.97- 3.25(m,2H)3.29-3.80(m,2H)4.18-4.39(m,1H)7.06(td,1H)7.12-7.18(m,1H)7.19-7.27(m,3H)7.31(br d,1H)7.36-7.43(m,1H).

[1173] Step 2: 6S,7S)-6-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-7-(fluoromethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate

[1174]

[1175] To a solution of (6S,7S)-7-amino-6-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (280 mg, 676 μmol, 1 eq) in acetonitrile (2.8 mL) was added pyridine (1.07 g, 13.5 mmol, 1.09 mL, 20 eq). Fluoromethanesulfonyl chloride (116 mg, 878 μmol, 1.5 eq) was then added to the reaction at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction was poured into saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×10 mL). The organic phases were combined and washed with brine (5 mL). The organic phases were dried over magnesium sulfate and concentrated to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 2:1) to give tert-butyl (6S,7S)-6-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-7-(fluoromethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate (205 mg, 59% yield) as a black oil.

[1176] LCMS method E: (ESI+): m / z 533.2 (M+Na) + ,RT:0.860min. 1 H NMR: (400MHz, CDCl3) δppm 0.26-0.51(m,1H)0.55-0.72(m,3H)1.28-1.47(m,9H)2.85-3.20(m,3H)3.51-3.76(m,1H)4.22(br dd,1H)4.32-5.15(m,4H)7.04-7.13(m,1H)7.17-7.25(m,2H)7.26-7.35(m,3H)7.37-7.45(m,1H).

[1177] Step 3: 1-Fluoro-N-[(6S,7S)-6-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-5-azaspiro[2.4]heptane-7-yl]methanesulfonamide

[1178]

[1179] A solution of (6S,7S)-tert-butyl 6-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-7-(fluoromethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate (205 mg, 402 μmol, 1 eq) in HCl / dioxane (4M, 8.2 mL) was stirred at 20 °C for 3 h. The mixture was concentrated under reduced pressure to give 1-fluoro-N-[(6S,7S)-6-[[2-fluoro-3-(3-fluorophenyl)phenyl]-methyl]-5-azaspiro[2.4]heptane-7-yl]methanesulfonamide (160 mg, 97% yield), which was used directly in the next step without purification. LCMS Method E (ESI+): m / z 411 (M+H) + ,RT:0.65min. Step 4: N-[(6S,7S)-5-(3,3-difluoro-2-hydroxy-2-methyl-propionyl)-6-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-5-azaspiro[2.4]heptane-7-yl]-1-fluoro-methanesulfonamide

[1180]

[1181] To a solution of 1-fluoro-N-[(6S,7S)-6-[[2-fluoro-3-(3-fluorophenyl)phenyl]-methyl]-5-azaspiro[2.4]heptan-7-yl]methanesulfonamide (110.5 mg, 269 μmol, 1 eq) in dimethylformamide (2.2 mL) was added sodium (3,3-difluoro-2-hydroxy-2-methyl-propionyl)oxy (48 mg, 296 μmol, 1.1 eq), then HATU (102 mg, 269 μmol, 1 eq) and DIEA (104 mg, 808 μmol, 141 μL, 3 eq) were added to the reaction mixture. The mixture was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Phenomenex C1875*30mm*3μm; mobile phase: [water(NH3H2O+NH4HCO3)-acetonitrile]; B%: 25%-55%, 8 min) to give N-[(6S,7S)-5-[(2S)-3,3-difluoro-2-hydroxy-2-methyl-propionyl]-6-[[2-fluoro-3-(3-fluorophenyl)phenyl]methyl]-5-azaspiro[2.4]heptane-7-yl]-1-fluoro-methanesulfonamide (32 mg, yield 22%) as a white solid.

[1182] Example 7

[1183] Step 1: N-[(6S,7S)-5-(1-cyanocyclobutanecarbonyl)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-7-yl]-1,1-difluoro-methanesulfonamide

[1184]

[1185] To a solution of N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptan-7-yl]-1,1-difluoro-methanesulfonamide (0.1 g, 224 μmol, 1 eq) in N,N-dimethylformamide (1 mL) at 0° C., 1-cyanocyclobutanecarboxylic acid (36 mg, 291 μmol, 1.3 eq) and N,N-diisopropylethylamine (145 mg, 1.12 mmol, 195 μL, 5 eq), o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (111 mg, 291 μmol, 1.3 eq) were added. The mixture was stirred at 25° C. for 12 h. The mixture was purified by preparative HPLC (NH4HCO3 conditions: column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water(NH4HCO3)-acetonitrile]; B%: 42%-62%, 8 min) to give N-[(6S,7S)-5-(1-cyanocyclobutanecarbonyl)-6-[[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl-]-5-azaspiro[2.4]heptane-7-yl]-1,1-difluoro-methanesulfonamide (0.030 g, yield 24%) as a white solid.

[1186] Example 8

[1187] Step 1: N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-[(2S)-3-fluoro-2-hydroxy-propionyl]-5-azaspiro[2.4]heptane-7-yl]-1,1-difluoro-methanesulfonamide

[1188]

[1189] To a solution of N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptan-7-yl]-1,1-difluoro-methanesulfonamide (100 mg, 224 μmol, 1 eq) in DMF (1 mL) at 0° C. were added (2S)-3-fluoro-2-hydroxy-propionic acid (36 mg, 336 μmol, 1.5 eq), DIEA (145 mg, 1.12 mmol, 195 μL, 5 eq) and HATU (102 mg, 269 μmol, 1.2 eq). The resulting mixture was stirred at 25° C. for 12 h, during which time the mixture remained a yellow solution. The reaction mixture was purified by preparative HPLC (basic conditions) (column: Waters XbridgePrep OBD C18 150*40mm*10μm; mobile phase: [water(NH4HCO3)-acetonitrile]; B%: 30%-60%, 8 min) to give N-[(6S,7S)-6-[[3-(3,5-difluorophenyl)-2-fluoro-phenyl]methyl]-5-[(2S)-3-fluoro-2-hydroxy-propionyl]-5-azaspiro[2.4]heptane-7-yl]-1,1-difluoro-methanesulfonamide (38 mg, yield 32%) as a white solid.

[1190] Example 9

[1191] Step 1: (6S,7S)-6-[(2,5-difluoro-3-phenyl-phenyl)methyl]-7-(isopropylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester

[1192]

[1193] DBU (735 mg, 4.83 mmol, 727 μL, 10 equiv) was added to a solution of propane-2-sulfonyl chloride (688 mg, 4.83 mmol, 538 μL, 10 equiv) in dichloromethane (16 mL). The mixture was then stirred at -20 °C for 10 min. A solution of (6S,7S)-7-amino-6-((2,5-difluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (Intermediate 15) (200 mg, 483 μmol, 1 equiv) in dichloromethane (4 mL) was added to the reaction at -20 °C. The mixture was then stirred at -20 °C for 10 min. The reaction was poured into a saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (3×10 mL). The organic phases were combined and washed with brine (10 mL). The organic phase was dried over magnesium sulfate and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give (6S, 7S)-6-[(2,5-difluoro-3-phenyl-phenyl)methyl]-7-(isopropylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (190 mg, yield 73%) as a white solid. LCMS, method E: (ESI+): m / z 421.1 (M-100+H) + ,RT:0.772min.

[1194] Step 2: N-((6S,7S)-6-((2,5-difluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-7-yl)propane-2-sulfonamide

[1195]

[1196] A solution of (6S,7S)-6-[(2,5-difluoro-3-phenyl-phenyl)methyl]-7-(isopropylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (80 mg, 151 μmol, 1 eq) in HCl / dioxane (4M, 2 mL) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give N-((6S,7S)-6-((2,5-difluoro-[1,1′-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-7-yl)propane-2-sulfonamide (55 mg, 85% yield) as a yellow solid, which was used directly without any purification. LCMS, Method E: (ESI+): m / z 421.1 (M+H) + ,RT:0.547min.

[1197] Step 3: N-((6S,7S)-6-((2,5-difluoro-[1,1'-biphenyl]-3-yl)methyl)-5-((R)-oxetane-2-carbonyl)-5-azaspiro[2.4]heptane-7-yl)propane-2-sulfonamide

[1198]

[1199] To a solution of N-((6S,7S)-6-((2,5-difluoro-[1,1'-biphenyl]-3-yl)methyl)-5-azaspiro[2.4]heptane-7-yl)propane-2-sulfonamide (55 mg, 131 μmol, 1 eq) in dimethylformamide (1.65 mL) was added diisopropylethylamine (51 mg, 392 μmol, 68 μL, 3 eq) and (2R)-oxetane-2-carboxylic acid (17 mg, 170 μmol, 1.2 eq). HATU (50 mg, 131 μmol, 1 eq) was then added to the reaction mixture. The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEHC18 100*30mm*10μm; mobile phase: [water(NH3H2O+NH4HCO3)-acetonitrile]; B%: 20%-60%, 8 min) to give N-((6S,7S)-6-((2,5-difluoro-[1,1'-biphenyl]-3-yl)methyl)-5-((R)-oxetane-2-carbonyl)-5-azaspiro[2.4]heptane-7-yl)propane-2-sulfonamide (32 mg, yield 49%) as a white solid.

[1200] Table A: Experimental details of Example No. 1-91

[1201]

[1202]

[1203]

[1204]

[1205]

[1206]

[1207]

[1208]

[1209]

[1210]

[1211]

[1212]

[1213]

[1214]

[1215]

[1216]

[1217]

[1218]

[1219]

[1220]

[1221]

[1222]

[1223]

[1224]

[1225]

[1226] Example 92. Biological activities of compounds of the present disclosure.

[1227] The biological activity of the compounds of the present disclosure was determined using the assays described herein.

[1228] Orexin type 2 receptor agonist activity of exemplary compounds.

[1229] Stable cell line generation. Obtaining cells stably expressing human orexin type 2 or human orexin type 1 receptor: To obtain stable cell lines, orexin receptor cDNA was inserted into the pcDNA3.1(+) plasmid vector and clones were identified by G418 resistance selection. Clones showing functionally active orexin A were selected and cultured continuously. Individual clones of OX2R-CHO and OX1R-CHO were cultured in large quantities and frozen to generate cell banks for routine screening.

[1230] Measurement of orexin type 2 receptor agonist activity. Chinese hamster ovary (CHO) cells expressing human orexin type 2 receptor (hOX2R) or human orexin type 2 receptor (hOX1R) were seeded at 10,000 cells per well in each well of a 384-well black transparent bottom plate (BD Flacon) and cultured for 24 hours at 37°C, 5% CO2 in Ham's F12 (Gibco) medium containing 10% fetal bovine serum (SigmaAldrich). After removing the culture medium, 50 μl of assay buffer 1 (0.1% bovine serum albumin (Sigma Aldrich), 20 mM HEPES (Molecular Dimensions), 250 mM probenecid (Sigma Aldrich), 1X Calcium 5 dye (Molecular Devices) in Hank's balanced salt solution (Invitrogen)) was added, and the cells were incubated at 37°C, 5% CO2 for 60 min. The test compound was dissolved in dimethyl sulfoxide (Sigma Aldrich) to 10 mM, and then diluted with assay buffer 2 (20 mM HEPES, Hank's balanced salt solution, 0.1% bovine serum albumin). For the reaction, the test compound solution (10 μl) was added using a fluorescent imaging plate reader TETRA (FLIPR TETRA: manufactured by Molecular Devices), and the fluorescence value of each well was measured every second for 2 minutes (excitation wavelength 488 nm, measurement wavelength 570 nm), and the area of ​​the fluorescence value was used as the intracellular Ca 2+ The agonist activity was determined based on the concentration of the test compound. Assuming that the fluorescence value of the wells with only the dilution buffer added was 0% and the fluorescence value of the wells with the 10 nM human orexin A (Tocris) buffer added was 100%, the agonist activity of the test compound was calculated. The agonist activity value EC of each compound was 50 Shown in Table B below.

[1231] For the hOx2 pEC shown in Table B 50 Value, "*" indicates pEC 50 Range <6.0; "**" indicates pEC 50 Range is between 6.0 and 7.0; "***" indicates pEC 50 Range is between 7.0 and 8.0; "****" indicates pEC 50 Range is between 8.0 and 9.0; "*****" indicates pEC 50 The range is between 9.0 and 10.2.

[1232] Table B

[1233]

[1234]

[1235]

[1236] Equivalent solution

[1237] The details of one or more embodiments of the present disclosure are set forth in the above attached description. Although any methods and materials similar or equivalent to those described herein can be used to practice or test the present disclosure, preferred methods and materials are now described. Other features, objects and advantages of the present disclosure will be apparent from the specification and from the claims. In the specification and the appended claims, singular forms include plural indicators unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used in this article have the same meanings as those of ordinary skill in the art to which the present disclosure belongs. All patents and publications cited in this specification are incorporated by reference.

[1238] The foregoing description is presented for purposes of illustration only and is not intended to limit the present disclosure to the precise form disclosed except as defined by the appended claims.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Z is -NH-; X is -C(R X1 )3 or -N(R X2 )2; Each R X1 are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl, or two R X1 Together with the atoms to which they are attached, they form a C3-C4 cycloalkyl or a 4-membered heterocycloalkyl; Each R X2 are independently H, C1-C6 alkyl or C1-C6 haloalkyl; Ar1 is a C6 aryl group substituted by one or more R3; R3 is halogen; R1 is C1-C6 alkyl or C1-C6 haloalkyl; R2 is optionally replaced by one or more R 2S Substituted C6 aryl; Each R 2S are independently halogen; R 4a is H; and R 4b It's H.

2. A compound of formula (I'): or a pharmaceutically acceptable salt thereof, wherein: Z is -NH-; X is -C(R X1 )3 or -N(R X2 )2; Each R X1 is independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy, or two R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted with one or more halogens; Each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens, or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group; Ar1 is a C6 aryl group substituted by one or more R3; R3 is halogen; R1 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen; R2 is optionally replaced by one or more R 2S Substituted C6 aryl; Each R 2S are independently halogen; R 4a It is H; R 4b is H; and n is 0, 1 or 2.

3. A compound of formula (I"): or a pharmaceutically acceptable salt thereof, wherein: Z is -NH-; X is -C(R X1 )3 or -N(R X2 )2; Each R X1 is independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy, or two R X1 Together with the atoms to which they are attached, they form a C3-C5 cycloalkyl or a 4-membered or 5-membered heterocycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted with one or more halogens; Each R X2 are independently H, C1-C6 alkyl, C1-C6 haloalkyl or -(CH2) n -C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more halogens, or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group; Ar1 is a C6 aryl group substituted by one or more R3; R3 is halogen; R1 is C3-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen; R2 is optionally replaced by one or more R 2S Substituted C6 aryl; Each R 2S are independently halogen; R 4a It is H; R 4b is H; and n is 0, 1 or 2.

4. A compound of formula (I''): or a pharmaceutically acceptable salt thereof, wherein: Z is -NH-; X is -C(R X1 )3 or -N(R X2 )2; Each R X1 are independently H, -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the alkyl is optionally substituted with one or more -OH or C1-C6 alkoxy groups, or two R X1 Together with the atoms to which they are attached, they form a C3-C4 cycloalkyl group or a 4-membered or 5-membered heterocycloalkyl group; Each R X2 are independently H, C1-C6 alkyl or C1-C6 haloalkyl, or two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocycloalkyl group optionally substituted with a C1-C6 alkoxy group; Ar1 is a C6 aryl group substituted by one or more R3; R3 is halogen or C1-C6 alkoxy; R1 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C7 cycloalkyl optionally substituted by one halogen; R2 is optionally replaced by one or more R 2S Substituted C6 aryl; Each R 2S are independently halogen or C1-C6 alkyl; R 4a is H; and R 4b It's H.

5. A compound as claimed in any one of the preceding claims, wherein X is -C(R X1 )3.

6. A compound as described in any one of claims 1 to 4, wherein X is -N(R X2 )2.

7. A compound as claimed in any one of the preceding claims, wherein each R X1 Independently H.

8. A compound as described in any one of claims 1 to 6, wherein each R X1 are independently -CN, -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl.

9. A compound as claimed in any one of the preceding claims, wherein each R X2 Independently H.

10. The compound of any one of claims 1 to 8, wherein each R X2 are independently C1-C6 alkyl or C1-C6 haloalkyl.

11. A compound as claimed in any one of the preceding claims, wherein Ar1 is C6-aryl substituted with one R3.

12. A compound as claimed in any one of the preceding claims, wherein Ar1 is C6-aryl substituted by two R3.

13. A compound as claimed in any one of the preceding claims, wherein R1 is C1-C6 alkyl or C1-C6 haloalkyl.

14. A compound as claimed in any one of the preceding claims, wherein R2 is C6 aryl.

15. A compound as claimed in any one of the preceding claims, wherein R2 is replaced by one or more R 2S Substituted phenyl.

16. A compound as claimed in any one of the preceding claims, wherein each R 2S are independently halogen.

17. A compound as claimed in any one of the preceding claims, wherein each R3 is independently halogen.

18. A compound as claimed in any one of the preceding claims, wherein the compound has formula (I-1a) or (I-1b): or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3 or 4 and q is 0, 1, 2, 3, 4 or 5.

19. A compound as claimed in any one of the preceding claims, selected from the compounds described in Table 1, Table 2, Table 3 or Table 4, and prodrugs and pharmaceutically acceptable salts thereof.

20. 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.

21. The pharmaceutical composition of claim 20, wherein the compound is selected from the compounds described in Table 1, Table 2, Table 3 or Table 4.

22. A method for modulating orexin-2 receptor activity, comprising contacting a cell with a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

23. 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 1-19 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 20 or claim 21.

24. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20 or claim 21, for use in modulating orexin-2 receptor activity.

25. A compound as claimed in any one of claims 1 to 19, or a pharmaceutical composition as claimed in claim 20 or claim 21, for use in treating or preventing a disease or disorder.

26. Use of the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for regulating orexin-2 receptor activity.

27. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease or disorder.

28. The method, compound, pharmaceutical composition or use of any one of claims 22-27, wherein the disease or disorder is associated with an orexin receptor being involved.

29. The method, compound, pharmaceutical composition or use of any one of claims 22-28, 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.

30. The method, compound, pharmaceutical composition or use of any one of claims 22-28, wherein the disease or disorder is narcolepsy, idiopathic hypersomnia or sleep apnea.

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