Bicyclic heterocyclic derivatives and their use as orexin-2 receptor agonists

Abstract

The present disclosure relates to compounds of formula (I') and their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for modulating orexin receptor activity and may be used in the treatment of disorders in which orexin receptor activity is implicated, such as narcolepsy, hypersomnia, neurodegenerative disorders, symptoms of rare genetic diseases, mental health disorders, metabolic syndrome, osteoporosis, heart failure, coma, or complications during emergence from anesthesia. TIFF2023540344000503.tif31128

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Application No. 63 / 074,216, filed on 3 September 2020, the entirety of which is incorporated herein by reference. [Background technology]

[0002] background This disclosure relates to a small-molecule, potent orexin-2 receptor (OX2R) agonist designed for the treatment of narcolepsy and other disorders associated with orexin deficiency and / or excessive sleepiness. Narcolepsy affects 1 in 2000 people worldwide. Onset occurs in adolescence and can have a devastating impact on quality of life throughout 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 crucial for treating the underlying cause of NT1.

[0003] In narcolepsy type 1 (NT1), the sole neuronal population that produces orexin A and B (also known as hypocretin-1 and 2) peptides is destroyed by an immune mechanism that causes borderline disturbances in the state of wakefulness. A mouse model of narcolepsy type 1 replicates the loss of orexin neurons, as well as the two main symptoms observed in NT1 patients, specifically excessive daytime sleepiness and cataplexy. Symptoms common to both narcolepsy types 1 and 2 include excessive daytime sleepiness, nocturnal sleep disturbances, and inappropriately timed rapid eye movement (REM) sleep, as well as sleep paralysis and waking / hypnagogic hallucinations. Cataplexy is a sudden, reversible loss of muscle tone during wakefulness (atony of REM sleep) in response to emotional stimuli and is characteristic of NT1.

[0004] Two major symptoms of narcolepsy type 1, excessive daytime sleepiness and cataplexy, can be mitigated in a mouse model by reactivating orexin neurotransmission at OX2R. Improvements in cataplexy-like events and sleep / wake fragmentation were achieved by genetic local restoration of OX2R signaling in mice deficient in orexin receptors in the dorsal raphe nucleus of the pons and the tuberomammillary nucleus of the hypothalamus, respectively. Intraventricular (ICV) administration of orexin A (OXA) has been shown to prolong wake-up time and reduce cataplexy-like behavior in orexin neuron-deficient mice. YNT-185, a selective OX2R agonist administered intraperitoneally or via ICV, slightly enhances wakefulness in wild-type (WT) and orexin ligand-deficient mice and reduces sleep-onset REM sleep and cataplexy-like events in the NT1 mouse model. Subcutaneous administration of the selective OX2R agonist TAK-925 slightly enhanced arousal in wild-type mice but not in OX2R knockout mice. A brain-penetrating and stable OX2R agonist that is bioavailable after alternative administration routes (including but not limited to oral, intranasal, mucosal, and transdermal) and binds with high affinity to highly excitable arousal-controlling neurons would improve current treatments for patients with NT1. Indeed, early clinical studies have reported that TAK-925 exhibits both significant levels of hyperarousal and a tendency to reduce cataplexy in individuals with NT1. OX1R activation is linked to the regulation of emotional and reward behaviors and may also contribute to arousal.

[0005] Orexin receptor agonists may also be useful in other indications characterized by some degree of orexin-induced neurodegeneration and excessive daytime sleepiness, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, and traumatic brain injury. Since OX2R stimulation promotes wakefulness in animals where orexin is intact, orexin receptor agonists may treat excessive daytime sleepiness in patients with normal levels of orexin, including narcolepsy type 2, idiopathic hypersomnia, or sleep apnea. Similarly, orexin receptor agonists may confer wakefulness-promoting effects in recurrent hypersomnias such as Kleine-Levin syndrome, or in disorders of inappropriate timing of sleep (i.e., circadian rhythm sleep disorders) such as delayed or advanced sleep phase disorder, shift work disorder, and jet lag disorder. Orexin receptor agonists may alleviate abnormal daytime sleepiness, sleep-onset REM sleep, and cataplexy-like symptoms in rare genetic disorders (e.g., ADCA-DN, Coffin-Lowry syndrome, Moebius syndrome, Norie disease, Niemann-Pick disease type C, and Prader-Willi syndrome). Other indications in which orexin receptor agonists are suggested to benefit include attention deficit hyperactivity disorder, age-related cognitive impairment, metabolic syndrome and obesity, osteoporosis, heart failure, coma, and recovery from anesthesia.

[0006] This disclosure arises from the need to provide further compounds with improved therapeutic potential for modulation of orexin receptor activity in the brain (including activation of the orexin-2 receptor). In particular, compounds having improved physicochemical, pharmacological, and pharmaceutical properties compared to existing compounds are desired. [Overview of the project]

[0007] overview In some aspects, this disclosure provides compounds of formula (I''') or pharmaceutically acceptable salts thereof: TIFF0007840517000001.tif38128In formula, X is -C(R X1 )3, -OR X2or -N(R X2 )2; Y is -(C(R Y )2) m -, -O-(C(R Y )2) m -, -(C(R Y )2) m -O-, -N(R Y )-(C(R Y )2) m -, or -(C(R Y )2) m -N(R Y )-; Z is -O- or -NR Z -; Each R X1 is independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C3-C6 cycloalkyl, or 3-7 member heterocycloalkyl, or two Rs X1 together with the atom to which they are attached form C3-C7 cycloalkyl or 3-7 member heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, or three Rs X1 together with the atom to which they are attached form C4-C 10 cycloalkyl, where the cycloalkyl may be substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each RX2 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocycloalkyl, where alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocycloalkyl. Or, two R's X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl, where the heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R Y These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; Each R Z is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; Ar1 is C6-C 10 It is an aryl or 5-10 member heteroaryl, where the C6-C 10 The aryl or 5- to 10-membered heteroaryl may be substituted with one or more R3 groups; R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -N(C1-C6 alkyl)(C3-C 10 Cycloalkyl), -S(C1-C6 alkyl), -S(C6-C 10Aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 1S It may also be replaced with; Each R 1S These are independently oxo, halogen, -CN, -OH, -O-(CH2)2-OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; R2 is a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C6-C 10 Aaryl), -SO2(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It may also be replaced with; Each R 2S These are independently oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; Each R3 can be independently a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; R 4a This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; R 4b This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; n is 0, 1, 2, or 3; and m is 0, 1, 2, 3, 4, or 5.

[0008] In some aspects, the present disclosure provides compounds that can be obtained by, or are obtained by, methods for preparing such compounds as described herein (for example, methods comprising one or more steps described in Scheme 1).

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

[0010] In some aspects, this disclosure provides intermediates as described herein (for example, the intermediates are selected from the intermediates described in Examples 1 to 82) that are suitable for use in methods for preparing compounds as described herein.

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

[0012] In some aspects, the present disclosure provides a method for modulating orexin-2 receptor activity (e.g., in vitro or in vivo), comprising the step of contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0013] In some aspects, the Disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject where such treatment is needed, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically effective amount of a pharmaceutically effective composition of the pharmaceutically effective composition of the pharmaceutically effective.

[0014] In some aspects, the present disclosure provides a method for treating a disease or disorder disclosed herein in a subject where such treatment is needed, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically effective amount of a pharmaceutically effective composition of the present disclosure.

[0015] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in modulating orexin receptor activity (e.g., in vitro or in vivo).

[0016] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in modulating orexin-2 receptor activity (e.g., in vitro or in vivo).

[0017] In some aspects, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in treating or preventing diseases or disorders disclosed herein.

[0018] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in treating diseases or disorders disclosed herein.

[0019] In some aspects, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for modulating orexin receptor activity (e.g., in vitro or in vivo).

[0020] In some aspects, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for modulating orexin-2 receptor activity (e.g., in vitro or in vivo).

[0021] In some aspects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder disclosed herein.

[0022] In some aspects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of a disease or disorder disclosed herein.

[0023] In some aspects, this disclosure provides methods for preparing the compounds of this disclosure.

[0024] In some aspects, this disclosure provides a method for preparing a compound, comprising one or more steps described herein.

[0025] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs. In this specification, singular nouns include plural nouns unless the context explicitly indicates otherwise. Methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, but preferred methods and materials are listed below. All publications, patent applications, patents, and other references referenced herein are incorporated herein by reference. References cited herein are not considered prior art to the claimed invention. In case of any conflict, including definitions, this specification shall prevail. Furthermore, materials, methods, and examples are illustrative and not intended to limit the scope. In case of any conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0026] Other features and advantages of this disclosure will be apparent from the following detailed description and claims. [Modes for carrying out the invention]

[0027] Detailed explanation This disclosure relates to spiroheterocyclic derivatives, their prodrugs, and pharmaceutically acceptable salts that may modulate orexin-2 receptor activity and are therefore useful in methods of treating human or animal bodies. This disclosure also relates to processes for the preparation of these compounds, pharmaceutically acceptable compositions comprising them, and their use in the treatment of disorders associated with the orexin-2 receptor, such as neurodegenerative disorders, neuropathy, symptoms of rare genetic diseases, psychiatric disorders, mental health disorders, circadian rhythm disorders, metabolic syndrome, osteoporosis, heart failure, coma, or complications upon awakening from anesthesia.

[0028] definition Unless otherwise specified, the following terms used in this specification and in the claims have the meanings set forth below.

[0029] As used herein, “alkyl,” “C1, C2, C3, C4, C5 or C6 alkyl,” or “C1-C6 alkyl” is intended to include a linear saturated aliphatic hydrocarbon group of C1, C2, C3, C4, C5 or C6, and a branched saturated aliphatic hydrocarbon group of C3, C4, C5 or C6. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyls include moieties having 1 to 6 carbon atoms, such as, but are not limited to, methyl, ethyl, n-propyl, I-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, the linear or branched alkyl has 6 or fewer carbon atoms (e.g., C1-C6 in the linear case, C3-C6 in the branched case), and in other embodiments, the linear or branched alkyl has 4 or fewer carbon atoms.

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

[0031] As used herein, the term “alkenyl” includes unsaturated aliphatic groups that are similar in length and possible substitutions to the alkyls described above but contain at least one double bond. For example, the term “alkenyl” includes linear alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, linear or branched alkenyl groups have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

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

[0033] As used herein, the term "alkynyl" includes unsaturated aliphatic groups that are similar in length and possible substitutions to the alkyls described above but contain at least one triple bond. For example, "alkynyl" includes linear alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, noninyl, desynyl) and branched alkynyl groups. In certain embodiments, linear or branched alkynyl groups have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term "C2-C6" includes alkynyl groups containing two to six carbon atoms. The term "C3-C6" includes alkynyl groups containing three to six carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to contain a chain (linear or branched) of C2, C3, C4, C5, or C6 divalent unsaturated aliphatic hydrocarbon group. For example, C2-C6 alkenylene linker is intended to contain C2, C3, C4, C5, and C6 alkenylene linker groups.

[0034] As used herein, the term "optionally substituted alkynyl" means an unsubstituted alkynyl or an alkynyl having a specified substituent that replaces one or more hydrogen atoms on carbon atoms of one or more hydrocarbon skeletons. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0035] Other optionally substituted portions (e.g., optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both an unsubstituted portion and a portion having one or more of the specified substituents. For example, substituted heterocycloalkyls include those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0036] As used herein, the term "cycloalkyl" refers to a group of 3 to 30 carbon atoms (e.g., C3-C3-C3). 12 , C3-C 10This refers to saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused ring, bridging ring, or spirocycle) systems having C3-C8 rings. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyls, only one of the cycloalkyl rings must be non-aromatic.

[0037] As used herein, the term "heterocycloalkyl" means, unless otherwise specified, one or more heteroatoms (e.g., O, N, S, P, or Se) independently selected from the group consisting of nitrogen, oxygen, and sulfur, for example, one or one-two or one-three or one-four or one-five or one-six heteroatoms, or saturated or partially unsaturated 3- to 8-membered monocyclic, 7- to 12-membered bicyclic (fused, bridging, or spiro-ring) or 11- to 14-membered tricyclic ring systems (fused, bridging, or spiro-ring) having, for example, one, two, three, four, five, or six heteroatoms.Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, pyrrolidinyl, dioxanil, tetrahydrofuranil, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxyranil, azetidinyl, oxetanil, thietanil, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranil, dihydropyranil, pyranil, morpholinil, tetrahydrothiopyranil, 1,4-diazepanil, and 1,4-oxa Zepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]yl, 7'H-spiro[cyclohex San-1,5'-Flo[3,4-b]pyridine]-yl, 3'H-Spiro[cyclohexane-1,1'-Flo[3,4-c]pyridine]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexane-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 Examples include, but are not limited to, [3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxazaspiro[3.4]octanyl, 2-oxazaspiro[3.4]octan-6-yl, and 5,6-dihydro-4H-cyclopenta[b]thiophenyl. In the case of polycyclic heterocycloalkyls, only one of the heterocycloalkyl rings must be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0038] As used herein, the term “aryl” includes aromatic groups having one or more aromatic rings, including “conjugated” or polycyclic systems that do not contain any heteroatoms in their ring structure. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. Conveniently, aryl is phenyl.

[0039] As used herein, the term "heteroaryl" is intended to include stable 5, 6, or 7-membered monocyclic or 7, 8, 9, 10, 11, or 12-membered bicyclic aromatic heterocycles consisting of a carbon atom and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 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. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituent as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N → O and S(O) p (wherein p=1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocyclic ring does not exceed 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic rings to form polycyclic systems (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). In some embodiments, the heteroaryl is thiophenyl or benzothiophenyl. In some embodiments, the heteroaryl is thiophenyl. In some embodiments, the heteroaryl is benzothiophenyl.

[0040] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, such as tricyclic and bicyclic groups, including naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, and indoridine.

[0041] A cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may have substituents at one or more ring positions (e.g., ring-forming carbons or heteroatoms such as N) as described above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, The groups may be substituted with minocarbonyl, alkylthiocarbonyl, phosphat, 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, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. The aryl and heteroaryl groups may also be condensed or crosslinked with nonaromatic alicyclic or heterocyclic rings to form polycyclic systems (e.g., tetralin, methylenedioxyphenyl, e.g., benzo[d][1,3]dioxol-5-yl).

[0042] As used herein, the term “substituted” means that one or more hydrogen atoms on a designated atom are replaced with a group selected from the indicated groups, provided that the substitution does not exceed the normal valence of the designated atom and the result is a stable compound. If the substituent is oxo or keto (i.e., =O), two hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. A ring double bond, as used herein, is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). “Stable compound” and “stable structure” are intended to indicate a compound that is robust enough to withstand isolation from RM to a useful purity and formulation into an effective therapeutic agent.

[0043] If the bond to a substituent is shown to intersect a bond connecting two atoms in the ring, such substituent may be bonded to any atom in the ring. If such substituents are listed without indicating the atoms through which they bond to the remainder of the compound represented by a given formula, such substituents may be bonded via any atom in such formula. Combinations of substituents and / or variable parts are acceptable, but only if such combinations result in a stable compound.

[0044] If any component or variable (e.g., R) appears more than once in a compound's formula, its definition in each appearance is independent of its definition in all other appearances. Therefore, for example, if a group is shown to be substituted with 0 to 2 R moieties, that group may be substituted with up to 2 R moieties, and the R in each appearance is selected independently of the definition of R. Furthermore, combinations of substituents and / or variable moieties are acceptable, but only if such combinations result in a stable compound.

[0045] As used herein, the terms "hydroxy" or "hydroxyl" refer to -OH or -O - It contains a group having a group.

[0046] As used herein, the terms "halo" or "halogen" refer to fluoro, chloro, bromo, and iodine.

[0047] The terms "haloalkyl" or "haloalkoxyl" refer to alkyl or alkoxyl molecules that are substituted with one or more halogen atoms.

[0048] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl having specified substituents that replace one or more hydrogen atoms on carbon atoms of one or more hydrocarbon skeletons. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0049] As used herein, the terms “alkoxy” or “alkoxyl” include substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy group may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0050] Where used herein, expressions such as “one or more A, B, or C,” “one or more A, B, or C,” “one or more A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C,” and “selected from A, B, and C” are used interchangeably and all refer, unless otherwise indicated, to a selection from the group consisting of A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof.

[0051] It should be understood that this disclosure provides methods for synthesizing compounds represented by any of the formulas described herein. This disclosure also provides detailed methods for synthesizing various disclosed compounds of this disclosure, as well as the compounds shown in the examples, according to the scheme described below.

[0052] Throughout this description, when a composition is described as having, including, or comprising certain components, it should be understood that the composition is also intended to essentially consist of or comprise the listed components. Similarly, when a method or process is described as having, including, or comprising certain process steps, the process is also intended to essentially consist of or comprise the listed process steps. Furthermore, it should be understood that the order of steps or the order in which certain actions are performed is not important as long as the invention is operable. Moreover, two or more steps or actions can be performed simultaneously.

[0053] It should be understood that the synthesis process described herein is tolerant of a wide variety of functional groups and therefore can use a variety of substituted starting materials. The process generally provides the desired final compound at or near the end of the entire process, but in certain specific cases it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0054] It should be understood that the compounds of this disclosure can be prepared in various ways using commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art or evident to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules, as well as the transformation and manipulation of functional groups, can be obtained from relevant scientific literature or standard textbooks in the art. Not limited to any one or more of the sources of information, but incorporated herein by reference, is Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition, John Wiley & Sons: New York, 2001;Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd Older publications such as John Wiley & Sons, New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) are useful and well-known reference textbooks on organic synthesis that are common knowledge to those skilled in the art.

[0055] Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, may be altered during the reaction sequences and synthetic schemes described herein. Those skilled in the art will recognize that certain groups may need to be protected from reaction conditions using protecting groups. Protecting groups may also be used to distinguish similar functional groups in a molecule. A list of protecting groups and methods for introducing and removing these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3. rd This can be confirmed in the edition, John Wiley & Sons: New York, 1999.

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

[0057] Unless otherwise specified, any description of a treatment method should be understood to include the use of compounds to provide such treatment as described herein. Furthermore, unless otherwise specified, any description of a treatment method should be understood to include the use of compounds to prepare a medicament for treating such a condition. Treatment includes treatment of humans or non-human animals (including rodents and other disease models used herein).

[0058] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. Mammals may be, for example, humans or suitable non-human mammals, such as primates, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. The subject may also be a bird or poultry. In some embodiments, the subject is a human.

[0059] Where used herein, the term “subject in need” refers to both subjects having a disease and subjects at high risk of developing a disease. “Subject” includes mammals. Mammals may be, for example, humans or appropriate non-human mammals, such as primates, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. Subjects may also be birds or poultry. In one embodiment, mammal is human. Subject in need may be subjects who have previously been diagnosed or identified as having a disease or disorder disclosed herein. Subjects in need may also be subjects suffering from a disease or disorder disclosed herein. Alternatively, subjects in need may be subjects at higher risk of developing such a disease or disorder compared to the general population (i.e., subjects more likely to develop such a disorder compared to the general population). Subjects in need may have refractory or resistant diseases or disorders disclosed herein (i.e., diseases or disorders disclosed herein that do not respond to or have not yet responded to treatment). The subjects may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, the subjects requiring this treatment are those who have received all known effective treatments for the disease or disorder disclosed herein and have been unsuccessful. In some embodiments, the subjects requiring this treatment are those who have received at least one prior treatment.

[0060] As used herein, the terms “treating” or “treat” refer to the management and care of a patient aimed at combating a disease, condition, or disorder, and include administering the compounds of this disclosure, or their pharmaceutically acceptable salts, polymorphs, or solvates, to alleviate the symptoms or complications of a disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term “treat” may also include the treatment of in vitro cell or animal models. References to “treating” or “treatment” should be understood to include the alleviation of established symptoms of a condition. Therefore, “treating” or “treatment” of a condition, disorder or pathology includes (1) preventing the onset of clinical symptoms of a condition, disorder or pathology in a person who has or is susceptible to the condition but has not yet experienced or exhibited any clinical or subclinical symptoms of the condition, disorder or pathology; (2) suppressing the condition, disorder or pathology, i.e., preventing, reducing or delaying the onset or recurrence of the disease (in the case of maintenance therapy) or at least one clinical or subclinical symptom of the disease; or (3) alleviating or reducing the disease, i.e., causing regression of at least one clinical or subclinical symptom of the condition, disorder or pathology or its clinical or subclinical symptom.

[0061] It should be understood that the compounds of this disclosure, or any pharmaceutically acceptable salts, polymorphs, or solvates thereof, may be used or used to prevent related diseases, conditions, or disorders, or may be used or used to identify suitable candidates for such purposes.

[0062] As used herein, the terms “preventing,” “prevent,” or “protecting against” describe reducing or eliminating the occurrence of symptoms or complications of such disease, condition, or disorder.

[0063] Those skilled in the art should understand that they may refer to general reference books for a detailed description of the known or equivalent technologies discussed herein. These reference books include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3 rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000);Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY;Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY;Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 th This includes the 1990 edition. These reference materials can, of course, be consulted when creating or using the aspects of this disclosure.

[0064] It should be understood that this disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0065] As used herein, the term “pharmaceutical composition” refers to a formulation containing the compound of this disclosure in a form suitable for administration to a target. In one embodiment, the pharmaceutical composition is in bulk form or unit dosage form. A unit dosage form is any of various forms, including, for example, capsules, IV bags, tablets, single pumps or vials in aerosol inhalers. The amount of the active ingredient (e.g., formulations of the disclosed compound or its salts, hydrates, solvates or isomers) in a unit dose of the composition is an effective amount and will vary according to the specific treatment concerned. Those skilled in the art will understand that it may sometimes be necessary to make routine adjustments to the dosage depending on the patient’s age and condition. The dosage will also depend on the route of administration. Various routes are envisioned, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrathoracic, intrathecal, and intranasal. Dosage forms for topical or transdermal administration of the compounds of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives, buffers, or propellants.

[0066] As used herein, the term “pharmaceutically acceptable” means a compound, anion, cation, substance, composition, carrier, and / or dosage form that is suitable for use in contact with human and animal tissues, within reasonable medical judgment, in proportion to a reasonable benefit-risk ratio, without excessive toxicity, irritation, allergic reactions, or other problems or complications.

[0067] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable, and is useful in preparing a pharmaceutical composition, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used herein and in the claims, “pharmaceutically acceptable excipient” includes both one or more such excipients.

[0068] It should be understood that the pharmaceutical compositions of this disclosure are formulated to suit their intended route of administration. Examples of routes of administration include parenteral administration, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Liquids or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: sterile diluents, e.g., water for injection, saline, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents, e.g., benzyl alcohol or methylparaben; antioxidants, e.g., ascorbic acid or sodium bisulfite; chelating agents, e.g., ethylenediaminetetraacetic acid; buffers, e.g., acetate, citrate, or phosphate; and tonic adjusters, e.g., sodium chloride or dextrose. pH can be adjusted with an acid or base, e.g., hydrochloric acid or sodium hydroxide. Parenteral preparations may be sealed in ampoules made of glass or plastic, disposable syringes, or multi-dose vials.

[0069] It should be understood that the compounds or pharmaceutical compositions of this disclosure can be administered to subjects by many of the well-known methods currently used for chemotherapeutic treatment. For example, the compounds of this disclosure may be injected into the bloodstream or body cavities, taken orally, or applied through the skin by transdermal patches. The selected dose should be sufficient to constitute an effective treatment, but should not be so high as to cause unacceptable side effects. The state of the disease (e.g., the disease or disorder disclosed herein) and the patient's health should preferably be carefully monitored for a reasonable period during and after treatment.

[0070] As used herein, the term “therapeutic dose” refers to the amount of a pharmaceutically active substance necessary to treat, improve or prevent a specific disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay known in the art. The exact effective dose for a subject will depend on the subject’s weight, size, and health status; the nature and severity of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. A therapeutic dose for a given situation can be determined by routine experimentation within the scope of the clinician’s skill and judgment.

[0071] As used herein, the term “therapeutic dose” refers to the amount of a pharmaceutically active substance required to treat or improve a specific disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay known in the art. The exact effective dose for a subject will depend on the subject’s weight, size, and health status; the nature and severity of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. A therapeutic dose for a given situation can be determined by routine experimentation within the scope of the clinician’s skill and judgment.

[0072] It should be understood that for any compound, the therapeutically effective dose can first be estimated, for example, in a cell culture assay of tumor cells, or in an animal model, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Then, using such information, useful doses and routes for administration to humans can be determined. Therapeutic / prophylactic efficacy and toxicity, e.g., ED 50 (A therapeutically effective dose for 50% of the population) and LD 50 The dose (lethal to 50% of the population) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose-to-toxicity ratio is the therapeutic index, which is the LD ratio. 50 / ED 50It can be expressed as follows. Pharmaceutical compositions exhibiting a large therapeutic index are preferred. The dosage may vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0073] Dosage and administration are adjusted to provide a sufficient level of active substance or to maintain the desired effect. Factors to consider include the severity of the condition, the subject's overall health, age, weight and sex, dietary habits, timing and frequency of administration, combination drugs, sensitivity to response, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered every 3-4 days, weekly, or every 2 weeks, depending on the half-life and clearance rate of the particular formulation.

[0074] Pharmaceutical compositions containing the active compounds of this disclosure may be produced in a generally known manner, for example, by conventional mixing, dissolution, granulation, sugar-coated tablet production, levigating, emulsification, encapsulation, encapsulation, or lyophilization processes. The pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers containing excipients and / or adjuvants that facilitate the processing of the active compounds into pharmaceutically usable preparations. Naturally, appropriate formulation depends on the chosen route of administration.

[0075] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (if water-soluble) or dispersants, and sterile powders for the immediate preparation of sterile injection solutions or dispersants. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid enough to be easily injected. It must be stable under manufacturing and storage conditions and protected from contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol) and suitable mixtures thereof. Adequate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersants, and by the use of surfactants. Inhibition of microbial activity can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, such as sugars, polyalcohols like mannitol and sorbitol, and sodium chloride in the composition. Extending the absorption of the injectable composition can be achieved by including absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0076] Sterile injectable solutions can be prepared by incorporating the required amount of the active compound into a suitable solvent, along with one or a combination of the components listed above as needed, followed by sterilization by filtration. Generally, dispersants are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and other components required from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation method is vacuum drying and freeze-drying, which yield a powder of the active component from a pre-sterilized filtered solution with any additional desired components added.

[0077] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable food-grade carrier. These can be encapsulated in gelatin capsules or compressed into tablets. For therapeutic oral administration, the active compound can be incorporated with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions may also be prepared using a liquid carrier for use as an oral rinse, where the compound in the liquid carrier is applied orally, swished in the mouth, and then coughed up or swallowed. Pharmaceutically compatible binders and / or adjuvants may be included as part of the composition. These tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar properties: binders, e.g., microcrystalline cellulose, tragacanth gum, or gelatin; excipients, e.g., starch, or lactose; disintegrants, e.g., alginic acid, Primogel, or corn starch; lubricants, e.g., magnesium stearate or Sterotes; flow enhancers, e.g., colloidal silicon dioxide; sweeteners, e.g., sucrose, or saccharin; or flavoring agents, e.g., peppermint, methyl salicylate, or orange flavoring.

[0078] For administration by inhalation, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser, or atomizer, containing a suitable propellant, such as a gas like carbon dioxide.

[0079] Systemic administration may be carried out by transmucosal or transdermal means. In transmucosal or transdermal administration, a penetrating agent suitable for the barrier to be penetrated is used in the formulation. Such penetrating agents are generally known in the art and, for example, in transmucosal administration, include surfactants, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved by the use of nasal sprays or suppositories. In transdermal administration, the active compound is formulated into ointments, plasters, gels, or creams, as are generally known in the art.

[0080] The active compound can be prepared with a pharmaceutically acceptable carrier that protects the compound from rapid removal from the body, such as a controlled-release formulation including implants and microencapsulation delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Methods for preparing such formulations will be apparent to those skilled in the art. The materials can also be commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (containing liposomes that target infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0081] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions in dose unit form. When used herein, a dose unit form refers to a physically separated unit suitable as a single dose for the target being treated; each unit contains a predetermined amount of the active compound calculated to produce the desired therapeutic effect in conjunction with the required pharmaceutical carrier. The specifications of the dose unit forms in this disclosure are determined by and rely directly on the inherent characteristics of the active compound and the specific therapeutic effect to be achieved.

[0082] In therapeutic applications, the dosage of a pharmaceutical composition used in accordance with this disclosure will vary depending on factors influencing the selected dosage, particularly the drug, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the treatment. Generally, the dose should be sufficient to result in a reduction, preferably regression, of the symptoms of the disease or disorder disclosed herein, and preferably to cause complete regression of the disease or disorder. The dosage may range from about 0.01 mg / kg / day to about 5000 mg / kg / day. The effective amount of the pharmaceutically active substance is the amount that produces an objectively identifiable improvement that is noticeable to a clinician or other authorized observer. Improvement in survival and growth indicates regression. As used herein, the term “dosage effective manner” refers to the amount of the active compound necessary to produce the desired biological effect in a subject or cell.

[0083] It should be understood that pharmaceutical compositions may be included in containers, packs, or dispensers along with instructions for administration.

[0084] It should be understood that the compounds of this disclosure may further form salts, and all of these forms are also assumed to be within the scope of the claimed disclosure.

[0085] As used herein, the term “pharmaceutically acceptable salt” refers to a derivative of a compound of the disclosed wherein the parent compound is modified by producing an acidic or basic salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic salts of basic residues such as amines or alkalis, or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolyarsanilic acid, hexylresorcinol, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactoic acid Examples include, but are not limited to, salts derived from inorganic and organic acids selected from commonly occurring amine acids, such as glycine, alanine, phenylalanine, arginine, etc.

[0086] In some embodiments, pharmaceutically acceptable salts are sodium salts, potassium salts, calcium salts, magnesium salts, diethylamine salts, choline salts, meglumine salts, benzathine salts, trometamic acid salts, ammonia salts, arginine salts, or lysine salts.

[0087] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvate, 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]-octa-2-en-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, and muconic acid. The disclosure also includes salts formed when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or when it coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, or N-methylglucamine. In salt form, it is understood that the ratio of the compound to the salt's cation or anion can be 1:1, or any other ratio, such as 3:1, 2:1, 1:2, or 1:3.

[0088] It should be understood that all references to pharmaceutically acceptable salts include the same salt in either a solubilated form (solvate) or a crystalline form (polymorph) as defined herein.

[0089] The compound or a pharmaceutically acceptable salt thereof may be administered orally, nasally, percutaneously, pulmonaryly, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrathoracically, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0090] A drug regimen utilizing the aforementioned compound is selected according to various factors, including the patient's type, breed, age, weight, sex, and medical condition; the severity of the condition to be treated; the route of administration; the patient's renal and hepatic function; and the specific compound or salt thereof to be employed. A physician or veterinarian with ordinary skills can easily determine and prescribe the effective dose of the drug required to prevent, counteract, or halt the progression of a disease. A physician or veterinarian with ordinary skills can easily determine and prescribe the effective dose of the drug required to counteract or halt the progression of a disease.

[0091] The techniques for formulation and administration of the disclosed compounds in this disclosure are described in Remington: the Science and Practice of Pharmacy, 19 th This can be confirmed in edition, Mack Publishing Co., Easton, PA (1995). In some embodiments, the compounds described herein and their pharmaceutically acceptable salts are used in combination with pharmaceutically acceptable carriers or diluents in pharmaceutical preparations. Suitable pharmaceutically acceptable carriers include inert solid extenders or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dose within the range described herein.

[0092] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of this disclosure are evident from various examples. The examples provided illustrate various components and methodologies useful in carrying out this disclosure. The examples are not intended to limit the claimed disclosure. Based on this disclosure, those skilled in the art can identify and adopt other components and methodologies useful in carrying out this disclosure.

[0093] In the synthetic schemes described herein, compounds may be described in a specific stereoconfiguration for simplification. Such a specific stereoconfiguration should not be interpreted as limiting this disclosure to any isomer, tautomer, regioisomer, or stereoisomer, nor should it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer, or stereoisomer.

[0094] All publications and patent documents referenced herein are incorporated herein by reference in the same manner as each such publication or document is specifically and individually indicated as being incorporated herein by reference. No reference to any publication or patent document is intended to constitute an acknowledgment of appropriate prior art, nor does it constitute any acknowledgment of its content or date. As the present invention has been described in writing, those skilled in the art will recognize that the invention can be carried out in various embodiments, and that the foregoing description and the following examples are illustrative and not intended to limit the scope of the following claims.

[0095] As used herein, the phrase "compounds of the disclosure" refers to the compounds disclosed herein both generally and specifically.

[0096] Compounds of the Disclosure In some aspects, this disclosure provides compounds of formula (I''') or pharmaceutically acceptable salts thereof: TIFF0007840517000002.tif38128In formula, X is -C(R X1 )3, -OR X2 , or -N(R X2 )2; Y is -(C(R Y )2) m -, -O-(C(R Y )2)m -,-(C(R Y )2) m -O-, -N(R Y )-(C(R Y )2) m -, or -(C(R Y )2) m -N(R Y )-and; Z is -O- or -NR Z -and; Each R X1 These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C3-C6 cycloalkyl, or 3-7 member heterocycloalkyl. Or, two R's X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl or a 3-7 membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy. Or, the three R's X1 These, together with the atoms to which they are bonded, form a C4-C 10 A cycloalkyl group is formed, where the cycloalkyl group may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy groups; Each R X2is, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-member heterocycloalkyl, where the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-member heterocycloalkyl; or, two Rs X2 together with the atom to which they are attached form a 3- to 7-member heterocycloalkyl, where the heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy; each R Y is, independently, H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 1-C6 alkoxy; each R Z is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; Ar1 is C6-C 10 aryl or 5- to 10-member heteroaryl, where the C6-C 10 ​​​​​​​10 Aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5- to 10-membered heteroaryl), -O-(C3-C 10 cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5- to 10-membered heteroaryl), -NH-(C3-C 10 cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl may be substituted with one or more R 1S ; Each R 1S is independently oxo, halogen, -CN, -OH, -O-(CH2)2-OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; R2 is halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C6-C 10 aryl), -SO2(C6-C 10 aryl), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, -O-(C$6-C 10 aryl), -O-(5- to 10-membered heteroaryl), -O-(C3-C 10 cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5- to 10-membered heteroaryl), -NH-(C3-C 10A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It may also be replaced with; Each R 2S These are independently oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; Each R3 can be independently a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; R 4a This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; R 4b This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; n is 0, 1, 2, or 3; and m is 0, 1, 2, 3, 4, or 5.

[0097] In some aspects, this disclosure provides compounds of formula (I'') or pharmaceutically acceptable salts thereof: TIFF0007840517000003.tif38128In formula, X is -C(R X1 )3, -ORX2 , or -N(R X2 )2; Y is -(C(R Y )2) m -, -O-(C(R Y )2) m -,-(C(R Y )2) m -O-, -N(R Y )-(C(R Y )2) m -, or -(C(R Y )2) m -N(R Y )-and; Z is -O- or -NR Z -and; Each R X1 These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, or C3-C6 cycloalkyl. Or, two R's X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl or a 3-7 membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy. Or, the three R's X1 These, together with the atoms to which they are bonded, form a C4-C 10 A cycloalkyl group is formed, where the cycloalkyl group may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy groups; Each R X2These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocycloalkyl, where alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocycloalkyl. Or, two R's X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl, where the heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R Y These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; Each R Z is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; Ar1 is C6-C 10 It is an aryl or 5-10 member heteroaryl, where the C6-C 10 The aryl or 5- to 10-membered heteroaryl may be substituted with one or more R3 groups; R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -N(C1-C6 alkyl)(C3-C 10 Cycloalkyl), -S(C1-C6 alkyl), -S(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 1S It may also be replaced with; Each R 1S These are independently oxo, halogen, -CN, -OH, -O-(CH2)2-OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; R2 is a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C6-C 10 Aaryl), -SO2(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It may also be replaced with; Each R 2S These are independently oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; Each R3 can be independently a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; R 4a This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; R 4b This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; n is 0, 1, 2, or 3; and m is 0, 1, 2, 3, 4, or 5.

[0098] In some aspects, this disclosure provides compounds of formula (I') or pharmaceutically acceptable salts thereof: TIFF0007840517000004.tif38128In formula, X is -C(R X1 )3, -ORX2 , or -N(R X2 )2; Y is -(C(R Y )2) m -, -O-(C(R Y )2) m -,-(C(R Y )2) m -O-, -N(R Y )-(C(R Y )2) m -, or -(C(R Y )2) m -N(R Y )-and; Z is -O- or -NR Z -and; Each R X1 These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, or two R X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R X2 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or two R X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl, where the heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each RY These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; Each R Z is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; Ar1 is C6-C 10 It is an aryl or 5-10 member heteroaryl, where the C6-C 10 The aryl or 5- to 10-membered heteroaryl may be substituted with one or more R3 groups; R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -S(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 1S It may also be replaced with; Each R 1SThese are independently oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; R2 is a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C6-C 10 Aaryl), -SO2(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It may also be replaced with; Each R 2S These are independently oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; Each R3 can be independently a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; R 4a This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; R 4b This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; n is 0, 1, 2, or 3; and m is 0, 1, 2, 3, 4, or 5.

[0099] In some aspects, this disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof: TIFF0007840517000005.tif46128In formula, X is -C(R X1 )3, -OR X2 , or -N(R X2 )2; Y is -(C(R Y )2) m -, -O-(C(R Y )2) m -,-(C(R Y )2) m -O-, -N(R Y )-(C(R Y )2) m -, or -(C(R Y )2) m -N(R Y )-and; Z is -O- or -NR Z -and; Each RX1 These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, or two R X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R X2 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or two R X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl, where the heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R Y These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; Each R Z is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -S(C6-C 10Aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 1S It may also be replaced with; Each R 1S These are independently oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; R2 is a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C6-C 10 Aaryl), -SO2(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It may also be replaced with; Each R 2S These are independently oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; Each R3 can be independently a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; R 4a This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; R 4b This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; n is 0, 1, 2, or 3; m is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, or 4.

[0100] In some aspects, this disclosure provides compounds of formula (II) or pharmaceutically acceptable salts thereof: TIFF0007840517000006.tif42128In formula, X is -C(R X1 )3, -OR X2 , or -N(R X2 )2; Y is -(C(R Y )2) m -, -O-(C(R Y )2) m -,-(C(R Y )2) m -O-, -N(R Y )-(C(R Y )2) m -, or -(C(R Y )2) m -N(R Y )-and; Z is -O- or -NR Z -and; Each R X1 These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, or two R X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R X2 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or two R X2These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl, where the heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R Y These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; Each R Z is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -S(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 1S It may also be replaced with; Each R 1SThese are independently oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; R2 is a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C6-C 10 Aaryl), -SO2(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It may also be replaced with; Each R 2S These are independently oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; Each R3 can be independently a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; R 4a This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; R 4b This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; n is 0, 1, 2, or 3; m is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3.

[0101] In some aspects, this disclosure provides compounds of formula (III) or pharmaceutically acceptable salts thereof: TIFF0007840517000007.tif41128In formula, X is -C(R X1 )3, -OR X2 , or -N(R X2 )2; Y is -(C(R Y )2) m -, -O-(C(R Y )2) m -,-(C(R Y )2) m -O-, -N(R Y )-(C(R Y )2) m -, or -(C(R Y )2) m -N(R Y )-and; Z is -O- or -NRZ -and; Each R X1 These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, or two R X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R X2 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or two R X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl, where the heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy; Each R Y These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; Each R Z is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -S(C6-C 10Aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 1S It may also be replaced with; Each R 1S These are independently oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; R2 is a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C6-C 10 Aaryl), -SO2(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It may also be replaced with; Each R 2S These are independently oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; Each R3 can be independently a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; R 4a This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; R 4b This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy; n is 0, 1, 2, or 3; m is 0, 1, 2, 3, 4, or 5; and p is either 0 or 1.

[0102] In some contexts, this disclosure is relevant. Z, -NR Z -and; and R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or a -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group comprises one or more R groups. 1S It may be replaced with The compound of formula (I') or a pharmaceutically acceptable salt thereof is provided.

[0103] In some contexts, this disclosure is relevant. Z, -NR Z -and; and R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 member heteroaryl, C3-C7 cycloalkyl, 3-7 member heterocycloalkyl, -NH-(C3-C 10 A cycloalkyl group, or a -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group comprises one or more R groups. 1S It may be replaced with; and Each R 1S However, they are independently halogens, -CN, -OH, or C1-C6 alkoxys. The compound of formula (I') or a pharmaceutically acceptable salt thereof is provided.

[0104] In some contexts, this disclosure is relevant. Z is -NH- and R1 is a C1-C6 alkyl group. The compound of formula (I') or a pharmaceutically acceptable salt thereof is provided.

[0105] In some contexts, this disclosure is relevant. Z, -NR Z -and; and R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or a -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group comprises one or more R groups. 1S It may be replaced with The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0106] In some contexts, this disclosure is relevant. Z, -NR Z -and; and R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 member heteroaryl, C3-C7 cycloalkyl, 3-7 member heterocycloalkyl, -NH-(C3-C 10A cycloalkyl group, or a -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group comprises one or more R groups. 1S It may be replaced with; and Each R 1S However, they are independently halogens, -CN, -OH, or C1-C6 alkoxys. The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0107] In some contexts, this disclosure is relevant. Z is -NH- and R1 is a C1-C6 alkyl group. The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0108] In some contexts, this disclosure is relevant. Z, -NR Z -and; and R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or a -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group comprises one or more R groups. 1S It may be replaced with The present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0109] In some contexts, this disclosure is relevant. Z, -NR Z -and; and R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 member heteroaryl, C3-C7 cycloalkyl, 3-7 member heterocycloalkyl, -NH-(C3-C 10 A cycloalkyl group, or a -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group comprises one or more R groups. 1S It may be replaced with; and Each R 1S However, they are independently halogens, -CN, -OH, or C1-C6 alkoxys. The present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0110] In some contexts, this disclosure is relevant. Z is -NH- and R1 is a C1-C6 alkyl group. The present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0111] In some contexts, this disclosure is relevant. Z, -NR Z -and; and R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or a -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group comprises one or more R groups. 1S It may be replaced with The present invention provides a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0112] In some contexts, this disclosure is relevant. Z, -NR Z -and; and R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 member heteroaryl, C3-C7 cycloalkyl, 3-7 member heterocycloalkyl, -NH-(C3-C 10 A cycloalkyl group, or a -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group comprises one or more R groups. 1S It may be replaced with; and Each R 1S However, they are independently halogens, -CN, -OH, or C1-C6 alkoxys. The present invention provides a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0113] In some contexts, this disclosure is relevant. Z is -NH- and R1 is a C1-C6 alkyl group. The present invention provides a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0114] For compounds of formula (I''), (I'), (I), (II), or (III), X, Y, Z, R X1 , R X2 , R Y , R Z Ar1, R 1、 R 1S, R 2、 R 2S , R3, R 4a , R 4b n, m, or p may, where applicable, be selected from the groups described herein, and X, Y, Z, R X1 , R X2 , R Y , R Z Ar1, R 1、 R 1S , R 2、 R 2S , R3, R 4a , R 4b Any group described herein for any of n, m, or p, where applicable, is X, Y, Z, R X1 , R X2 , R Y , R Z Ar1, R 1、 R 1S , R 2、 R 2S , R3, R 4a , R 4b It is understood that these can be combined with any of the groups described herein for the remaining one or more of n, m, or p.

[0115] In some embodiments, X is -C(R X1 )3, -OR X2 , or -N(R X2 )2.

[0116] In some aspects, X is -OR X2 or -N(R X2 )2.

[0117] In some embodiments, X is -C(R X1 )3. In some embodiments, X is -OR X2 In some embodiments, X is -N(R X2 )2.

[0118] In some embodiments, X is The filename is TIFF0007840517000008.tif107160.

[0119] In some embodiments, X is The filename is TIFF0007840517000009.tif17128.

[0120] In some embodiments, X is -O (methyl).

[0121] In some embodiments, X is The filename is TIFF0007840517000010.tif18128.

[0122] In some embodiments, X is The filename is TIFF0007840517000011.tif16128.

[0123] In some embodiments, X is The filename is TIFF0007840517000012.tif19128.

[0124] In some embodiments, X is The filename is TIFF0007840517000013.tif18128.

[0125] In some embodiments, X is The filename is TIFF0007840517000014.tif15128.

[0126] In some embodiments, X is The filename is TIFF0007840517000015.tif22128.

[0127] In some embodiments, X is The filename is TIFF0007840517000016.tif24128.

[0128] In some embodiments, X is The filename is TIFF0007840517000017.tif15128.

[0129] In some embodiments, Y is -(C(R Y)2) m -, -O-(C(R Y )2) m -,-(C(R Y )2) m -O-, -N(R Y )-(C(R Y )2) m -, or -(C(R Y )2) m -N(R Y )-is.

[0130] In some embodiments, Y is -O-(C(R Y )2) m -,-(C(R Y )2) m -O-, -N(R Y )-(C(R Y )2) m -, or -(C(R Y )2) m -N(R Y )-is.

[0131] In some embodiments, Y is -(C(R Y )2) m - is

[0132] In some embodiments, Y is -O-(C(R Y )2) m -or-(C(R Y )2) m It is -O-.

[0133] In some embodiments, Y is -O-(C(R Y )2) m -. In some embodiments, Y is -(C(R Y )2) m It is -O-.

[0134] In some embodiments, Y is -N(R Y )-(C(R Y )2) m -or-(C(R Y )2) m -N(R Y )-is.

[0135] In some embodiments, Y is -N(R Y )-(C(R Y )2) m -. In some embodiments, Y is -(C(R Y )2) m -N(R Y )-is.

[0136] In some embodiments, Y is -CH2-, -CF2-, -CH2-O-, -O-CH2-, -CH2-NH-, -NH-CH2-, -CH2-N(CH2CF3)-, or -N(CH2-CF3)-CH2-.

[0137] In some embodiments, Y is -CH2--.

[0138] In some embodiments, Y is -CH2-O- or -O-CH2.

[0139] In some embodiments, Y is -CH2-NH-, -NH-CH2-, -CH2-N(CH2CF3)-, or -N(CH2-CF3)-CH2-.

[0140] In some embodiments, Y is -CH2-NH- or -NH-CH2-.

[0141] In some embodiments, Y is -CH2-N(CH2CF3)- or -N(CH2-CF3)-CH2-.

[0142] In some embodiments, Z is -O- or -NR Z - is

[0143] In some embodiments, Z is -O-. In some embodiments, Z is -NR Z - is

[0144] In some embodiments, Z is -NH-.

[0145] In some embodiments, each RX1 These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C3-C7 cycloalkyl, or 3-7 membered heterocycloalkyl. Or, two R's X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl or a 3-7 membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy. The three Rs X1 These, together with the atoms to which they are bonded, form a C4-C 10 A cycloalkyl group is formed, where the cycloalkyl group may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy groups.

[0146] In some embodiments, each R X1 These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, or C3-C7 cycloalkyl. Or, two R's X1These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl or a 3-7 membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy. The three Rs X1 These, together with the atoms to which they are bonded, form a C4-C 10 A cycloalkyl group is formed, where the cycloalkyl group may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy groups.

[0147] In some embodiments, each R X1 These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C7 cycloalkyl. Or, two R's X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl or a 3-7 membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy. The three Rs X1 These, together with the atoms to which they are bonded, form a C4-C 10A cycloalkyl group is formed, where the cycloalkyl group may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy groups.

[0148] In some embodiments, each R X1 These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C7 cycloalkyl. Or, two R's X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0149] In some embodiments, each R X1 These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy. Or, two R's X1These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0150] In some embodiments, each R X1 These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl.

[0151] In some embodiments, each R X1 These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C7 cycloalkyl.

[0152] In some embodiments, each R X1 These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0153] In some embodiments, each R X1 These are H independently.

[0154] In some embodiments, each R X1These are independently halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0155] In some embodiments, each R X1 These are independently halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0156] In some embodiments, each R X1 These are, independently, halogens.

[0157] In some embodiments, each R X1 These are independently F, Cl, Br, or I. In some embodiments, each R X1 R is independently F, Cl, or Br. In some embodiments, each R X1 These are independently F or Cl.

[0158] In some embodiments, each R X1 Independently, F. In some embodiments, each R X1 Independently, each R is Cl. In some embodiments, each R X1 Independently, each R is Br. In some embodiments, each R X1 These are independently I.

[0159] In some embodiments, each R X1 It is independently -CN.

[0160] In some embodiments, each R X1 These are independently -OH.

[0161] In some embodiments, each R X1 These are independently -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0162] In some embodiments, each R X1These are independently -NH2.

[0163] In some embodiments, each R X1 These are independently -NH(C1-C6 alkyl).

[0164] In some embodiments, each R X1 Independently, each R is -NH (methyl). In some embodiments, each R X1 R is independently -NH(ethyl). In some embodiments, each R X1 Independently, each R is -NH(propyl). In some embodiments, each R X1 Independently, each R is -NH (butyl). In some embodiments, each R X1 Independently, each R is -NH (pentyl). In some embodiments, each R X1 It is independently -NH (hexyl).

[0165] In some embodiments, each R X1 These are independently -N(C1-C6 alkyl)2.

[0166] In some embodiments, each R X1 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0167] In some embodiments, each R X1 These are independently C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0168] In some embodiments, each R X1 These are independently C1-C6 alkyl groups.

[0169] In some embodiments, each R X1 R is independently methyl. In some embodiments, each R X1 is independently ethyl. In some embodiments, each R X1 R is independently propyl. In some embodiments, each R X1is independently butyl. In some embodiments, each R X1 In some embodiments, each R is independently pentill. X1 In some embodiments, each R is independently hexyl. X1 is independently isopropyl. In some embodiments, each R X1 is independently isobutyl. In some embodiments, each R X1 is independently isopentyl. In some embodiments, each R X1 is independently isohexyl. In some embodiments, each R X1 In some embodiments, each R is independently sec-butyl. X1 Independently, each R is secpentyl. In some embodiments, each R X1 Independently, each R is sec hexyl. In some embodiments, each R X1 It is independently tert-butyl.

[0170] In some embodiments, each R X1 These are independently C2-C6 alkenyls.

[0171] In some embodiments, each R X1 These are independently C2 alkenyls. In some embodiments, each R X1 Independently, each R is a C3 alkenyl. In some embodiments, each R X1 Independently, each R is a C4 alkenyl. In some embodiments, each R X1 Independently, each R is a C5 alkenyl. In some embodiments, each R X1 It is independently a C6 alkenyl.

[0172] In some embodiments, each R X1 These are independently C2-C6 alkynyl compounds.

[0173] In some embodiments, each R X1 These are independently C2 alkynyls. In some embodiments, each R X1 Independently, each R is a C3 alkynyl. In some embodiments, each R X1Independently, each R is a C4 alkynyl. In some embodiments, each R X1 Independently, each R is a C5 alkynyl. In some embodiments, each R X1 It is independently a C6 alkynyl.

[0174] In some embodiments, each R X1 These are independently C1-C6 haloalkyl or C1-C6 alkoxy.

[0175] In some embodiments, each R X1 These are independently C1-C6 haloalkyl groups.

[0176] In some embodiments, each R X1 In some embodiments, each R is independently a halomethyl compound. X1 Independently, each R is a haloethyl compound. In some embodiments, each R X1 Independently, each R is a halopropyl. In some embodiments, each R X1 Independently, each R is a halobutyl. In some embodiments, each R X1 Independently, each R is halopentyl. In some embodiments, each R X1 It is independently a halohexyl.

[0177] In some embodiments, each R X1 These are independently C1-C6 alkoxy compounds.

[0178] In some embodiments, each R X1 In some embodiments, each R is methoxy. X1 Independently, each R is ethoxy. In some embodiments, each R X1 In some embodiments, each R is a propoxy. X1 Independently, each R is butoxy. In some embodiments, each R X1 In some embodiments, each R is independently pentoxy. X1 It is independently hexoxy.

[0179] In some embodiments, each R X1These are independently C1-C6 alkyl-C1-C6 alkoxy compounds.

[0180] In some embodiments, each R X1 These are independently C1 alkyl-C1-C6 alkoxy. In some embodiments, each R X1 These are independently C2 alkyl-C1-C6 alkoxy. In some embodiments, each R X1 These are independently C3 alkyl-C1-C6 alkoxy. In some embodiments, each R X1 These are independently C4 alkyl-C1-C6 alkoxy. In some embodiments, each R X1 These are independently C5 alkyl-C1-C6 alkoxy. In some embodiments, each R X1 These are independently C6 alkyl-C1-C6 alkoxy compounds.

[0181] In some embodiments, each R X1 These are independently C1-C6 alkyl-C1 alkoxy. In some embodiments, each R X1 These are independently C1-C6 alkyl-C2 alkoxy. In some embodiments, each R X1 These are independently C1-C6 alkyl-C3 alkoxy. In some embodiments, each R X1 These are independently C1-C6 alkyl-C4 alkoxy. In some embodiments, each R X1 These are independently C1-C6 alkyl-C5 alkoxy. In some embodiments, each R X1 These are independently C1-C6 alkyl-C6 alkoxy compounds.

[0182] In some embodiments, each R X1 These are independently C3-C6 cycloalkyl groups.

[0183] In some embodiments, each R X1 Each R is independently a C3 cycloalkyl. In some embodiments, each R X1 Each R is independently a C4 cycloalkyl. In some embodiments, each R X1 Each R is independently a C5 cycloalkyl. In some embodiments, each RX1 These are independently C6 cycloalkyl groups.

[0184] In some embodiments, each R X1 These are independently 3- to 7-membered heterocycloalkyl groups.

[0185] In some embodiments, each R X1 Each R is independently a 3-membered heterocycloalkyl. In some embodiments, each R X1 Each R is independently a 4-membered heterocycloalkyl. In some embodiments, each R X1 Each R is independently a 5-membered heterocycloalkyl. In some embodiments, each R X1 Each R is independently a 6-membered heterocycloalkyl. In some embodiments, each R X1 These are independently 7-membered heterocycloalkyl groups.

[0186] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0187] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0188] In some embodiments, two RX1 These atoms, together with the atoms to which they are bonded, form C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl groups.

[0189] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl group.

[0190] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl which may be substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0191] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0192] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C3-C7 cycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0193] In some embodiments, two R X1 These atoms, together with the atoms to which they are bonded, form a C3 cycloalkyl group.

[0194] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C3 cycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0195] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C3 cycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0196] In some embodiments, two R X1 These atoms, together with the atoms to which they are bonded, form a C4 cycloalkyl group.

[0197] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C4 cycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0198] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C4 cycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0199] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C5 cycloalkyl group.

[0200] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C5 cycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0201] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C5 cycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0202] In some embodiments, two R X1 These atoms, together with the atoms to which they are bonded, form a C6 cycloalkyl group.

[0203] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C6 cycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0204] In some embodiments, two R X1These, together with the atoms to which they are bonded, form a C6 cycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0205] In some embodiments, two R X1 These atoms, together with the atoms to which they are bonded, form a C7 cycloalkyl group.

[0206] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C7 cycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0207] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a C7 cycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0208] In some embodiments, two R X1 These atoms, together with the atoms to which they are bonded, form 3- to 7-membered heterocycloalkyl groups.

[0209] In some embodiments, two R X1These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl that may be substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0210] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl group substituted with one or more oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy atoms.

[0211] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0212] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl group substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0213] In some embodiments, two R X1 These atoms, together with the atoms to which they are bonded, form a three-membered heterocycloalkyl group.

[0214] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a three-membered heterocycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0215] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a three-membered heterocycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0216] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form oxetanyl.

[0217] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form an oxetanyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0218] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form oxetanyl molecules substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0219] In some embodiments, two R X1 These atoms, together with the atoms to which they are bonded, form a four-membered heterocycloalkyl group.

[0220] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a four-membered heterocycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0221] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a four-membered heterocycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0222] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a five-membered heterocycloalkyl group.

[0223] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a 5-membered heterocycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0224] In some embodiments, two R X1These, together with the atoms to which they are bonded, form a five-membered heterocycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0225] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a six-membered heterocycloalkyl group.

[0226] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a 6-membered heterocycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0227] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a 6-membered heterocycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0228] In some embodiments, two R X1 These atoms, together with the atoms to which they are bonded, form a 7-membered heterocycloalkyl group.

[0229] In some embodiments, two R X1These, together with the atoms to which they are bonded, form a 7-membered heterocycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0230] In some embodiments, two R X1 These, together with the atoms to which they are bonded, form a 7-membered heterocycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0231] In some aspects, the three R's X1 These, together with the atoms to which they are bonded, form a C4-C 10 It forms a cycloalkyl group.

[0232] In some aspects, the three R's X1 These atoms, together with the atoms to which they are bonded, may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy C4-C 10 It forms a cycloalkyl group.

[0233] In some aspects, the three R's X1 These atoms, together with the atoms to which they are bonded, are substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy C4-C 10 It forms a cycloalkyl group.

[0234] In some aspects, the three R's X1 These atoms, together with the atoms to which they are bonded, form a C4 cycloalkyl group.

[0235] In some aspects, the three R's X1 These, together with the atoms to which they are bonded, form a C4 cycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0236] In some aspects, the three R's X1 These, together with the atoms to which they are bonded, form a C4 cycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0237] In some aspects, the three R's X1 These, together with the atoms to which they are bonded, form a C5 cycloalkyl group.

[0238] In some aspects, the three R's X1 These, together with the atoms to which they are bonded, form a C5 cycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0239] In some aspects, the three R's X1These, together with the atoms to which they are bonded, form a C5 cycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0240] In some aspects, the three R's X1 These atoms, together with the atoms to which they are bonded, form a C6 cycloalkyl group.

[0241] In some aspects, the three R's X1 These, together with the atoms to which they are bonded, form a C6 cycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0242] In some aspects, the three R's X1 These, together with the atoms to which they are bonded, form a C6 cycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0243] In some aspects, the three R's X1 These atoms, together with the atoms to which they are bonded, form a C7 cycloalkyl group.

[0244] In some aspects, the three R's X1These, together with the atoms to which they are bonded, form a C7 cycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0245] In some aspects, the three R's X1 These, together with the atoms to which they are bonded, form a C7 cycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0246] In some aspects, the three R's X1 These, together with the atoms to which they are bonded, form a C8 cycloalkyl group.

[0247] In some aspects, the three R's X1 These, together with the atoms to which they are bonded, form a C8 cycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0248] In some aspects, the three R's X1 These, together with the atoms to which they are bonded, form a C8 cycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0249] In some aspects, the three R'sX1 These atoms, together with the atoms to which they are bonded, form a C9 cycloalkyl group.

[0250] In some aspects, the three R's X1 These, together with the atoms to which they are bonded, form a C9 cycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0251] In some aspects, the three R's X1 These, together with the atoms to which they are bonded, form a C9 cycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0252] In some aspects, the three R's X1 These, together with the atoms to which they are bonded, C 10 It forms a cycloalkyl group.

[0253] In some aspects, the three R's X1 These atoms may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy atoms together with the atoms to which they are bonded. 10 It forms a cycloalkyl group.

[0254] In some aspects, the three R's X1These atoms, together with the atoms to which they are bonded, are substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy. 10 It forms a cycloalkyl group.

[0255] In some embodiments, each R X2 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocycloalkyl, where alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocycloalkyl. Or, two R's X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl, where the heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0256] In some embodiments, each R X2 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl, Or, two R's X2These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl, where the heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0257] In some embodiments, each R X2 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or two R X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl, where the heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0258] In some embodiments, each R X2 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl, where alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocycloalkyl may be substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.

[0259] In some embodiments, each R X2 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0260] In some embodiments, each R X2 These are H independently.

[0261] In some embodiments, each R X2 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0262] In some embodiments, each R X2 These are independently a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, or a C1-C6 haloalkyl, where the alkyl, alkenyl, alkynyl, or haloalkyl may be substituted with one or more halogens, -CN, -OH, a C1-C6 alkyl, a C1-C6 alkoxy, a C1-C6 haloalkyl, a C3-C6 cycloalkyl, or a 3- to 7-membered heterocycloalkyl.

[0263] In some embodiments, each R X2 These are independently C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0264] In some embodiments, each R X2 These are independently a C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl, where the alkyl, alkenyl, or alkynyl may be substituted with one or more halogens, -CN, -OH, a C1-C6 alkyl, a C1-C6 alkoxy, a C1-C6 haloalkyl, a C3-C6 cycloalkyl, or a 3- to 7-membered heterocycloalkyl.

[0265] In some embodiments, each R X2 These are independently C1-C6 alkyl groups.

[0266] In some embodiments, each R X2 These are independently C1-C6 alkyl groups which may be substituted with one or more halogens, -CN, -OH, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, or 3- to 7-membered heterocycloalkyl groups.

[0267] In some embodiments, each R X2 These are C1-C6 alkyl groups independently substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl groups.

[0268] In some embodiments, each R X2 R is independently methyl. In some embodiments, each R X2 is independently ethyl. In some embodiments, each R X2 R is independently propyl. In some embodiments, each R X2 is independently butyl. In some embodiments, each R X2 In some embodiments, each R is independently pentill. X2 In some embodiments, each R is independently hexyl. X2 is independently isopropyl. In some embodiments, each R X2 is independently isobutyl. In some embodiments, each R X2 is independently isopentyl. In some embodiments, each R X2 is independently isohexyl. In some embodiments, each R X2 In some embodiments, each R is independently sec-butyl. X2 Independently, each R is secpentyl. In some embodiments, each R X2 Independently, each R is sec hexyl. In some embodiments, each R X2 It is independently tert-butyl.

[0269] In some embodiments, each R X2 These are independently C2-C6 alkenyls.

[0270] In some embodiments, each R X2 These are independently C2-C6 alkenyl molecules which may be substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl molecules.

[0271] In some embodiments, each R X2 These are independently C2-C6 alkenyl molecules substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl groups.

[0272] In some embodiments, each R X2 These are independently C2 alkenyls. In some embodiments, each R X2 Independently, each R is a C3 alkenyl. In some embodiments, each R X2 Independently, each R is a C4 alkenyl. In some embodiments, each R X2 Independently, each R is a C5 alkenyl. In some embodiments, each R X2 It is independently a C6 alkenyl.

[0273] In some embodiments, each R X2 These are independently C2-C6 alkynyl compounds.

[0274] In some embodiments, each R X2 These are C2-C6 alkynyl molecules that may be independently substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl molecules.

[0275] In some embodiments, each R X2 These are C2-C6 alkynyl molecules independently substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl molecules.

[0276] In some embodiments, each R X2 These are independently C2 alkynyls. In some embodiments, each R X2 Independently, each R is a C3 alkynyl. In some embodiments, each RX2 Independently, each R is a C4 alkynyl. In some embodiments, each R X2 Independently, each R is a C5 alkynyl. In some embodiments, each R X2 It is independently a C6 alkynyl.

[0277] In some embodiments, each R X2 These are independently C1-C6 haloalkyl groups.

[0278] In some embodiments, each R X2 These are independently C1-C6 haloalkyls which may be substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyls.

[0279] In some embodiments, each R X2 These are independently C1-C6 haloalkyls substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyls.

[0280] In some embodiments, each R X2 In some embodiments, each R is independently a halomethyl compound. X2 Independently, each R is a haloethyl compound. In some embodiments, each R X2 Independently, each R is a halopropyl. In some embodiments, each R X2 Independently, each R is a halobutyl. In some embodiments, each R X2 Independently, each R is halopentyl. In some embodiments, each R X2 It is independently a halohexyl.

[0281] In some embodiments, each R X2 These are independently C3-C6 cycloalkyl groups.

[0282] In some embodiments, each R X2These are independently C3-C6 cycloalkyls which may be substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyls.

[0283] In some embodiments, each R X2 These are independently C3-C6 cycloalkyls substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyls.

[0284] In some embodiments, each R X2 Each R is independently a C3 cycloalkyl. In some embodiments, each R X2 Each R is independently a C4 cycloalkyl. In some embodiments, each R X2 Each R is independently a C5 cycloalkyl. In some embodiments, each R X2 These are independently C6 cycloalkyl groups.

[0285] In some embodiments, each R X2 These are independently 3- to 7-membered heterocycloalkyl groups.

[0286] In some embodiments, each R X2 These are independently a 3- to 7-membered heterocycloalkyl which may be substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or a 3- to 7-membered heterocycloalkyl.

[0287] In some embodiments, each R X2 These are independently substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocycloalkyls.

[0288] In some embodiments, each R X2 Each R is independently a 3-membered heterocycloalkyl. In some embodiments, each R X2 Each R is independently a 4-membered heterocycloalkyl. In some embodiments, each R X2 Each R is independently a 5-membered heterocycloalkyl. In some embodiments, each R X2 Each R is independently a 6-membered heterocycloalkyl. In some embodiments, each R X2 These are independently 7-membered heterocycloalkyl groups.

[0289] In some embodiments, two R X2 These atoms, together with the atoms to which they are bonded, form 3- to 7-membered heterocycloalkyl groups.

[0290] In some embodiments, two R X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0291] In some embodiments, two R X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl group substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0292] In some embodiments, two R X2 These atoms, together with the atoms to which they are bonded, form a three-membered heterocycloalkyl group.

[0293] In some embodiments, two R X2These, together with the atoms to which they are bonded, form a three-membered heterocycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0294] In some embodiments, two R X2 These, together with the atoms to which they are bonded, form a three-membered heterocycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0295] In some embodiments, two R X2 These atoms, together with the atoms to which they are bonded, form a four-membered heterocycloalkyl group.

[0296] In some embodiments, two R X2 These, together with the atoms to which they are bonded, form a four-membered heterocycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0297] In some embodiments, two R X2 These, together with the atoms to which they are bonded, form a four-membered heterocycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0298] In some embodiments, two R X2 These, together with the atoms to which they are bonded, form a five-membered heterocycloalkyl group.

[0299] In some embodiments, two R X2 These, together with the atoms to which they are bonded, form a 5-membered heterocycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0300] In some embodiments, two R X2 These, together with the atoms to which they are bonded, form a five-membered heterocycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0301] In some embodiments, two R X2 These, together with the atoms to which they are bonded, form a six-membered heterocycloalkyl group.

[0302] In some embodiments, two R X2 These, together with the atoms to which they are bonded, form a 6-membered heterocycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0303] In some embodiments, two R X2These, together with the atoms to which they are bonded, form a 6-membered heterocycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0304] In some embodiments, two R X2 These atoms, together with the atoms to which they are bonded, form a 7-membered heterocycloalkyl group.

[0305] In some embodiments, two R X2 These, together with the atoms to which they are bonded, form a 7-membered heterocycloalkyl which may be substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0306] In some embodiments, two R X2 These, together with the atoms to which they are bonded, form a 7-membered heterocycloalkyl substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0307] In some embodiments, each R Y These are independently H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy.

[0308] In some embodiments, each R Y These are H independently.

[0309] In some embodiments, each R Y These are independently halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy.

[0310] In some embodiments, each R Y These are independently halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0311] In some embodiments, each R Y These are, independently, halogens.

[0312] In some embodiments, each R Y These are independently F, Cl, Br, or I. In some embodiments, each R Y R is independently F, Cl, or Br. In some embodiments, each R Y These are independently F or Cl.

[0313] In some embodiments, each R Y Independently, F. In some embodiments, each R Y Independently, each R is Cl. In some embodiments, each R Y Independently, each R is Br. In some embodiments, each R Y These are independently I.

[0314] In some embodiments, each R Y These are independently -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0315] In some embodiments, each R Y It is independently -CN.

[0316] In some embodiments, each R YThese are independently -OH.

[0317] In some embodiments, each R Y These are independently -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0318] In some embodiments, each R Y These are independently -NH2.

[0319] In some embodiments, each R Y These are independently -NH(C1-C6 alkyl).

[0320] In some embodiments, each R Y Independently, each R is -NH (methyl). In some embodiments, each R Y R is independently -NH(ethyl). In some embodiments, each R Y Independently, each R is -NH(propyl). In some embodiments, each R Y Independently, each R is -NH (butyl). In some embodiments, each R Y Independently, each R is -NH (pentyl). In some embodiments, each R Y It is independently -NH (hexyl).

[0321] In some embodiments, each R Y These are independently -N(C1-C6 alkyl)2.

[0322] In some embodiments, each R Y These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy.

[0323] In some embodiments, each R Y These are independently C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0324] In some embodiments, each R YThese are independently C1-C6 alkyl groups.

[0325] In some embodiments, each R Y R is independently methyl. In some embodiments, each R Y is independently ethyl. In some embodiments, each R Y R is independently propyl. In some embodiments, each R Y is independently butyl. In some embodiments, each R Y In some embodiments, each R is independently pentill. Y In some embodiments, each R is independently hexyl. Y is independently isopropyl. In some embodiments, each R Y is independently isobutyl. In some embodiments, each R Y is independently isopentyl. In some embodiments, each R Y is independently isohexyl. In some embodiments, each R Y In some embodiments, each R is independently sec-butyl. Y Independently, each R is secpentyl. In some embodiments, each R Y Independently, each R is sec hexyl. In some embodiments, each R Y It is independently tert-butyl.

[0326] In some embodiments, each R Y These are independently C2-C6 alkenyls.

[0327] In some embodiments, each R Y These are independently C2 alkenyls. In some embodiments, each R Y Independently, each R is a C3 alkenyl. In some embodiments, each R Y Independently, each R is a C4 alkenyl. In some embodiments, each R Y Independently, each R is a C5 alkenyl. In some embodiments, each R Y It is independently a C6 alkenyl.

[0328] In some embodiments, each R Y These are independently C2-C6 alkynyl compounds.

[0329] In some embodiments, each R Y These are independently C2 alkynyls. In some embodiments, each R Y Independently, each R is a C3 alkynyl. In some embodiments, each R Y Independently, each R is a C4 alkynyl. In some embodiments, each R Y Independently, each R is a C5 alkynyl. In some embodiments, each R Y It is independently a C6 alkynyl.

[0330] In some embodiments, each R Y These are independently C1-C6 haloalkyl or C 1-6 It is an alkoxy.

[0331] In some embodiments, each R Y These are independently C1-C6 haloalkyl groups.

[0332] In some embodiments, each R Y In some embodiments, each R is independently a halomethyl compound. Y Independently, each R is a haloethyl compound. In some embodiments, each R Y Independently, each R is a halopropyl. In some embodiments, each R Y Independently, each R is a halobutyl. In some embodiments, each R Y Independently, each R is halopentyl. In some embodiments, each R Y It is independently a halohexyl.

[0333] In some embodiments, each R Y Independently, C 1-6 It is an alkoxy.

[0334] In some embodiments, each R Y In some embodiments, each R is methoxy. Y Independently, each R is ethoxy. In some embodiments, each R YIn some embodiments, each R is a propoxy. Y Independently, each R is butoxy. In some embodiments, each R Y In some embodiments, each R is independently pentoxy. Y It is independently hexoxy.

[0335] In some embodiments, each R Z This is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0336] In some embodiments, R Z H is H.

[0337] In some embodiments, R Z These are C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0338] In some embodiments, R Z These are C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl compounds.

[0339] In some embodiments, R Z It is a C1-C6 alkyl group.

[0340] In some embodiments, R Z is methyl. In some embodiments, R Z is ethyl. In some embodiments, R Z is propyl. In some embodiments, R Z is butyl. In some embodiments, R Z is pentyl. In some embodiments, R Z is hexyl. In some embodiments, R Z is isopropyl. In some embodiments, R Z isobutyl. In some embodiments, R Z is isopentyl. In some embodiments, R Zis isohexyl. In some embodiments, R Z is secbutyl. In some embodiments, R Z secpentyl is secpentyl. In some embodiments, R Z is sec hexyl. In some embodiments, R Z It is tert-butyl.

[0341] In some embodiments, R Z It is a C2-C6 alkenyl.

[0342] In some embodiments, R Z is a C2 alkenyl. In some embodiments, R Z is a C3 alkenyl. In some embodiments, R Z is a C4 alkenyl. In some embodiments, R Z is a C5 alkenyl. In some embodiments, R Z This is a C6 alkenyl.

[0343] In some embodiments, R Z This is a C2-C6 alkynyl compound.

[0344] In some embodiments, R Z is C2 alkynyl. In some embodiments, R Z is C3 alkynyl. In some embodiments, R Z is C4 alkynyl. In some embodiments, R Z is C5 alkynyl. In some embodiments, R Z This is C6 alkynyl.

[0345] In some embodiments, R Z It is a C1-C6 haloalkyl group.

[0346] In some embodiments, R Z is a halomethyl. In some embodiments, R Z is haloethyl. In some embodiments, R Z is a halopropyl. In some embodiments, RZ is halobutyl. In some embodiments, R Z is halopentyl. In some embodiments, R Z It is a halohexyl.

[0347] In some embodiments, Ar1 is C6-C 10 They are aryl or 5-10 member heteroaryl.

[0348] In some embodiments, Ar1 is C6-C 10 It is an aryl or 5-10 member heteroaryl, where the C6-C 10 The aryl or 5- to 10-membered heteroaryl may be substituted with one or more R3 groups.

[0349] In some embodiments, Ar1 is C6-C 10 It is Ariel.

[0350] In some embodiments, Ar1 may be replaced by one or more R3s C6-C 10 It is Ariel.

[0351] In some embodiments, Ar1 is replaced by one or more R3s in C6-C 10 These are aryl groups (for example, phenyl groups).

[0352] In some embodiments, Ar1 is replaced by one R3 in C6-C 10 It is an aryl (e.g., phenyl). In some embodiments, Ar1 is a C6-C substituted with two R3s. 10 It is an aryl (e.g., phenyl). In some embodiments, Ar1 is a C6-C substituted with three R3s. 10 These are aryl groups (for example, phenyl groups).

[0353] In some embodiments, Ar1 is a C6 aryl (e.g., phenyl).

[0354] In some embodiments, Ar1 is a C6 aryl (e.g., phenyl) which may be substituted with one or more R3s.

[0355] In some embodiments, Ar1 is a C6 aryl (e.g., phenyl) substituted with one or more R3s.

[0356] In some embodiments, Ar1 is a C6 aryl (e.g., phenyl) substituted with one R3. In some embodiments, Ar1 is a C6 aryl (e.g., phenyl) substituted with two R3s. In some embodiments, Ar1 is a C6 aryl (e.g., phenyl) substituted with three R3s.

[0357] In some embodiments, Ar1 is phenyl.

[0358] In some embodiments, Ar1 is a phenyl which may be substituted with one or more R3s.

[0359] In some embodiments, Ar1 is a phenyl molecule substituted with one or more R3 groups.

[0360] In some embodiments, Ar1 is a phenyl molecule substituted with one R3. In some embodiments, Ar1 is a phenyl molecule substituted with two R3. In some embodiments, Ar1 is a phenyl molecule substituted with three R3.

[0361] In some embodiments, Ar1 is a phenyl which may be substituted with one or more halos (e.g., F, Cl, or Br).

[0362] In some embodiments, Ar1 is a phenyl compound substituted with one or more halos (e.g., F, Cl, or Br).

[0363] In some embodiments, Ar1 is a phenyl molecule substituted with one halo (e.g., F, Cl, or Br). In some embodiments, Ar1 is a phenyl molecule substituted with two halos (e.g., F, Cl, or Br). In some embodiments, Ar1 is a phenyl molecule substituted with three halos (e.g., F, Cl, or Br).

[0364] In some embodiments, Ar1 is a C8 aryl.

[0365] In some embodiments, Ar1 is a C8 aryl which may be substituted with one or more R3s.

[0366] In some embodiments, Ar1 is a C8 aryl (e.g., phenyl) substituted with one or more R3s.

[0367] In some embodiments, Ar1 is a C8 aryl (e.g., phenyl) substituted with one R3. In some embodiments, Ar1 is a C8 aryl (e.g., phenyl) substituted with two R3s. In some embodiments, Ar1 is a C8 aryl (e.g., phenyl) substituted with three R3s.

[0368] In some embodiments, Ar1 is C 10 It is Ariel.

[0369] In some embodiments, Ar1 may be replaced by one or more R3s. 10 It is Ariel.

[0370] In some embodiments, Ar1 is replaced by one or more R3s. 10 These are aryl groups (for example, phenyl groups).

[0371] In some embodiments, Ar1 is replaced by one R3 C 10 It is an aryl (e.g., phenyl). In some embodiments, Ar1 is substituted with two R3s. 10It is an aryl (e.g., phenyl). In some embodiments, Ar1 is substituted with three R3s. 10 These are aryl groups (for example, phenyl groups).

[0372] In some embodiments, Ar1 is a 5- to 10-membered heteroaryl.

[0373] In some embodiments, Ar1 is a 5- to 10-membered heteroaryl which may be substituted with one or more R3s.

[0374] In some embodiments, Ar1 is a 5- to 10-membered heteroaryl substituted with one or more R3s.

[0375] In some embodiments, Ar1 is a 5- to 10-membered heteroaryl substituted with one R3. In some embodiments, Ar1 is a 5- to 10-membered heteroaryl substituted with two R3s. In some embodiments, Ar1 is a 5- to 10-membered heteroaryl substituted with three R3s.

[0376] In some embodiments, Ar1 is a five-membered heteroaryl.

[0377] In some embodiments, Ar1 is a five-membered heteroaryl which may be substituted with one or more R3s.

[0378] In some embodiments, Ar1 is a five-membered heteroaryl substituted with one or more R3s.

[0379] In some embodiments, Ar1 is a five-membered heteroaryl substituted with one R3. In some embodiments, Ar1 is a five-membered heteroaryl substituted with two R3. In some embodiments, Ar1 is a five-membered heteroaryl substituted with three R3.

[0380] In some embodiments, Ar1 is thiazolyl.

[0381] In some embodiments, Ar1 is a thiazolyl which may be substituted with one or more R3s.

[0382] In some embodiments, Ar1 is a thiazolyl substituted with one or more R3s.

[0383] In some embodiments, Ar1 is a thiazolyl substituted with one R3. In some embodiments, Ar1 is a thiazolyl substituted with two R3. In some embodiments, Ar1 is a thiazolyl substituted with three R3.

[0384] In some embodiments, Ar1 is a 6-membered heteroaryl.

[0385] In some embodiments, Ar1 is a six-membered heteroaryl which may be substituted with one or more R3s.

[0386] In some embodiments, Ar1 is a six-membered heteroaryl substituted with one or more R3s.

[0387] In some embodiments, Ar1 is a six-membered heteroaryl substituted with one R3. In some embodiments, Ar1 is a six-membered heteroaryl substituted with two R3. In some embodiments, Ar1 is a six-membered heteroaryl substituted with three R3.

[0388] In some embodiments, Ar1 is pyridyl.

[0389] In some embodiments, Ar1 is a pyridyl which may be substituted with one or more R3s.

[0390] In some embodiments, Ar1 is a pyridyl substituted with one or more R3s.

[0391] In some embodiments, Ar1 is a pyridyl substituted with one R3. In some embodiments, Ar1 is a pyridyl substituted with two R3. In some embodiments, Ar1 is a pyridyl substituted with three R3.

[0392] In some embodiments, Ar1 is a 7-membered heteroaryl.

[0393] In some embodiments, Ar1 is a seven-membered heteroaryl which may be substituted with one or more R3s.

[0394] In some embodiments, Ar1 is a seven-membered heteroaryl substituted with one or more R3s.

[0395] In some embodiments, Ar1 is a seven-membered heteroaryl substituted with one R3. In some embodiments, Ar1 is a seven-membered heteroaryl substituted with two R3. In some embodiments, Ar1 is a seven-membered heteroaryl substituted with three R3.

[0396] In some embodiments, Ar1 is an 8-membered heteroaryl.

[0397] In some embodiments, Ar1 is an eight-membered heteroaryl which may be substituted with one or more R3s.

[0398] In some embodiments, Ar1 is an 8-membered heteroaryl substituted with one or more R3s.

[0399] In some embodiments, Ar1 is an 8-membered heteroaryl substituted with one R3. In some embodiments, Ar1 is an 8-membered heteroaryl substituted with two R3s. In some embodiments, Ar1 is an 8-membered heteroaryl substituted with three R3s.

[0400] In some embodiments, Ar1 is a 9-membered heteroaryl.

[0401] In some embodiments, Ar1 is a nine-membered heteroaryl which may be substituted with one or more R3s.

[0402] In some embodiments, Ar1 is a nine-membered heteroaryl substituted with one or more R3s.

[0403] In some embodiments, Ar1 is a nine-membered heteroaryl substituted with one R3. In some embodiments, Ar1 is a nine-membered heteroaryl substituted with two R3s. In some embodiments, Ar1 is a nine-membered heteroaryl substituted with three R3s.

[0404] In some embodiments, Ar1 is a 10-membered heteroaryl.

[0405] In some embodiments, Ar1 is a 10-membered heteroaryl which may be substituted with one or more R3s.

[0406] In some embodiments, Ar1 is a 10-membered heteroaryl substituted with one or more R3s.

[0407] In some embodiments, Ar1 is a 10-membered heteroaryl substituted with one R3. In some embodiments, Ar1 is a 10-membered heteroaryl substituted with two R3. In some embodiments, Ar1 is a 10-membered heteroaryl substituted with three R3.

[0408] In some embodiments, R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -S(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 It is a cycloalkyl group, or a -NH- (3-7 member heterocycloalkyl group).

[0409] In some embodiments, R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -N(C1-C6 alkyl)(C3-C 10 Cycloalkyl), -S(C1-C6 alkyl), -S(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 It is a cycloalkyl group, or a -NH- (3-7 member heterocycloalkyl group).

[0410] In some embodiments, R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -S(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 1S It may be replaced with .

[0411] In some embodiments, R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -N(C1-C6 alkyl)(C3-C 10 Cycloalkyl), -S(C1-C6 alkyl), or -S(C6-C 10 It is Ariel.

[0412] In some embodiments, R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), or -S(C6-C 10 It is Ariel.

[0413] In some embodiments, R1 is -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2, or -N(C1-C6 alkyl)(C3-C 10 It is a cycloalkyl group.

[0414] In some embodiments, R1 is -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0415] In some embodiments, R1 is -NH2.

[0416] In some embodiments, R1 is -NH(C1-C6 alkyl).

[0417] In some embodiments, R1 is -NH(methyl). In some embodiments, R1 is -NH(ethyl). In some embodiments, R1 is -NH(propyl). In some embodiments, R1 is -NH(butyl). In some embodiments, R1 is -NH(pentyl). In some embodiments, R1 is -NH(hexyl).

[0418] In some embodiments, R1 is -N(C1-C6 alkyl)2.

[0419] In some embodiments, R1 is -N(C1-C6 alkyl)(C3-C 10 cycloalkyl).

[0420] In some embodiments, R1 is -N(C1-C6 alkyl)(C3 cycloalkyl). In some embodiments, R1 is -N(C1-C6 alkyl)(C4 cycloalkyl). In some embodiments, R1 is -N(C1-C6 alkyl)(C5 cycloalkyl). In some embodiments, R1 is -N(C1-C6 alkyl)(C6 cycloalkyl). In some embodiments, R1 is -N(C1-C6 alkyl)(C7 cycloalkyl). In some embodiments, R1 is -N(C1-C6 alkyl)(C8 cycloalkyl). In some embodiments, R1 is -N(C1-C6 alkyl)(C9 cycloalkyl). In some embodiments, R1 is -N(C1-C6 alkyl)(C 10 cycloalkyl).

[0421] In some embodiments, R1 is -S(C1-C6 alkyl) or -S(C6-C 10 aryl).

[0422] In some embodiments, R1 is -S(C1-C6 alkyl).

[0423] In some embodiments, R1 is -S(methyl). In some embodiments, R1 is -S(ethyl). In some embodiments, R1 is -S(propyl). In some embodiments, R1 is -S(butyl). In some embodiments, R1 is -S(heptyl). In some embodiments, R1 is -S(hexyl).

[0424] In some embodiments, R1 is -S(C6-C 10 aryl).

[0425] In some embodiments, R1 is -S(C6 aryl). In some embodiments, R1 is -S(C8 aryl). In some embodiments, R1 is -S(C 10 aryl).

[0426] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 aryl, 5-10 member heteroaryl, C3-C7 cycloalkyl, 3-7 member heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 cycloalkyl), or -NH-(3-7 member heterocycloalkyl).

[0427] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 aryl, 5-10 member heteroaryl, C3-C7 cycloalkyl, 3-7 member heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 1S It may be replaced with .

[0428] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0429] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, where alkyl, alkenyl, or alkynyl is one or more R 1S It may be replaced with .

[0430] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, where alkyl, alkenyl, or alkynyl is one or more R 1S It has been replaced with.

[0431] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, where alkyl, alkenyl, or alkynyl is one R 1S It has been replaced with.

[0432] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, where alkyl, alkenyl, or alkynyl is two R 1SIt has been replaced with.

[0433] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, where alkyl, alkenyl, or alkynyl is one of three R 1S It has been replaced with.

[0434] In some embodiments, R1 is a C1-C6 alkyl group.

[0435] 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.

[0436] In some embodiments, R1 is one or more R 1S It is a C1-C6 alkyl group which may be substituted with [another molecule].

[0437] In some embodiments, R1 is one or more R 1S It is a C1-C6 alkyl group that is substituted with [a specific compound].

[0438] In some embodiments, R1 is one R 1S It is a C1-C6 alkyl group that is substituted with [a specific compound].

[0439] In some embodiments, R1 is two R 1S It is a C1-C6 alkyl group that is substituted with [a specific compound].

[0440] In some embodiments, R1 is one of three R 1S It is a C1-C6 alkyl group that is substituted with [a specific compound].

[0441] In some embodiments, R1 is a C2-C6 alkenyl.

[0442] In some embodiments, R1 is a C2 alkenyl. In some embodiments, R1 is a C3 alkenyl. In some embodiments, R1 is a C4 alkenyl. In some embodiments, R1 is a C5 alkenyl. In some embodiments, R1 is a C6 alkenyl.

[0443] In some embodiments, R1 is one or more R 1S It is a C2-C6 alkenyl that may be substituted with [another compound].

[0444] In some embodiments, R1 is one or more R 1S It is a C2-C6 alkenyl that is substituted with [a specific compound].

[0445] In some embodiments, R1 is one R 1S It is a C2-C6 alkenyl that is substituted with [a specific compound].

[0446] In some embodiments, R1 is two R 1S It is a C2-C6 alkenyl that is substituted with [a specific compound].

[0447] In some embodiments, R1 is one of three R 1S It is a C2-C6 alkenyl that is substituted with [a specific compound].

[0448] In some embodiments, R1 is a C2-C6 alkynyl.

[0449] In some embodiments, R1 is C2 alkynyl. In some embodiments, R1 is C3 alkynyl. In some embodiments, R1 is C4 alkynyl. In some embodiments, R1 is C5 alkynyl. In some embodiments, R1 is C6 alkynyl.

[0450] In some embodiments, R1 is one or more R 1S It is a C2-C6 alkynyl that may be substituted with [another compound].

[0451] In some embodiments, R1 is one or more R 1S It is a C2-C6 alkynyl that is substituted with [a specific compound].

[0452] In some embodiments, R1 is one R 1S It is a C2-C6 alkynyl that is substituted with [a specific compound].

[0453] In some embodiments, R1 is two R 1S It is a C2-C6 alkynyl that is substituted with [a specific compound].

[0454] In some embodiments, R1 is one of three R 1S It is a C2-C6 alkynyl that is substituted with [a specific compound].

[0455] In some embodiments, R1 is a C1-C6 haloalkyl group.

[0456] In some embodiments, R1 is halomethyl. In some embodiments, R1 is haloethyl. In some embodiments, R1 is halopropyl. In some embodiments, R1 is halobutyl. In some embodiments, R1 is halopentyl. In some embodiments, R1 is halohexyl.

[0457] In some embodiments, R1 is one or more R 1S It is a C1-C6 haloalkyl which may be substituted with [another compound].

[0458] In some embodiments, R1 is one or more R 1S It is a C1-C6 haloalkyl that is substituted with [a specific compound].

[0459] In some embodiments, R1 is one R 1S It is a C1-C6 haloalkyl that is substituted with [a specific compound].

[0460] In some embodiments, R1 is two R 1S It is a C1-C6 haloalkyl that is substituted with [a specific compound].

[0461] In some embodiments, R1 is one of three R 1S It is a C1-C6 haloalkyl that is substituted with [a specific compound].

[0462] In some embodiments, R1 is a C1-C6 alkoxy.

[0463] In some embodiments, R1 is methoxy. In some embodiments, R1 is ethoxy. In some embodiments, R1 is propoxy. In some embodiments, R1 is butoxy. In some embodiments, R1 is pentoxy. In some embodiments, R1 is hexoxy.

[0464] In some embodiments, R1 is one or more R 1S It is a C1-C6 alkoxy that may be substituted with [another compound].

[0465] In some embodiments, R1 is one or more R 1S It is a C1-C6 alkoxy that is substituted with [a specific compound].

[0466] In some embodiments, R1 is one R 1S It is a C1-C6 alkoxy that is substituted with [a specific compound].

[0467] In some embodiments, R1 is two R 1S It is a C1-C6 alkoxy that is substituted with [a specific compound].

[0468] In some embodiments, R1 is one of three R 1S It is a C1-C6 alkoxy that is substituted with [a specific compound].

[0469] In some embodiments, R1 is C6-C 10 These are aryl, 5-10 member heteroaryl, C3-C7 cycloalkyl, or 3-7 member heterocycloalkyl.

[0470] In some embodiments, R1 is C6-C 10 The aryl group is an aryl group, a 5-10 member heteroaryl group, a C3-C7 cycloalkyl group, or a 3-7 member heterocycloalkyl group, where the aryl group, heteroaryl group, cycloalkyl group, and heterocycloalkyl group are one or more R groups. 1S It may be replaced with .

[0471] In some embodiments, R1 is C6-C 10 The aryl group is an aryl group, a 5-10 member heteroaryl group, a C3-C7 cycloalkyl group, or a 3-7 member heterocycloalkyl group, where the aryl group, heteroaryl group, cycloalkyl group, and heterocycloalkyl group are one or more R groups. 1S It has been replaced with.

[0472] In some embodiments, R1 is C6-C 10 These are aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, or 3-7 membered heterocycloalkyl, where aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are one R 1S It has been replaced with.

[0473] In some embodiments, R1 is C6-C 10 These are aryl, 5-10 member heteroaryl, C3-C7 cycloalkyl, or 3-7 member heterocycloalkyl, where aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are two R 1S It has been replaced with.

[0474] In some embodiments, R1 is C6-C10 These are aryl, 5-10 member heteroaryl, C3-C7 cycloalkyl, or 3-7 member heterocycloalkyl, where aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are 3R 1S It has been replaced with.

[0475] In some embodiments, R1 is C6-C 10 It is Ariel.

[0476] In some embodiments, R1 is a C6 aryl (e.g., phenyl). In some embodiments, R1 is a C8 aryl. In some embodiments, R1 is C 10 It is Ariel.

[0477] In some embodiments, R1 is one or more R 1S C6-C may be replaced with 10 It is Ariel.

[0478] In some embodiments, R1 is one or more R 1S C6-C is replaced by 10 It is Ariel.

[0479] In some embodiments, R1 is one R 1S C6-C is replaced by 10 It is an arrow. In some embodiments, R1 is two R 1S C6-C is replaced by 10 It is an arrow. In some embodiments, R1 is three R 1S C6-C is replaced by 10 It is Ariel.

[0480] In some embodiments, R1 is a 5- to 10-membered heteroaryl.

[0481] In some embodiments, R1 is a 5-member heteroaryl. In some embodiments, R1 is a 6-member heteroaryl. In some embodiments, R1 is a 7-member heteroaryl. In some embodiments, R1 is an 8-member heteroaryl. In some embodiments, R1 is a 9-member heteroaryl. In some embodiments, R1 is a 10-member heteroaryl.

[0482] In some embodiments, R1 is a 5- to 10-member heteroaryl optionally substituted with one or more Rs. 1S

[0483] In some embodiments, R1 is a 5- to 10-member heteroaryl substituted with one or more Rs. 1S

[0484] In some embodiments, R1 is a 5- to 10-member heteroaryl substituted with one R. In some embodiments, R1 is a 5- to 10-member heteroaryl substituted with two Rs. 1S 1S 1S In some embodiments, R1 is a 5- to 10-member heteroaryl substituted with three Rs.

[0485] In some embodiments, R1 is a C3-C7 cycloalkyl.

[0486] 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.

[0487] In some embodiments, R1 is a C3-C7 cycloalkyl optionally substituted with one or more Rs. 1S

[0488] In some embodiments, R1 is a C3-C7 cycloalkyl substituted with one or more Rs. 1S ​

[0489] In some embodiments, R1 is one R 1S It is a C3-C7 cycloalkyl that is substituted with. In some embodiments, R1 is two R 1S It is a C3-C7 cycloalkyl that is substituted with. In some embodiments, R1 is three R 1S It is a C3-C7 cycloalkyl group that is substituted with [a specific compound].

[0490] In some embodiments, R1 is a 3- to 7-membered heterocycloalkyl group.

[0491] In some embodiments, R1 is a 3-membered heterocycloalkyl. In some embodiments, R1 is a 4-membered heterocycloalkyl. In some embodiments, R1 is a 5-membered heterocycloalkyl. In some embodiments, R1 is a 6-membered heterocycloalkyl. In some embodiments, R1 is a 7-membered heterocycloalkyl.

[0492] In some embodiments, R1 is one or more R 1S It is a 3- to 7-membered heterocycloalkyl group which may be substituted with a different compound.

[0493] In some embodiments, R1 is one or more R 1S It is a 3- to 7-membered heterocycloalkyl group that is substituted with [a specific compound].

[0494] In some embodiments, R1 is one R 1S It is a 3- to 7-membered heterocycloalkyl that is substituted with R. In some embodiments, R1 is two R 1S It is a 3- to 7-membered heterocycloalkyl that is substituted with R. In some embodiments, R1 is three R 1S It is a 3- to 7-membered heterocycloalkyl group that is substituted with [a specific compound].

[0495] In some embodiments, when R1 is a heterocycloalkyl, R1 is bonded via a nitrogen atom.

[0496] In some embodiments, R1 is -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 It is a cycloalkyl group, or a -NH- (3-7 member heterocycloalkyl group).

[0497] In some embodiments, R1 is -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 It is a cycloalkyl group, or an -O- (3-7 member heterocycloalkyl group).

[0498] In some embodiments, R1 is -O-(C6-C 10 It is Ariel.

[0499] In some embodiments, R1 is -O-(C6 aryl). In some embodiments, R1 is -O-(C8 aryl). In some embodiments, R1 is -O-(C 10 It is Ariel.

[0500] In some embodiments, R1 is -O-(5-10 member heteroaryl).

[0501] In some embodiments, R1 is -O- (5-membered heteroaryl). In some embodiments, R1 is -O- (6-membered heteroaryl). In some embodiments, R1 is -O- (7-membered heteroaryl). In some embodiments, R1 is -O- (8-membered heteroaryl). In some embodiments, R1 is -O- (9-membered heteroaryl). In some embodiments, R1 is -O- (10-membered heteroaryl).

[0502] In some embodiments, R1 is -O-(C3-C 10 It is a cycloalkyl group.

[0503] In some embodiments, R1 is -O-(C3 cycloalkyl). In some embodiments, R1 is -O-(C4 cycloalkyl). In some embodiments, R1 is -O-(C5 cycloalkyl). In some embodiments, R1 is -O-(C6 cycloalkyl). In some embodiments, R1 is -O-(C7 cycloalkyl). In some embodiments, R1 is -O-(C8 cycloalkyl). In some embodiments, R1 is -O-(C9 cycloalkyl). In some embodiments, R1 is -O-(C 10 It is a cycloalkyl group.

[0504] In some embodiments, R1 is -O-(3-7 member heterocycloalkyl).

[0505] In some embodiments, R1 is -O-(3-membered heterocycloalkyl). In some embodiments, R1 is -O-(4-membered heterocycloalkyl). In some embodiments, R1 is -O-(5-membered heterocycloalkyl). In some embodiments, R1 is -O-(6-membered heterocycloalkyl). In some embodiments, R1 is -O-(7-membered heterocycloalkyl).

[0506] In some embodiments, R1 is -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 It is a cycloalkyl group, or a -NH- (3-7 member heterocycloalkyl group).

[0507] In some embodiments, R1 is -NH-(C6-C 10 It is Ariel.

[0508] In some embodiments, R1 is -NH-(C6 aryl). In some embodiments, R1 is -NH-(C8 aryl). In some embodiments, R1 is -NH-(C 10 It is Ariel.

[0509] In some embodiments, R1 is -NH- (5-10 member heteroaryl).

[0510] In some embodiments, R1 is -NH- (5-membered heteroaryl). In some embodiments, R1 is -NH- (6-membered heteroaryl). In some embodiments, R1 is -NH- (7-membered heteroaryl). In some embodiments, R1 is -NH- (8-membered heteroaryl). In some embodiments, R1 is -NH- (9-membered heteroaryl). In some embodiments, R1 is -NH- (10-membered heteroaryl).

[0511] In some embodiments, R1 is -NH-(C3-C 10 It is a cycloalkyl group.

[0512] In some embodiments, R1 is -NH-(C3 cycloalkyl). In some embodiments, R1 is -NH-(C4 cycloalkyl). In some embodiments, R1 is -NH-(C5 cycloalkyl). In some embodiments, R1 is -NH-(C6 cycloalkyl). In some embodiments, R1 is -NH-(C7 cycloalkyl). In some embodiments, R1 is -NH-(C8 cycloalkyl). In some embodiments, R1 is -NH-(C9 cycloalkyl). In some embodiments, R1 is -NH-(C 10 It is a cycloalkyl group.

[0513] In some embodiments, R1 is -NH- (3-7 member heterocycloalkyl).

[0514] In some embodiments, R1 is -NH- (3-membered heterocycloalkyl). In some embodiments, R1 is -NH- (4-membered heterocycloalkyl). In some embodiments, R1 is -NH- (5-membered heterocycloalkyl). In some embodiments, R1 is -NH- (6-membered heterocycloalkyl). In some embodiments, R1 is -NH- (7-membered heterocycloalkyl).

[0515] In some embodiments, R1 is methyl, isopropyl, ethyl, -CF3, -CHF2, CH2F, -CF2CH3, -CF(CH3)2, cyclopropyl, or flurocyclopropyl.

[0516] In some embodiments, R1 is methyl, ethyl, -CF3, CHF2, or CH2F.

[0517] In some embodiments, R1 is methyl or ethyl.

[0518] In some embodiments, R1 is -CF3, CHF2, or CH2F.

[0519] In some embodiments, each R 1S These are independently oxo, halogen, -CN, -OH, -O-(CH2)2-OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl.

[0520] In some embodiments, each R 1S These are independently oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl.

[0521] In some embodiments, each R 1S These are independently oxo, halogen, or -CN.

[0522] In some embodiments, each R 1S It is independently oxo.

[0523] In some embodiments, each R 1S These are, independently, halogens.

[0524] In some embodiments, each R 1S These are independently F, Cl, Br, or I. In some embodiments, each R 1S R is independently F, Cl, or Br. In some embodiments, each R 1S These are independently F or Cl.

[0525] In some embodiments, each R 1S Independently, F. In some embodiments, each R 1S Independently, each R is Cl. In some embodiments, each R 1S Independently, each R is Br. In some embodiments, each R 1S These are independently I.

[0526] In some embodiments, each R 1S It is independently -CN.

[0527] In some embodiments, each R 1S These are independently -OH, -O-(CH2)2-OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -S(C1-C6alkyl), or -SO2(C1-C6alkyl).

[0528] In some embodiments, each R 1S These are independently -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), or -SO2(C1-C6 alkyl).

[0529] In some embodiments, each R 1S These are independently -OH.

[0530] In some embodiments, each R 1S These are independently -O-(CH2)2-OC1-C6 alkyl groups.

[0531] In some embodiments, each R 1S These are independently -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), or -SO2(C1-C6 alkyl).

[0532] In some embodiments, each R 1S These are independently -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0533] In some embodiments, each R 1S These are independently -NH2.

[0534] In some embodiments, each R 1S These are independently -NH(C1-C6 alkyl).

[0535] In some embodiments, each R 1S Independently, each R is -NH (methyl). In some embodiments, each R 1S R is independently -NH(ethyl). In some embodiments, each R 1S Independently, each R is -NH(propyl). In some embodiments, each R 1S Independently, each R is -NH (butyl). In some embodiments, each R 1S Independently, each R is -NH (pentyl). In some embodiments, each R 1S It is independently -NH (hexyl).

[0536] In some embodiments, each R 1S These are independently -N(C1-C6 alkyl)2.

[0537] In some embodiments, each R 1S These are independently -S(C1-C6 alkyl) or -SO2(C1-C6 alkyl).

[0538] In some embodiments, each R 1S These are independently -S(C1-C6 alkyl).

[0539] In some embodiments, each R 1S Independently, each R is -S (methyl). In some embodiments, each R 1S Independently, each R is -S (ethyl). In some embodiments, each R 1S Independently, each R is -S (propyl). In some embodiments, each R 1S These are independently -S (butyl). In some embodiments, each R 1S These are independently -S (heptyl). In some embodiments, each R 1S These are independently -S (hexyl).

[0540] In some embodiments, each R 1S These are independently -SO2(C1-C6 alkyl).

[0541] In some embodiments, each R 1S R is independently -SO2(methyl). In some embodiments, each R 1S R is independently -SO2(ethyl). In some embodiments, each R 1S R is independently -SO2(propyl). In some embodiments, each R 1S R is independently -SO2(butyl). In some embodiments, each R 2S These are independently -SO2 (heptyl). In some embodiments, each R 1S It is independently -SO2 (hexyl).

[0542] In some embodiments, each R 1S These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl.

[0543] In some embodiments, each R 1S These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy.

[0544] In some embodiments, each R 1S These are independently C1-C6 alkyl groups.

[0545] In some embodiments, each R 1S R is independently methyl. In some embodiments, each R 1S is independently ethyl. In some embodiments, each R 1S R is independently propyl. In some embodiments, each R 1S is independently butyl. In some embodiments, each R 1S In some embodiments, each R is independently pentill. 1S In some embodiments, each R is independently hexyl. 1S is independently isopropyl. In some embodiments, each R 1S is independently isobutyl. In some embodiments, each R 1S is independently isopentyl. In some embodiments, each R 1S is independently isohexyl. In some embodiments, each R 1S In some embodiments, each R is independently sec-butyl. 1S Independently, each R is secpentyl. In some embodiments, each R 1S Independently, each R is sec hexyl. In some embodiments, each R 1S It is independently tert-butyl.

[0546] In some embodiments, each R 1S These are independently C2-C6 alkenyls.

[0547] In some embodiments, each R 1S These are independently C2 alkenyls. In some embodiments, each R 1S Independently, each R is a C3 alkenyl. In some embodiments, each R 1S Independently, each R is a C4 alkenyl. In some embodiments, each R 1S Independently, each R is a C5 alkenyl. In some embodiments, each R 1S It is independently a C6 alkenyl.

[0548] In some embodiments, each R 1S These are independently C2-C6 alkynyl compounds.

[0549] In some embodiments, each R 1S These are independently C2 alkynyls. In some embodiments, each R 1S Independently, each R is a C3 alkynyl. In some embodiments, each R 1S Independently, each R is a C4 alkynyl. In some embodiments, each R 1S Independently, each R is a C5 alkynyl. In some embodiments, each R 1S It is independently a C6 alkynyl.

[0550] In some embodiments, each R 1S These are independently C1-C6 alkoxy compounds.

[0551] In some embodiments, each R 1S In some embodiments, each R is methoxy. 1S Independently, each R is ethoxy. In some embodiments, each R 1S In some embodiments, each R is a propoxy. 1S Independently, each R is butoxy. In some embodiments, each R 1S In some embodiments, each R is independently pentoxy. 1S It is independently hexoxy.

[0552] In some embodiments, each R 1S These are independently C3-C7 cycloalkyl or 3-7 member heterocycloalkyl.

[0553] In some embodiments, each R 1S These are independently C3-C7 cycloalkyl groups.

[0554] In some embodiments, each R 1S In some embodiments, each R is cyclopropyl. 1S In some embodiments, each R is cyclobutyl. 1SIndependently, each R is cyclopentyl. In some embodiments, each R 1S In some embodiments, each R is independently cyclohexyl. 1S Independently, each R is cycloheptyl. In some embodiments, each R 1S It is independently cyclooctyl.

[0555] In some embodiments, each R 1S These are independently 3- to 7-membered heterocycloalkyl groups.

[0556] In some embodiments, each R 1S Each R is independently a 3-membered heterocycloalkyl. In some embodiments, each R 1S Each R is independently a 4-membered heterocycloalkyl. In some embodiments, each R 1S Each R is independently a 5-membered heterocycloalkyl. In some embodiments, each R 1S Each R is independently a 6-membered heterocycloalkyl. In some embodiments, each R 1S These are independently 7-membered heterocycloalkyl groups.

[0557] In some embodiments, R2 is a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C6-C 10 Aaryl), -SO2(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 It is a cycloalkyl group, or a -NH- (3-7 member heterocycloalkyl group).

[0558] In some embodiments, R2 is a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C6-C 10 Aaryl), -SO2(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It may be replaced with .

[0559] In some embodiments, R2 is a halogen or -CN.

[0560] In some embodiments, R2 is a halogen.

[0561] In some embodiments, R2 is F, Cl, Br, or I. In some embodiments, R2 is F, Cl, or Br. In some embodiments, R2 is F or Cl.

[0562] In some embodiments, R2 is F. In some embodiments, R2 is Cl. In some embodiments, R2 is Br. In some embodiments, R2 is I.

[0563] In some embodiments, R2 is -CN.

[0564] In some embodiments, R2 is -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C6-C 10 Aaryl), -SO2(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 It is a cycloalkyl group, or a -NH- (3-7 member heterocycloalkyl group).

[0565] In some embodiments, R2 is -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C6-C 10 Aaryl), -SO2(C6-C 10 Aryl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It may be replaced with .

[0566] In some embodiments, R2 is -OH.

[0567] In some embodiments, R2 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), or -S(C6-C 10 It is Ariel.

[0568] In some embodiments, R2 is -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0569] In some embodiments, R2 is -NH2.

[0570] In some embodiments, R2 is -NH(C1-C6 alkyl).

[0571] In some embodiments, R2 is -NH (methyl). In some embodiments, R2 is -NH (ethyl). In some embodiments, R2 is -NH (propyl). In some embodiments, R2 is -NH (butyl). In some embodiments, R2 is -NH (pentyl). In some embodiments, R2 is -NH (hexyl).

[0572] In some embodiments, R2 is --N(C1-C6 alkyl)2.

[0573] In some embodiments, R2 is -SH, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -S(C6-C 10 aryl), or -SO2(C6-C 10 It is Ariel.

[0574] In some embodiments, R2 is -SH.

[0575] In some embodiments, R2 is -S(C1-C6 alkyl) or -S(C6-C 10 It is Ariel.

[0576] In some embodiments, R2 is -S(C1-C6 alkyl).

[0577] In some embodiments, R2 is -S (methyl). In some embodiments, R2 is -S (ethyl). In some embodiments, R2 is -S (propyl). In some embodiments, R2 is -S (butyl). In some embodiments, R2 is -S (heptyl). In some embodiments, R2 is -S (hexyl).

[0578] In some embodiments, R2 is -S(C6-C 10 It is Ariel.

[0579] In some embodiments, R2 is -S(C6 aryl). In some embodiments, R2 is -S(C8 aryl). In some embodiments, R2 is -S(C 10 It is Ariel.

[0580] In some embodiments, R2 is -SO2(C1-C6 alkyl) or -SO2(C6-C 10 It is Ariel.

[0581] In some embodiments, R2 is -SO2(C1-C6 alkyl).

[0582] In some embodiments, R2 is -SO2 (methyl). In some embodiments, R2 is -SO2 (ethyl). In some embodiments, R2 is -SO2 (propyl). In some embodiments, R2 is -SO2 (butyl). In some embodiments, R2 is -SO2 (heptyl). In some embodiments, R2 is -SO2 (hexyl).

[0583] In some embodiments, R2 is -SO2(C6-C 10 It is Ariel.

[0584] In some embodiments, R2 is -SO2(C6 aryl). In some embodiments, R2 is -SO2(C8 aryl). In some embodiments, R2 is -SO2(C 10 It is Ariel.

[0585] In some embodiments, R2 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 It is a cycloalkyl group, or a -NH- (3-7 member heterocycloalkyl group).

[0586] In some embodiments, R2 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2SIt may be replaced with .

[0587] In some embodiments, R2 is a C1-C6 alkyl, a C2-C6 alkenyl, a C1-C6 haloalkyl, or a C1-C6 alkoxy.

[0588] In some embodiments, R2 is a C1-C6 alkyl, a C2-C6 alkenyl, a C1-C6 haloalkyl, or a C1-C6 alkoxy, where the alkyl or alkenyl is one or more R 2S It may be replaced with .

[0589] In some embodiments, R2 is a C1-C6 alkyl, a C2-C6 alkenyl, a C1-C6 haloalkyl, or a C1-C6 alkoxy, where the alkyl or alkenyl is one or more R 2S It has been replaced with.

[0590] In some embodiments, R2 is a C1-C6 alkyl, a C2-C6 alkenyl, a C1-C6 haloalkyl, or a C1-C6 alkoxy, where the alkyl or alkenyl is one R 2S It has been replaced with.

[0591] In some embodiments, R2 is a C1-C6 alkyl, a C2-C6 alkenyl, a C1-C6 haloalkyl, or a C1-C6 alkoxy, where the alkyl or alkenyl is two R 2S It has been replaced with.

[0592] In some embodiments, R2 is a C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, or C1-C6 alkoxy, where alkyl or alkenyl is a three-R 2S It has been replaced with.

[0593] In some embodiments, R2 is a C1-C6 alkyl group.

[0594] In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is propyl. In some embodiments, R2 is butyl. In some embodiments, R2 is pentyl. In some embodiments, R2 is hexyl. In some embodiments, R2 is isopropyl. In some embodiments, R2 is isobutyl. In some embodiments, R2 is isopentyl. In some embodiments, R2 is isohexyl. In some embodiments, R2 is sec-butyl. In some embodiments, R2 is sec-pentyl. In some embodiments, R2 is sec-hexyl. In some embodiments, R2 is tert-butyl.

[0595] In some embodiments, R2 is one or more R 2S It is a C1-C6 alkyl group which may be substituted with [another molecule].

[0596] In some embodiments, R2 is one or more R 2S It is a C1-C6 alkyl group that is substituted with [a specific compound].

[0597] In some embodiments, R2 is one R 2S It is a C1-C6 alkyl group that is substituted with R. In some embodiments, R2 is two R 2S It is a C1-C6 alkyl group that is substituted with. In some embodiments, R2 is a C1-C6 alkyl group. 2S It is a C1-C6 alkyl group that is substituted with [a specific compound].

[0598] In some embodiments, R2 is a C2-C6 alkenyl.

[0599] In some embodiments, R2 is a C2 alkenyl. In some embodiments, R2 is a C3 alkenyl. In some embodiments, R2 is a C4 alkenyl. In some embodiments, R2 is a C5 alkenyl. In some embodiments, R2 is a C6 alkenyl.

[0600] In some embodiments, R2 is one or more R 2S It is a C2-C6 alkenyl that may be substituted with [another compound].

[0601] In some embodiments, R2 is one or more R 2S It is a C2-C6 alkenyl that is substituted with [a specific compound].

[0602] In some embodiments, R2 is one R 2S It is a C2-C6 alkenyl that is substituted with. In some embodiments, R2 is two R 2S It is a C2-C6 alkenyl that is substituted with. In some embodiments, R2 is three R 2S It is a C2-C6 alkenyl that is substituted with [a specific compound].

[0603] In some embodiments, R2 is a C1-C6 haloalkyl group.

[0604] In some embodiments, R2 is halomethyl. In some embodiments, R2 is haloethyl. In some embodiments, R2 is halopropyl. In some embodiments, R2 is halobutyl. In some embodiments, R2 is halopentyl. In some embodiments, R2 is halohexyl.

[0605] In some embodiments, R2 is one or more R 2S It is a C1-C6 haloalkyl which may be substituted with [another compound].

[0606] In some embodiments, R2 is one or more R 2S It is a C1-C6 haloalkyl that is substituted with [a specific compound].

[0607] In some embodiments, R2 is one R 2S It is a C1-C6 haloalkyl substituted with R. In some embodiments, R2 is two R 2S It is a C1-C6 haloalkyl substituted with. In some embodiments, R2 is three R 2SIt is a C1-C6 haloalkyl that is substituted with [a specific compound].

[0608] In some embodiments, R2 is a C1-C6 alkoxy.

[0609] In some embodiments, R2 is methoxy. In some embodiments, R2 is ethoxy. In some embodiments, R2 is propoxy. In some embodiments, R2 is butoxy. In some embodiments, R2 is pentoxy. In some embodiments, R2 is hexoxy.

[0610] In some embodiments, R2 is one or more R 2S It is a C1-C6 alkoxy that may be substituted with [another compound].

[0611] In some embodiments, R2 is one or more R 2S It is a C1-C6 alkoxy that is substituted with [a specific compound].

[0612] In some embodiments, R2 is one R 2S It is a C1-C6 alkoxy substituted with. In some embodiments, R2 is two R 2S It is a C1-C6 alkoxy substituted with. In some embodiments, R2 is three R 2S It is a C1-C6 alkoxy that is substituted with [a specific compound].

[0613] In some embodiments, R2 is C6-C 10 These are aryl, 5-10 member heteroaryl, C3-C7 cycloalkyl, or 3-7 member heterocycloalkyl.

[0614] In some embodiments, R2 is C6-C 10 The aryl group is an aryl group, a 5-10 member heteroaryl group, a C3-C7 cycloalkyl group, or a 3-7 member heterocycloalkyl group, where the aryl group, heteroaryl group, cycloalkyl group, and heterocycloalkyl group are one or more R groups. 2S It may be replaced with .

[0615] In some embodiments, R2 is C6-C 10 The aryl group is an aryl group, a 5-10 member heteroaryl group, a C3-C7 cycloalkyl group, or a 3-7 member heterocycloalkyl group, where the aryl group, heteroaryl group, cycloalkyl group, and heterocycloalkyl group are one or more R groups. 2S It has been replaced with.

[0616] In some embodiments, R2 is C6-C 10 These are aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, or 3-7 membered heterocycloalkyl, where aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are one R 2S It has been replaced with.

[0617] In some embodiments, R2 is C6-C 10 These are aryl, 5-10 member heteroaryl, C3-C7 cycloalkyl, or 3-7 member heterocycloalkyl, where aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are two R 2S It has been replaced with.

[0618] In some embodiments, R2 is C6-C 10 These are aryl, 5-10 member heteroaryl, C3-C7 cycloalkyl, or 3-7 member heterocycloalkyl, where aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are 3R 2S It has been replaced with.

[0619] In some embodiments, R2 is C6-C 10 It is Ariel.

[0620] In some embodiments, R2 is a C6 aryl (e.g., phenyl). In some embodiments, R2 is a C8 aryl. In some embodiments, R2 is C 10 It is Ariel.

[0621] In some embodiments, R2 is one or more R 2S C6-C may be replaced with 10 It is Ariel.

[0622] In some embodiments, R2 is one or more R 2S C6-C is replaced by 10 It is Ariel.

[0623] In some embodiments, R2 is one R 2S C6-C is replaced by 10 It is an arrow. In some embodiments, R2 is two R 2S C6-C is replaced by 10 It is an arrow. In some embodiments, R2 is three R 2S C6-C is replaced by 10 It is Ariel.

[0624] In some embodiments, R2 is a 5- to 10-membered heteroaryl.

[0625] In some embodiments, R2 is a 5-membered heteroaryl compound. In some embodiments, R2 is a 6-membered heteroaryl compound. In some embodiments, R2 is a 7-membered heteroaryl compound. In some embodiments, R2 is an 8-membered heteroaryl compound. In some embodiments, R2 is a 9-membered heteroaryl compound. In some embodiments, R2 is a 10-membered heteroaryl compound.

[0626] In some embodiments, R2 is one or more R 2S It is a 5- to 10-membered heteroaryl that may be substituted with [another compound].

[0627] In some embodiments, R2 is one or more R 2S It is a 5- to 10-membered heteroaryl that is substituted with [a specific compound].

[0628] In some embodiments, R2 is one R 2S It is a 5-10 member heteroaryl substituted with R. In some embodiments, R2 is two R2S It is a 5-10 member heteroaryl substituted with . In some embodiments, R2 is three R 2S It is a 5- to 10-membered heteroaryl that is substituted with [a specific compound].

[0629] In some embodiments, R2 is a C3-C7 cycloalkyl group.

[0630] In some embodiments, R2 is cyclopropyl. In some embodiments, R2 is cyclobutyl. In some embodiments, R2 is cyclopentyl. In some embodiments, R2 is cyclohexyl. In some embodiments, R2 is cycloheptyl.

[0631] In some embodiments, R2 is one or more R 2S It is a C3-C7 cycloalkyl that may be substituted with a different compound.

[0632] In some embodiments, R2 is one or more R 2S It is a C3-C7 cycloalkyl group that is substituted with [a specific compound].

[0633] In some embodiments, R2 is one R 2S It is a C3-C7 cycloalkyl that is substituted with. In some embodiments, R2 is two R 2S It is a C3-C7 cycloalkyl that is substituted with. In some embodiments, R2 is three R 2S It is a C3-C7 cycloalkyl group that is substituted with [a specific compound].

[0634] In some embodiments, R2 is a 3- to 7-membered heterocycloalkyl group.

[0635] In some embodiments, R2 is a 3-membered heterocycloalkyl. In some embodiments, R2 is a 4-membered heterocycloalkyl. In some embodiments, R2 is a 5-membered heterocycloalkyl. In some embodiments, R2 is a 6-membered heterocycloalkyl. In some embodiments, R2 is a 7-membered heterocycloalkyl.

[0636] In some embodiments, R2 is one or more R 2S It is a 3- to 7-membered heterocycloalkyl group which may be substituted with a different compound.

[0637] In some embodiments, R2 is one or more R 2S It is a 3- to 7-membered heterocycloalkyl group that is substituted with [a specific compound].

[0638] In some embodiments, R2 is one R 2S It is a 3- to 7-membered heterocycloalkyl that is substituted with R. In some embodiments, R2 is two R 2S It is a 3- to 7-membered heterocycloalkyl that is substituted with R. In some embodiments, R2 is 3 R 2S It is a 3- to 7-membered heterocycloalkyl group that is substituted with [a specific compound].

[0639] In some embodiments, R2 is -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 It is a cycloalkyl group, or a -NH- (3-7 member heterocycloalkyl group).

[0640] In some embodiments, R2 is -O-(C6-C 10 aryl), -O-(5-10 member heteroaryl), -O-(C3-C 10 It is a cycloalkyl group, or an -O- (3-7 member heterocycloalkyl group).

[0641] In some embodiments, R2 is -O-(C6-C 10 It is Ariel.

[0642] In some embodiments, R2 is -O-(C6 aryl). In some embodiments, R2 is -O-(C8 aryl). In some embodiments, R2 is -O-(C 10 It is Ariel.

[0643] In some embodiments, R2 is -O-(5-10 member heteroaryl).

[0644] In some embodiments, R2 is -O- (5-membered heteroaryl). In some embodiments, R2 is -O- (6-membered heteroaryl). In some embodiments, R2 is -O- (7-membered heteroaryl). In some embodiments, R2 is -O- (8-membered heteroaryl). In some embodiments, R2 is -O- (9-membered heteroaryl). In some embodiments, R2 is -O- (10-membered heteroaryl).

[0645] In some embodiments, R2 is -O-(C3-C 10 It is a cycloalkyl group.

[0646] In some embodiments, R2 is -O-(C3 cycloalkyl). In some embodiments, R2 is -O-(C4 cycloalkyl). In some embodiments, R2 is -O-(C5 cycloalkyl). In some embodiments, R2 is -O-(C6 cycloalkyl). In some embodiments, R2 is -O-(C7 cycloalkyl). In some embodiments, R2 is -O-(C8 cycloalkyl). In some embodiments, R2 is -O-(C9 cycloalkyl). In some embodiments, R2 is -O-(C 10 It is a cycloalkyl group.

[0647] In some embodiments, R2 is -O-(3-7 member heterocycloalkyl).

[0648] In some embodiments, R2 is -O-(3-membered heterocycloalkyl). In some embodiments, R2 is -O-(4-membered heterocycloalkyl). In some embodiments, R2 is -O-(5-membered heterocycloalkyl). In some embodiments, R2 is -O-(6-membered heterocycloalkyl). In some embodiments, R2 is -O-(7-membered heterocycloalkyl).

[0649] In some embodiments, R2 is -NH-(C6-C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C3-C 10 It is a cycloalkyl group, or a -NH- (3-7 member heterocycloalkyl group).

[0650] In some embodiments, R2 is -NH-(C6-C 10 It is Ariel.

[0651] In some embodiments, R2 is -NH-(C6 aryl). In some embodiments, R2 is -NH-(C8 aryl). In some embodiments, R2 is -NH-(C 10 It is Ariel.

[0652] In some embodiments, R2 is -NH- (5-10 member heteroaryl).

[0653] In some embodiments, R2 is -NH- (5-membered heteroaryl). In some embodiments, R2 is -NH- (6-membered heteroaryl). In some embodiments, R2 is -NH- (7-membered heteroaryl). In some embodiments, R2 is -NH- (8-membered heteroaryl). In some embodiments, R2 is -NH- (9-membered heteroaryl). In some embodiments, R2 is -NH- (10-membered heteroaryl).

[0654] In some embodiments, R2 is -NH-(C3-C 10 It is a cycloalkyl group.

[0655] In some embodiments, R2 is -NH-(C3 cycloalkyl). In some embodiments, R2 is -NH-(C4 cycloalkyl). In some embodiments, R2 is -NH-(C5 cycloalkyl). In some embodiments, R2 is -NH-(C6 cycloalkyl). In some embodiments, R2 is -NH-(C7 cycloalkyl). In some embodiments, R2 is -NH-(C8 cycloalkyl). In some embodiments, R2 is -NH-(C9 cycloalkyl). In some embodiments, R2 is -NH-(C 10 It is a cycloalkyl group.

[0656] In some embodiments, R2 is -NH-(3-7 member heterocycloalkyl).

[0657] In some embodiments, R2 is -NH- (3-membered heterocycloalkyl). In some embodiments, R2 is -NH- (4-membered heterocycloalkyl). In some embodiments, R2 is -NH- (5-membered heterocycloalkyl). In some embodiments, R2 is -NH- (6-membered heterocycloalkyl). In some embodiments, R2 is -NH- (7-membered heterocycloalkyl).

[0658] In some embodiments, R2 is The filename is TIFF0007840517000018.tif137148.

[0659] In some embodiments, R2 is The filename is TIFF0007840517000019.tif24128.

[0660] In some embodiments, R2 is The filename is TIFF0007840517000020.tif16128.

[0661] In some embodiments, R2 is The filename is TIFF0007840517000021.tif21128.

[0662] In some embodiments, R2 is The filename is TIFF0007840517000022.tif20128.

[0663] In some embodiments, R2 is The filename is TIFF0007840517000023.tif23128.

[0664] In some embodiments, R2 is -CN, The filename is TIFF0007840517000024.tif43128.

[0665] In some embodiments, R2 is The filename is TIFF0007840517000025.tif60147.

[0666] In some embodiments, R2 is The filename is TIFF0007840517000026.tif147160.

[0667] In some embodiments, each R 2S These are independently oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl.

[0668] In some embodiments, each R 2S These are independently oxo, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl.

[0669] In some embodiments, each R2S These are independently oxo, halogen, or -CN.

[0670] In some embodiments, each R 2S It is independently oxo.

[0671] In some embodiments, each R 2S These are, independently, halogens.

[0672] In some embodiments, each R 2S These are independently F, Cl, Br, or I. In some embodiments, each R 2S R is independently F, Cl, or Br. In some embodiments, each R 2S These are independently F or Cl.

[0673] In some embodiments, each R 2S Independently, F. In some embodiments, each R 2S Independently, each R is Cl. In some embodiments, each R 2S Independently, each R is Br. In some embodiments, each R 2S These are independently I.

[0674] In some embodiments, each R 2S It is independently -CN.

[0675] In some embodiments, each R 2S These are independently -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), or -SO2(C1-C6 alkyl).

[0676] In some embodiments, each R 2S These are independently -OH.

[0677] In some embodiments, each R 2S These are independently -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), or -SO2(C1-C6 alkyl).

[0678] In some embodiments, each R 2S These are independently -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0679] In some embodiments, each R 2S These are independently -NH2.

[0680] In some embodiments, each R 2S These are independently -NH(C1-C6 alkyl).

[0681] In some embodiments, each R 2S Independently, each R is -NH (methyl). In some embodiments, each R 2S R is independently -NH(ethyl). In some embodiments, each R 2S Independently, each R is -NH(propyl). In some embodiments, each R 2S Independently, each R is -NH (butyl). In some embodiments, each R 2S Independently, each R is -NH (pentyl). In some embodiments, each R 2S It is independently -NH (hexyl).

[0682] In some embodiments, each R 2S These are independently -N(C1-C6 alkyl)2.

[0683] In some embodiments, each R 2S These are independently -S(C1-C6 alkyl) or -SO2(C1-C6 alkyl).

[0684] In some embodiments, each R 2S These are independently -S(C1-C6 alkyl).

[0685] In some embodiments, each R 2S Independently, each R is -S (methyl). In some embodiments, each R 2S Independently, each R is -S (ethyl). In some embodiments, each R 2SIndependently, each R is -S (propyl). In some embodiments, each R 2S These are independently -S (butyl). In some embodiments, each R 2S These are independently -S (heptyl). In some embodiments, each R 2S These are independently -S (hexyl).

[0686] In some embodiments, each R 2S These are independently -SO2(C1-C6 alkyl).

[0687] In some embodiments, each R 2S R is independently -SO2(methyl). In some embodiments, each R 2S R is independently -SO2(ethyl). In some embodiments, each R 2S R is independently -SO2(propyl). In some embodiments, each R 2S R is independently -SO2(butyl). In some embodiments, each R 2S These are independently -SO2 (heptyl). In some embodiments, each R 2S It is independently -SO2 (hexyl).

[0688] In some embodiments, each R 2S These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl.

[0689] In some embodiments, each R 2S These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl.

[0690] In some embodiments, each R 2S These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0691] In some embodiments, each R 2S These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy.

[0692] In some embodiments, each R 2S These are independently C1-C6 alkyl groups.

[0693] In some embodiments, each R 2S R is independently methyl. In some embodiments, each R 2S is independently ethyl. In some embodiments, each R 2S R is independently propyl. In some embodiments, each R 2S is independently butyl. In some embodiments, each R 2S In some embodiments, each R is independently pentill. 2S In some embodiments, each R is independently hexyl. 2S is independently isopropyl. In some embodiments, each R 2S is independently isobutyl. In some embodiments, each R 2S is independently isopentyl. In some embodiments, each R 2S is independently isohexyl. In some embodiments, each R 2S In some embodiments, each R is independently sec-butyl. 1S Independently, each R is secpentyl. In some embodiments, each R 2S Independently, each R is sec hexyl. In some embodiments, each R 2S It is independently tert-butyl.

[0694] In some embodiments, each R 2S These are independently C2-C6 alkenyls.

[0695] In some embodiments, each R 2S These are independently C2 alkenyls. In some embodiments, each R 2SIndependently, each R is a C3 alkenyl. In some embodiments, each R 2S Independently, each R is a C4 alkenyl. In some embodiments, each R 2S Independently, each R is a C5 alkenyl. In some embodiments, each R 2S It is independently a C6 alkenyl.

[0696] In some embodiments, each R 2S These are independently C2-C6 alkynyl compounds.

[0697] In some embodiments, each R 2S These are independently C2 alkynyls. In some embodiments, each R 2S Independently, each R is a C3 alkynyl. In some embodiments, each R 2S Independently, each R is a C4 alkynyl. In some embodiments, each R 2S Independently, each R is a C5 alkynyl. In some embodiments, each R 2S It is independently a C6 alkynyl.

[0698] In some embodiments, each R 2S These are independently C1-C6 alkoxy compounds.

[0699] In some embodiments, each R 2S In some embodiments, each R is methoxy. 2S Independently, each R is ethoxy. In some embodiments, each R 2S In some embodiments, each R is a propoxy. 2S Independently, each R is butoxy. In some embodiments, each R 2S In some embodiments, each R is independently pentoxy. 2S It is independently hexoxy.

[0700] In some embodiments, each R 2S These are independently C1-C6 haloalkyl groups.

[0701] In some embodiments, each R 2SEach R is independently a C1 haloalkyl. In some embodiments, each R 2S Each R is independently a C2 haloalkyl. In some embodiments, each R 2S Each R is independently a C3 haloalkyl. In some embodiments, each R 2S Each R is independently a C4 haloalkyl. In some embodiments, each R 2S Each R is independently a C5 haloalkyl. In some embodiments, each R 2S These are independently C6 haloalkyl groups.

[0702] In some embodiments, each R 2S These are independently C3-C7 cycloalkyl or 3-7 member heterocycloalkyl.

[0703] In some embodiments, each R 2S These are independently C3-C7 cycloalkyl groups.

[0704] In some embodiments, each R 2S In some embodiments, each R is cyclopropyl. 2S In some embodiments, each R is cyclobutyl. 2S Independently, each R is cyclopentyl. In some embodiments, each R 2S In some embodiments, each R is independently cyclohexyl. 2S Independently, each R is cycloheptyl. In some embodiments, each R 2S It is independently cyclooctyl.

[0705] In some embodiments, each R 2S These are independently 3- to 7-membered heterocycloalkyl groups.

[0706] In some embodiments, each R 2S Each R is independently a 3-membered heterocycloalkyl. In some embodiments, each R 2S Each R is independently a 4-membered heterocycloalkyl. In some embodiments, each R 2S Each R is independently a 5-membered heterocycloalkyl. In some embodiments, each R2S Each R is independently a 6-membered heterocycloalkyl. In some embodiments, each R 2S These are independently 7-membered heterocycloalkyl groups.

[0707] In some embodiments, each R3 is independently a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy.

[0708] In some embodiments, each R3 is independently a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0709] In some embodiments, each R3 is independently a halogen.

[0710] 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.

[0711] 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.

[0712] In some embodiments, each R3 is independently -CN.

[0713] In some embodiments, each R3 is independently -OH.

[0714] In some embodiments, each R3 is independently -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0715] In some embodiments, each R3 is independently -NH2.

[0716] In some embodiments, each R3 is independently -NH(C1-C6 alkyl).

[0717] In some embodiments, each R3 is independently -NH (methyl). In some embodiments, each R3 is independently -NH (ethyl). In some embodiments, each R3 is independently -NH (propyl). In some embodiments, each R3 is independently -NH (butyl). In some embodiments, each R3 is independently -NH (pentyl). In some embodiments, each R3 is independently -NH (hexyl).

[0718] In some embodiments, each R3 is independently -N(C1-C6 alkyl)2.

[0719] In some embodiments, each R3 is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy.

[0720] In some embodiments, each R3 is independently a C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl.

[0721] In some embodiments, each R3 is independently a C1-C6 alkyl group.

[0722] In some embodiments, each R3 is independently methyl. In some embodiments, each R3 is independently ethyl. In some embodiments, each R3 is independently propyl. In some embodiments, each R3 is independently butyl. In some embodiments, each R3 is independently pentyl. In some embodiments, each R3 is independently hexyl. In some embodiments, each R3 is independently isopropyl. In some embodiments, each R3 is independently isobutyl. In some embodiments, each R3 is independently isopentyl. In some embodiments, each R3 is independently isohexyl. In some embodiments, each R3 is independently sec-butyl. In some embodiments, each R3 is independently sec-pentyl. In some embodiments, each R3 is independently sec-hexyl. In some embodiments, each R3 is independently tert-butyl.

[0723] In some embodiments, each R3 is independently a C2-C6 alkenyl.

[0724] In some embodiments, each R3 is independently a C2 alkenyl. In some embodiments, each R3 is independently a C3 alkenyl. In some embodiments, each R3 is independently a C4 alkenyl. In some embodiments, each R3 is independently a C5 alkenyl. In some embodiments, each R3 is independently a C6 alkenyl.

[0725] In some embodiments, each R3 is independently a C2-C6 alkynyl.

[0726] In some embodiments, each R3 is independently a C2 alkynyl. In some embodiments, each R3 is independently a C3 alkynyl. In some embodiments, each R3 is independently a C4 alkynyl. In some embodiments, each R3 is independently a C5 alkynyl. In some embodiments, each R3 is independently a C6 alkynyl.

[0727] In some embodiments, each R3 is independently a C1-C6 haloalkyl or C 1-6It is an alkoxy.

[0728] In some embodiments, each R3 is independently a C1-C6 haloalkyl.

[0729] In some embodiments, each R3 is independently halomethyl. In some embodiments, each R3 is independently haloethyl. In some embodiments, each R3 is independently halopropyl. In some embodiments, each R3 is independently halobutyl. In some embodiments, each R3 is independently halopentyl. In some embodiments, each R3 is independently halohexyl.

[0730] In some embodiments, each R3 independently, C 1-6 It is an alkoxy.

[0731] 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.

[0732] In some embodiments, R 4a This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy;

[0733] In some embodiments, R 4a These are halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0734] In some embodiments, R 4a It is a halogen.

[0735] In some embodiments, R 4a is F, Cl, Br, or I. In some embodiments, R 4a is F, Cl, or Br. In some embodiments, R 4a It is either F or Cl.

[0736] In some embodiments, R 4a is F. In some embodiments, R 4a is Cl. In some embodiments, R 4a is Br. In some embodiments, R 4a It is I.

[0737] In some embodiments, R 4a It is -CN.

[0738] In some embodiments, R 4a It is -OH.

[0739] In some embodiments, R 4a This is -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0740] In some embodiments, R 4a It is -NH2.

[0741] In some embodiments, R 4a It is -NH(C1-C6 alkyl).

[0742] In some embodiments, R 4a is -NH (methyl). In some embodiments, R 4a R is -NH (ethyl). In some embodiments, R 4a It is -NH (propyl). In some embodiments, R 4a is -NH (butyl). In some embodiments, R 4a It is -NH (pentyl). In some embodiments, R 4a It is -NH (hexyl).

[0743] In some embodiments, R 4a It is -N(C1-C6 alkyl)2.

[0744] In some embodiments, R 4a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy.

[0745] In some embodiments, R 4a This is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0746] In some embodiments, R 4a H is H.

[0747] In some embodiments, R 4a These are C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0748] In some embodiments, R 4a These are C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl compounds.

[0749] In some embodiments, R 4a It is a C1-C6 alkyl group.

[0750] In some embodiments, R 4a is methyl. In some embodiments, R 4a is ethyl. In some embodiments, R 4a is propyl. In some embodiments, R 4a is butyl. In some embodiments, R 4a is pentyl. In some embodiments, R 4a is hexyl. In some embodiments, R 4a is isopropyl. In some embodiments, R 4a isobutyl. In some embodiments, R 4ais isopentyl. In some embodiments, R 4a is isohexyl. In some embodiments, R 4a is secbutyl. In some embodiments, R 4a secpentyl is secpentyl. In some embodiments, R 4a is sec hexyl. In some embodiments, R 4a It is tert-butyl.

[0751] In some embodiments, R 4a It is a C2-C6 alkenyl.

[0752] In some embodiments, R 4a is a C2 alkenyl. In some embodiments, R 4a is a C3 alkenyl. In some embodiments, R 4a is a C4 alkenyl. In some embodiments, R 4a is a C5 alkenyl. In some embodiments, R 4a This is a C6 alkenyl.

[0753] In some embodiments, R 4a This is a C2-C6 alkynyl compound.

[0754] In some embodiments, R 4a is C2 alkynyl. In some embodiments, R 4a is C3 alkynyl. In some embodiments, R 4a is C4 alkynyl. In some embodiments, R 4a is C5 alkynyl. In some embodiments, R 4a This is C6 alkynyl.

[0755] In some embodiments, R 4a It is a C1-C6 haloalkyl group.

[0756] In some embodiments, R 4a is a halomethyl. In some embodiments, R 4a is haloethyl. In some embodiments, R4a is a halopropyl. In some embodiments, R 4a is halobutyl. In some embodiments, R 4a is halopentyl. In some embodiments, R 4a It is a halohexyl.

[0757] In some embodiments, R 4a C 1-6 It is an alkoxy.

[0758] In some embodiments, R 4a is methoxy. In some embodiments, R 4a is ethoxy. In some embodiments, R 4a is a propoxy. In some embodiments, R 4a is butoxy. In some embodiments, R 4a is pentoxy. In some embodiments, R 4a It is hexoxy.

[0759] In some embodiments, R 4b This includes H, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy;

[0760] In some embodiments, R 4b These are halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0761] In some embodiments, R 4b It is a halogen.

[0762] In some embodiments, R 4b is F, Cl, Br, or I. In some embodiments, R 4b is F, Cl, or Br. In some embodiments, R 4b It is either F or Cl.

[0763] In some embodiments, R 4b is F. In some embodiments, R 4b is Cl. In some embodiments, R 4b is Br. In some embodiments, R 4b It is I.

[0764] In some embodiments, R 4b It is -CN.

[0765] In some embodiments, R 4b It is -OH.

[0766] In some embodiments, R 4b This is -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0767] In some embodiments, R 4b It is -NH2.

[0768] In some embodiments, R 4b It is -NH(C1-C6 alkyl).

[0769] In some embodiments, R 4b is -NH (methyl). In some embodiments, R 4b R is -NH (ethyl). In some embodiments, R 4b It is -NH (propyl). In some embodiments, R 4b is -NH (butyl). In some embodiments, R 4b It is -NH (pentyl). In some embodiments, R 4b It is -NH (hexyl).

[0770] In some embodiments, R 4b It is -N(C1-C6 alkyl)2.

[0771] In some embodiments, R 4bC1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 It is an alkoxy.

[0772] In some embodiments, R 4b This is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0773] In some embodiments, R 4b H is H.

[0774] In some embodiments, R 4b These are C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0775] In some embodiments, R 4b These are C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl compounds.

[0776] In some embodiments, R 4b It is a C1-C6 alkyl group.

[0777] In some embodiments, R 4b is methyl. In some embodiments, R 4b is ethyl. In some embodiments, R 4b is propyl. In some embodiments, R 4b is butyl. In some embodiments, R 4b is pentyl. In some embodiments, R 4b is hexyl. In some embodiments, R 4b is isopropyl. In some embodiments, R 4b isobutyl. In some embodiments, R 4b is isopentyl. In some embodiments, R 4b is isohexyl. In some embodiments, R 4b is secbutyl. In some embodiments, R 4bsecpentyl is secpentyl. In some embodiments, R 4b is sec hexyl. In some embodiments, R 4b It is tert-butyl.

[0778] In some embodiments, R 4b It is a C2-C6 alkenyl.

[0779] In some embodiments, R 4b is a C2 alkenyl. In some embodiments, R 4b is a C3 alkenyl. In some embodiments, R 4b is a C4 alkenyl. In some embodiments, R 4b is a C5 alkenyl. In some embodiments, R 4b This is a C6 alkenyl.

[0780] In some embodiments, R 4b This is a C2-C6 alkynyl compound.

[0781] In some embodiments, R 4b is C2 alkynyl. In some embodiments, R 4b is C3 alkynyl. In some embodiments, R 4b is C4 alkynyl. In some embodiments, R 4b is C5 alkynyl. In some embodiments, R 4b This is C6 alkynyl.

[0782] In some embodiments, R 4b It is a C1-C6 haloalkyl group.

[0783] In some embodiments, R 4b is a halomethyl. In some embodiments, R 4b is haloethyl. In some embodiments, R 4b is a halopropyl. In some embodiments, R 4b is halobutyl. In some embodiments, R 4b is halopentyl. In some embodiments, R4b It is a halohexyl.

[0784] In some embodiments, R 4b C 1-6 It is an alkoxy.

[0785] In some embodiments, R 4b is methoxy. In some embodiments, R 4b is ethoxy. In some embodiments, R 4b is a propoxy. In some embodiments, R 4b is butoxy. In some embodiments, R 4b is pentoxy. In some embodiments, R 4b It is hexoxy.

[0786] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1.

[0787] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0788] In some embodiments, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1.

[0789] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0790] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1.

[0791] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0792] In some embodiments, the compound is a compound of formula (I-1) where q is 0, 1, 2, 3, 4, or 5: The compound TIFF0007840517000027.tif50128, or its prodrug, solvate, or pharmaceutically acceptable salt.

[0793] In some embodiments, the compound is the compound of formula (I-1), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0794] In some embodiments, the compound is of formula (I-1a), (I-1b), or (I-1c), where q is 0, 1, 2, 3, 4, or 5: The compound TIFF0007840517000028.tif106128, or its prodrug, solvate, or pharmaceutically acceptable salt.

[0795] In some embodiments, the compound is the compound of formula (I-1a), or its prodrug, solvate, or pharmaceutically acceptable salt.

[0796] In some embodiments, the compound is the compound of formula (I-1b), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0797] In some embodiments, the compound is the compound of formula (I-1c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0798] In some embodiments, the compound is a compound of formula (I-2) where q is 0, 1, 2, 3, 4, or 5: The compound TIFF0007840517000029.tif50128, or its prodrug, solvate, or pharmaceutically acceptable salt.

[0799] In some embodiments, the compound is the compound of formula (I-2), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0800] In some embodiments, the compound is of formula (I-2a), (I-2b), or (I-2c), where q is 0, 1, 2, 3, 4, or 5: The compound TIFF0007840517000030.tif112134, or its prodrug, solvate, or pharmaceutically acceptable salt.

[0801] In some embodiments, the compound is the compound of formula (I-2a), or its prodrug, solvate, or pharmaceutically acceptable salt.

[0802] In some embodiments, the compound is the compound of formula (I-2b), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0803] In some embodiments, the compound is the compound of formula (I-2c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0804] In some embodiments, the compound is a compound of formula (I-3) where q is 0, 1, 2, 3, 4, or 5: The compound TIFF0007840517000031.tif50128, or its prodrug, solvate, or pharmaceutically acceptable salt.

[0805] In some embodiments, the compound is a compound of formula (I-3), or a prodrug, solvate thereof, or a pharmaceutically acceptable salt thereof.

[0806] In some embodiments, the compound is of formula (I-3a), (I-3b), or (I-3c), where q is 0, 1, 2, 3, 4, or 5: The compound TIFF0007840517000032.tif107128, or its prodrug, solvate, or pharmaceutically acceptable salt.

[0807] In some embodiments, the compound is the compound of formula (I-3a), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0808] In some embodiments, the compound is the compound of formula (I-3b), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0809] In some embodiments, the compound is a compound of formula (I-3c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0810] In some embodiments, the compound is a compound of formula (II-1) where q is 0, 1, 2, 3, 4, or 5: The compound TIFF0007840517000033.tif46128, or its prodrug, solvate, or pharmaceutically acceptable salt.

[0811] In some embodiments, the compound is the compound of formula (II-1), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0812] In some embodiments, the compound is of formula (II-1a), (II-1b), or (II-1c), where q is 0, 1, 2, 3, 4, or 5: The compound TIFF0007840517000034.tif100128, or its prodrug, solvate, or pharmaceutically acceptable salt.

[0813] In some embodiments, the compound is the compound of formula (II-1a), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0814] In some embodiments, the compound is the compound of formula (II-1b), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0815] In some embodiments, the compound is the compound of formula (II-1c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0816] In some embodiments, the compound is a compound of formula (III-1) where q is 0, 1, 2, 3, 4, or 5: The compound TIFF0007840517000035.tif49128, or its prodrug, solvate, or pharmaceutically acceptable salt.

[0817] In some embodiments, the compound is the compound of formula (III-1), or a prodrug, solvate thereof, or a pharmaceutically acceptable salt thereof.

[0818] In some embodiments, the compound is of formula (III-1a), (III-1b), or (III-1c), where q is 0, 1, 2, 3, 4, or 5: The compound TIFF0007840517000036.tif107128, or its prodrug, solvate, or pharmaceutically acceptable salt.

[0819] In some embodiments, the compound is the compound of formula (III-1a), or its prodrug, solvate, or pharmaceutically acceptable salt.

[0820] In some embodiments, the compound is the compound of formula (III-1b), or a prodrug, solvate thereof, or a pharmaceutically acceptable salt thereof.

[0821] In some embodiments, the compound is the compound of formula (III-1c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0822] In some embodiments, the compound of formula (I''') is a compound of formula (I-1), formula (I-1a), formula (I-1b), formula (I-1c), formula (I-2), formula (I-2a), formula (I-2b), formula (I-2c), formula (I-3), formula (I-3a), formula (I-3b), formula (I-3c), formula (II-1), formula (II-1a), formula (II-1b), formula (II-1c), formula (III-1), formula (III-1a), formula (III-1b), or formula (III-1c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0823] In some embodiments, the compound of formula (I'') is a compound of formula (I-1), formula (I-1a), formula (I-1b), formula (I-1c), formula (I-2), formula (I-2a), formula (I-2b), formula (I-2c), formula (I-3), formula (I-3a), formula (I-3b), formula (I-3c), formula (II-1), formula (II-1a), formula (II-1b), formula (II-1c), formula (III-1), formula (III-1a), formula (III-1b), or formula (III-1c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0824] In some embodiments, the compound of formula (I') is a compound of formula (I-1), formula (I-1a), formula (I-1b), formula (I-1c), formula (I-2), formula (I-2a), formula (I-2b), formula (I-2c), formula (I-3), formula (I-3a), formula (I-3b), formula (I-3c), formula (II-1), formula (II-1a), formula (II-1b), formula (II-1c), formula (III-1), formula (III-1a), formula (III-1b), or formula (III-1c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0825] In some embodiments, the compound of formula (I) is a compound of formula (I-1), formula (I-1a), formula (I-1b), or formula (I-1c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0826] In some embodiments, the compound of formula (II) is a compound of formula (II-1), formula (II-1a), formula (II-1b), or formula (II-1c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0827] In some embodiments, the compound of formula (III) is a compound of formula (III-1), formula (III-1a), formula (III-1b), or formula (III-1c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0828] For any one of the compounds of the formulas described herein, X, Y, Z, R X1 , R X2 , R Y , R Z Ar1, R 1、 R 1S , R 2、 R 2S , R3, R 4a , R 4b n, m, or p may, where applicable, be selected from the groups described herein, and X, Y, Z, R X1 , R X2 , R Y , R Z Ar1, R 1、 R 1S , R 2、 R 2S , R3, R 4a , R 4b Any group described herein for any of n, m, or p, where applicable, is X, Y, Z, R X1 , R X2 , R Y , R Z Ar1, R 1、 R 1S , R 2、 R 2S, R3, R 4a , R 4b It is understood that these can be combined with any of the groups described herein for the remaining one or more of n, m, or p.

[0829] In some embodiments, the compound is selected from the compounds listed in Table 1, as well as their prodrugs and pharmaceutically acceptable salts.

[0830] In some embodiments, the compound is selected from the compounds listed in Table 1 and their pharmaceutically acceptable salts.

[0831] In some embodiments, the compound is selected from the prodrugs of the compounds listed in Table 1 and their pharmaceutically acceptable salts.

[0832] In some embodiments, the compound is selected from the compounds listed in Table 1.

[0833] In some embodiments, the compound is selected from the compounds listed in Table 2, as well as their prodrugs and pharmaceutically acceptable salts.

[0834] In some embodiments, the compound is selected from the compounds listed in Table 2 and their pharmaceutically acceptable salts.

[0835] In some embodiments, the compound is selected from the prodrugs of the compounds listed in Table 2 and their pharmaceutically acceptable salts.

[0836] In some embodiments, the compound is selected from the compounds listed in Table 2.

[0837] In some embodiments, the compound is selected from the compounds listed in Table 3, as well as their prodrugs and pharmaceutically acceptable salts.

[0838] In some embodiments, the compound is selected from the compounds listed in Table 3 and their pharmaceutically acceptable salts.

[0839] In some embodiments, the compound is selected from the prodrugs of the compounds listed in Table 3 and their pharmaceutically acceptable salts.

[0840] In some embodiments, the compound is selected from the compounds listed in Table 3.

[0841] In some embodiments, the compound is selected from the compounds listed in Table 4, as well as their prodrugs and pharmaceutically acceptable salts.

[0842] In some embodiments, the compound is selected from the compounds listed in Table 4 and their pharmaceutically acceptable salts.

[0843] In some embodiments, the compound is selected from the prodrugs of the compounds listed in Table 4 and their pharmaceutically acceptable salts.

[0844] In some embodiments, the compound is selected from the compounds listed in Table 4.

[0845] In some embodiments, the compound is selected from the compounds listed in Table 5, as well as their prodrugs and pharmaceutically acceptable salts.

[0846] In some embodiments, the compound is selected from the compounds listed in Table 5 and their pharmaceutically acceptable salts.

[0847] In some embodiments, the compound is selected from the prodrugs of the compounds listed in Table 5 and their pharmaceutically acceptable salts.

[0848] In some embodiments, the compound is selected from the compounds listed in Table 5.

[0849] (Table 1) TIFF0007840517000037.tif90137TIFF0007840517000038.tif220137TIFF0007840517000039.tif182137TIFF0007840517000040.tif218137TIFF0007840517000041.tif219137TIFF0007840517000042.tif208137TIFF0007840517000043.tif183137TIFF0007840517000044.tif215137TIFF0007840517000045.tif197137TIFF0007840517000046.tif198137TIFF0007840517000047.tif195137TIFF0007840517000048.tif197137TIFF0007840517000049.tif203137TIFF0007840517000050.tif194137TIFF0007840517000051.tif197137TIFF0007840517000052.tif194137TIFF0007840517000053.tif201137TIFF0007840517000054.tif216137TIFF0007840517000055.tif206137TIFF0007840517000056.tif205137TIFF0007840517000057.tif207137TIFF0007840517000058.tif215137TIFF0007840517000059.tif213137TIFF0007840517000060.tif205137TIFF0007840517000061.tif219137TIFF0007840517000062.tif217137TIFF0007840517000063.tif213137TIFF0007840517000064.tif215137TIFF0007840517000065.tif215137TIFF0007840517000066.tif209137TIFF0007840517000067.tif205137TIFF0007840517000068.tif217137TIFF0007840517000069.tif208137TIFF0007840517000070.tif214137TIFF0007840517000071.tif211137TIFF0007840517000072.tif181137TIFF0007840517000073.tif220137TIFF0007840517000074.tif214137TIFF0007840517000075.tif220137TIFF0007840517000076.tif182137TIFF0007840517000077.tif221137TIFF0007840517000078.tif217137TIFF0007840517000079.tif206137TIFF0007840517000080.tif211137TIFF0007840517000081.tif176137TIFF0007840517000082.tif184137TIFF0007840517000083.tif216137TIFF0007840517000084.tif181137TIFF0007840517000085.tif234137.

[0850] (Table 2) TIFF0007840517000086.tif111161TIFF0007840517000087.tif205161TIFF0007840517000088.tif164161TIFF0007840517000089.tif179161TIFF0007840517000090.tif194161TIFF0007840517000091.tif184161TIFF0007840517000092.tif204161TIFF0007840517000093.tif205161TIFF0007840517000094.tif214161TIFF0007840517000095.tif207161TIFF0007840517000096.tif208161TIFF0007840517000097.tif211161TIFF0007840517000098.tif208161TIFF0007840517000099.tif176161TIFF0007840517000100.tif176161TIFF0007840517000101.tif190161TIFF0007840517000102.tif202161

[0851] (Table 3) TIFF0007840517000103.tif201164TIFF0007840517000104.tif220164TIFF0007840517000105.tif213164TIFF0007840517000106.tif176164TIFF0007840517000107.tif176164TIFF0007840517000108.tif180164TIFF0007840517000109.tif184164TIFF0007840517000110.tif182164TIFF0007840517000111.tif178164TIFF0007840517000112.tif178164TIFF0007840517000113.tif178164TIFF0007840517000114.tif178164TIFF0007840517000115.tif178164TIFF0007840517000116.tif176164TIFF0007840517000117.tif176164TIFF0007840517000118.tif176164TIFF0007840517000119.tif180164TIFF0007840517000120.tif176164TIFF0007840517000121.tif180164TIFF0007840517000122.tif179164TIFF0007840517000123.tif176164TIFF0007840517000124.tif198164TIFF0007840517000125.tif192164TIFF0007840517000126.tif195164TIFF0007840517000127.tif176164TIFF0007840517000128.tif243164

[0852] (Table 4) TIFF0007840517000129.tif129160TIFF0007840517000130.tif180160TIFF0007840517000131.tif183160TIFF0007840517000132.tif176160TIFF0007840517000133.tif175160TIFF0007840517000134.tif175160TIFF0007840517000135.tif181160TIFF0007840517000136.tif177160TIFF0007840517000137.tif190160TIFF0007840517000138.tif186160TIFF0007840517000139.tif187160TIFF0007840517000140.tif178160TIFF0007840517000141.tif191160TIFF0007840517000142.tif199160TIFF0007840517000143.tif244160

[0853] (Table 5) TIFF0007840517000144.tif121159TIFF0007840517000145.tif190159TIFF00078405170 00146.tif188159TIFF0007840517000147.tif188159TIFF0007840517000148.tif195159 TIFF0007840517000149.tif189159TIFF0007840517000150.tif175159TIFF00078405170 00151.tif176159TIFF0007840517000152.tif171159TIFF0007840517000153.tif198159 TIFF0007840517000154.tif181159TIFF0007840517000155.tif220159TIFF00078405170 00156.tif174159TIFF0007840517000157.tif222159TIFF0007840517000158.tif220159 TIFF0007840517000159.tif221159TIFF0007840517000160.tif171159TIFF00078405170 00161.tif218159TIFF0007840517000162.tif178159TIFF0007840517000163.tif228159

[0854] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 1.

[0855] In some aspects, the present disclosure provides compounds that are isotopic derivatives (e.g., isotope-labeled compounds) of any one of the compounds represented by the formulas disclosed herein.

[0856] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 1, as well as their prodrugs and pharmaceutically acceptable salts.

[0857] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1 and their pharmaceutically acceptable salts.

[0858] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 1 or of their pharmaceutically acceptable salts.

[0859] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1.

[0860] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 2.

[0861] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 2, as well as their prodrugs and pharmaceutically acceptable salts.

[0862] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 2 or any of the pharmaceutically acceptable salts thereof.

[0863] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 2 or of any of the pharmaceutically acceptable salts thereof.

[0864] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 2.

[0865] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 3.

[0866] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 3, as well as their prodrugs and pharmaceutically acceptable salts.

[0867] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 3 or their pharmaceutically acceptable salts.

[0868] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 3 or of any pharmaceutically acceptable salts thereof.

[0869] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 3.

[0870] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 4.

[0871] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 4, as well as their prodrugs and pharmaceutically acceptable salts.

[0872] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 4 and their pharmaceutically acceptable salts.

[0873] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 4 or any of their pharmaceutically acceptable salts.

[0874] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 4.

[0875] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 5.

[0876] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 5, as well as their prodrugs and pharmaceutically acceptable salts.

[0877] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 5 and their pharmaceutically acceptable salts.

[0878] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 5 or any of their pharmaceutically acceptable salts.

[0879] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 5.

[0880] In some embodiments, the compound is selected from compound numbers 21, 39, 54, 56, 58-59, 64, 67, 69, 93, 95, 98-99, 104, 110, 114-116, 126, 128-129, 131-134, 137, 144-147, 154, 162, 170-171, 175-177, 180-181, 185, 192-195, 206, 220-221, 225-226, 228, 230-231, and 234-235, as well as their pharmaceutically acceptable salts.

[0881] In some embodiments, the compound is selected from compound numbers 21, 39, 54, 56, 58-59, 64, 67, 69, 93, 95, 98-99, 104, 110, 114-116, 126, 128-129, 131-134, 137, 144-147, 154, 162, 170-171, 175-177, 180-181, 185, 192-195, 206, 220-221, 225-226, 228, 230-231, and 234-235.

[0882] In some embodiments, the compound is selected from compound numbers 21, 59, 129, 144, 145, 154, and 175, as well as their pharmaceutically acceptable salts.

[0883] In some embodiments, the compound is selected from compound numbers 21, 59, 129, 144, 145, 154, and 175.

[0884] In some embodiments, the compound is selected from compound numbers 144, 154, and 175, as well as their pharmaceutically acceptable salts.

[0885] In some embodiments, the compound is selected from compound numbers 144, 154, and 175.

[0886] In some embodiments, the compound is compound number 21 and its pharmaceutically acceptable salt.

[0887] In some embodiments, the compound is compound number 59 and its pharmaceutically acceptable salt.

[0888] In some embodiments, the compound is compound number 129 and its pharmaceutically acceptable salt.

[0889] In some embodiments, the compound is compound number 144 and its pharmaceutically acceptable salt. In some embodiments, the compound is compound number 144.

[0890] In some embodiments, the compound is compound number 145 and its pharmaceutically acceptable salt.

[0891] In some embodiments, the compound is compound number 154 and its pharmaceutically acceptable salt.

[0892] In some embodiments, the compound is compound number 175 and its pharmaceutically acceptable salt.

[0893] It is understood that isotopic derivatives can be prepared using any of the various techniques recognized in the art. For example, isotopic derivatives can generally be prepared by using isotopically labeled reagents instead of unlabeled reagents by performing the procedures disclosed in the schemes and / or examples described herein.

[0894] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0895] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds represented by the formulas disclosed herein.

[0896] The term "isotope derivative," as used herein, refers to a derivative of a compound in which one or more atoms are isotope-enriched or isotope-labeled. For example, an isotope derivative of a compound of formula (I'), formula (I), formula (II), or formula (III) is isotope-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 isotope derivative is 2 H, 13 C, 14 C, 15 N, 18 O, 29 Si, 31 P, and 34 The isotope derivative is enriched with respect to one or more atoms selected from S, or is labeled with said atoms. In some embodiments, the isotope derivative is a deuterium-labeled compound (i.e., with respect to one or more of its atoms) 2 (It is concentrated with H). In some embodiments, the compound is 18 It is a compound labeled with F. In some embodiments, the compound is 123 Compounds labeled with I, 124 Compounds labeled with I, 125 Compounds labeled with I, 129 Compounds labeled with I,131 Compounds labeled with I, 135 A compound labeled with I, or any combination thereof. In some embodiments, the compound is 33 A compound labeled with S, 34 A compound labeled with S, 35 A compound labeled with S, 36 A compound labeled with S, or any combination thereof.

[0897] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 It is understood that compounds labeled with S can be prepared using any one of the various techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein instead of using isotopically labeled reagents. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 It can be prepared by using a reagent labeled with S.

[0898] As mentioned above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and 36Compounds of the present invention containing one or more S atoms, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present invention. Furthermore, 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 Substitution with S) may provide certain therapeutic benefits resulting from greater metabolic stability, such as an increased in vivo half-life or reduced dose requirements.

[0899] To avoid misunderstanding, in this specification, when a base is limited by "as described herein," it should be understood that such base includes the first and broadest definitions, as well as each and all of the specific definitions relating to that base.

[0900] The various functional groups and substituents constituting the compounds of formula (I'), formula (I), formula (II), or formula (III) are typically selected so that the molecular weight of the compound does not exceed 1000 daltons. More generally, the molecular weight of the compound will be less than 900 daltons, e.g., less than 800 daltons, or less than 750 daltons, or less than 700 daltons, or less than 650 daltons. More conveniently, the molecular weight will be less than 600 daltons, e.g., 550 daltons or less.

[0901] Suitable pharmaceutically acceptable salts of the compounds of this disclosure include, for example, acid addition salts of the compounds of this disclosure that are sufficiently basic, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonate, or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of this disclosure that are sufficiently acidic include alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that give pharmaceutically acceptable cations, such as methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0902] It will be understood that a compound represented by any one of the formulas disclosed herein and any pharmaceutically acceptable salt thereof includes stereoisomers of the said compound, mixtures of stereoisomers, and polymorphs of all isomer forms.

[0903] As used herein, the term "isomer" means a compound having the same molecular formula but differing in the order of its atomic bonding or the spatial arrangement of its atoms. Isomers with differing spatial arrangements of their atoms are called "stereoisomers." Stereoiomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomers of opposite chiralities is called a "racemic mixture."

[0904] As used herein, the term “chiral center” refers to a carbon atom bonded to four non-identical substituents.

[0905] As used herein, the term “chiral isomer” means a compound having at least one chiral center. Compounds having two or more chiral centers may exist either as individual diastereomers or as a mixture of diastereomers, referred to as a “diastereomer mixture.” Where a single chiral center is present, the stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are ranked according to the Cahn, Ingold, and Prelog priority rules (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).

[0906] As used herein, the term “geometric isomer” means a diastereomer that exists as a result of rotation being inhibited around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished by the prefixes cis and trans, or Z and E, which, according to the Cahn-Ingold-Prelog rule, indicate whether the group is on the same side or opposite side of the double bond in the molecule.

[0907] It should be understood that the compounds of this disclosure may be described as different chiral or geometric isomers. Furthermore, if a compound has chiral or geometric isomers, all isomers are intended to be included within the scope of this disclosure, and the naming of the compounds does not exclude any isomers, nor can all isomers necessarily have the same level of activity.

[0908] It should be understood that the structures and other compounds discussed in this disclosure include all of their atropisomers. It should also be understood that not all atropisomers may have the same level of activity.

[0909] As used herein, the term “atropisomer” refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropisomers exist as a result of bound rotation caused by the interference of rotation of a large group around a central bond. Such atropisomers typically exist as a mixture, but as a result of recent advances in chromatography techniques, it has become possible to separate a mixture of two atropisomers in limited cases.

[0910] As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomer to the other. This conversion results in a formal transfer of hydrogen atoms, which occurs in conjunction with the switching of adjacent conjugated double bonds. Tautomers exist in solution as a mixture of aggregates of tautomers. In a solution where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by this tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. Keto-enol tautomerism involves a simultaneous shift of electrons and hydrogen atoms. Ring chain tautomerism, as demonstrated by glucose, results from the reaction of an aldehyde group (-CHO) in a sugar chain molecule with one of the hydroxyl groups (-OH) in the same molecule to form a cyclic structure.

[0911] It should be understood that the compounds of this disclosure may be described as different tautomers. Furthermore, if a compound has tautomers, all tautomers are intended to be included within the scope of this disclosure, and the naming of the compounds does not exclude any tautomers. It should be understood that certain tautomers may exhibit higher levels of activity than others.

[0912] Compounds having the same molecular formula but differing in the nature or order of their atomic bonding or the spatial arrangement of their atoms are called "isomers." Isomers with different spatial arrangements of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers." If a compound has a chiral center, for example, if it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute stereoconfiguration of their chiral center, described by Cahn and Prelog's R- and S-order rules, or by the way the molecule rotates its plane of polarization, and are dextrorotatory or levorotatory (i.e., (+) isomer or (-) isomer, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

[0913] The compounds of this disclosure may possess one or more chiral centers; therefore, such compounds may be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the descriptions or nomenclature of specific compounds in this specification and the claims are intended to include both individual enantiomers, mixtures thereof, racemates, or otherwise. Methods for determining and separating the stereochemistry of stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolution of racemates. Some of the compounds of this disclosure may possess geometric isomers (E- and Z-isomers). It should be understood that this disclosure encompasses all optical isomers, diastereoisomers, and geometric isomers, as well as mixtures thereof, that possess orexin modulation activity.

[0914] This disclosure also includes compounds of this disclosure as defined herein, which include one or more isotopic substitutions.

[0915] It should be understood that the compounds represented by any of the formulas described herein include not only the compounds themselves but, where appropriate, their salts and their solvates. Salts can be formed, for example, between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include ions of chlorides, bromides, iodides, sulfuric acid, bisulfuric acid, sulfamic acid, nitric acid, phosphoric acid, citric acid, methanesulfonic acid, trifluoroacetic acid, glutamic acid, glucuronic acid, glutaric acid, malic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, tosylic acid, salicylic acid, lactic acid, naphthalenesulfonic acid, and acetic acid (e.g., trifluoroacetic acid).

[0916] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation and a negatively charged group (e.g., a carboxylic acid) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include their salts containing a quaternary nitrogen atom.

[0917] It should be understood that the compounds of this disclosure, for example, salts of the compounds, can exist in either a hydrated or unhydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates and dihydrates. Non-limiting examples of solvates include ethanol solvate and acetone solvate.

[0918] As used herein, the term “solvate” means a solubilized form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to capture solvent molecules in a constant molar ratio in their crystalline solid state, thus forming solvates. When the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by a combination of one or more water molecules and one molecule of a substance, where water retains its molecular state as H2O.

[0919] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but has a slightly different composition (such as the substitution of one atom with an atom of a different element, or the presence of a particular functional group, or the substitution of one functional group with another functional group). Thus, an analog is a compound that is similar or equivalent to a reference compound in function and appearance, but not similar or equivalent in structure or origin.

[0920] As used herein, the term “derivative” refers to a compound having a common core structure and being substituted with various groups as described herein.

[0921] As used herein, the term “biological equivalent” refers to a compound resulting from the exchange of one atom or group of atoms with another, more similar atom or group of atoms. The purpose of biological equivalent substitution is to create a new compound having similar biological properties to the parent compound. Biological equivalent substitution may be based on physical chemistry or topology. Examples of carboxylic acid biological equivalents include, but are not limited to, acylsulfonimides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0922] Furthermore, it should be understood that certain compounds represented by any one of the formulas disclosed herein may exist in solvated and non-solvated forms, such as hydrated forms. Preferred pharmaceutically acceptable solvates are hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that this disclosure encompasses all such solvated forms that possess orexin modulation activity.

[0923] Furthermore, it should be understood that certain compounds represented by any one of the formulas disclosed herein may exhibit polymorphism, and that this disclosure encompasses all such forms or mixtures thereof that possess orexin modulation activity. Crystalline materials are generally known to be analyzed using conventional techniques such as powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance Fourier transform infrared (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0924] Compounds represented by any one of the formulas disclosed herein may exist in a number of different tautomers, and references to compounds of formula (I'), formula (I), formula (II), or formula (III) include all such forms. To avoid misunderstanding, a compound may exist in one of several tautomers, and even if only one is specifically described or shown, formula (I'), formula (I), formula (II), or formula (III) encompasses all the others. Examples of tautomers include, for example, the keto, enol, and enolate forms, such as the following tautomer pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enthiol, and nitro / acy-nitro. TIFF0007840517000164.tif18128

[0925] Compounds represented by any one of the formulas disclosed herein that contain an amine functional group may also form N-oxides. References herein to compounds of formula (I'), formula (I), formula (II), or formula (III) that contain an amine functional group also include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of nitrogen atoms in 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., a peroxycarboxylic acid); see, for example, *Advanced Organic Chemistry*, by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be produced by the LW Deady (Syn. Comm. 1977, 7, 509-514) procedure, which involves reacting an amine compound with meta-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0926] Compounds represented by any one of the formulas disclosed herein may be administered in the form of a prodrug, which is broken down in the body of a human or animal to release the compound disclosed herein. Prodrugs may be used to modify the physical and / or pharmacokinetic properties of the compound disclosed herein. A prodrug can be formed if the compound disclosed herein contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing an alkyl or acyl substituent on the ester or amide group in any one of the formulas disclosed herein that is cleavable in vivo.

[0927] Accordingly, this disclosure includes compounds represented by any one of the formulas disclosed herein as defined herein, if they are available by organic synthesis and if they are available in the body of a human or animal by cleavage of their prodrugs. Accordingly, this disclosure includes not only compounds represented by any one of the formulas disclosed herein produced by organic synthesis means, but also such compounds produced in the body of a human or animal by metabolism of precursor compounds, i.e., compounds represented by any one of the formulas disclosed herein may be compounds produced by synthesis or compounds produced by metabolism.

[0928] A suitable pharmaceutically acceptable prodrug of a compound represented by any one of the formulas disclosed herein is, based on reasonable medical judgment, suitable for administration to the body of a human or animal, without exhibiting undesirable pharmacological activity and without excessive toxicity. Various forms of prodrugs are described in the following documents, for example: a) Methods in Enzymology, Vol. 42, p. 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", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", ACS Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0929] A preferred pharmaceutically acceptable prodrug of a compound represented by any one of the formulas disclosed herein that possesses a hydroxyl group is, for example, its in vivo cleavable ester or ether. An in vivo cleavable ester or ether of a compound represented by any one of the formulas disclosed herein that contains a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether that cleaves in the body of a human or animal to produce a parent hydroxy compound. Preferred pharmaceutically acceptable ester-forming groups for a hydroxyl group include inorganic esters such as phosphate esters (including phosphoroamidic acid cyclic esters). A further preferred pharmaceutically acceptable ester-forming group for a hydroxyl group is C1-C 10 Alkanoyl groups, for example, acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, C1-C 10 Alkoxycarbonyl groups include, for example, ethoxycarbonyl, N,N-(C1-C6 alkyl)2-carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxyl group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

[0930] A suitable pharmaceutically acceptable prodrug of a compound represented by any one of the formulas disclosed herein that has a carboxyl group is, for example, its amide that is cleavable in vivo, for example, an amine (such as ammonia), C 1-4 These are amides formed with alkylamines (such as methylamine), (C1-C4 alkyl)2-amines (such as dimethylamine, N-ethyl-N-methylamine, or diethylamine), C1-C4 alkoxy-C2-C4 alkylamines (such as 2-methoxyethylamine), phenyl-C1-C4 alkylamines (such as benzylamine), and amino acids (such as glycine) or their esters.

[0931] A preferred pharmaceutically acceptable prodrug of a compound represented by any one of the formulas disclosed herein that possesses an amino group is, for example, its amide derivative that is cleavable in vivo. A preferred pharmaceutically acceptable amide from an amino group is, for example, a C1-C 10 The alkanoyl groups include, for example, acetyl, benzoyl, phenylacetyl, and amides formed with substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl.

[0932] The in vivo effect of a compound represented by any one of the formulas disclosed herein may be exerted in part by one or more metabolites formed in the body of a human or animal after administration of the compound represented by any one of the formulas disclosed herein. As stated above herein, the in vivo effect of a compound represented by any one of the formulas disclosed herein may also be exerted by the metabolism of a precursor compound (prodrug).

[0933] Preferably, this disclosure excludes any individual compounds that do not possess the biological activity as defined herein.

[0934] Synthesis method In some aspects, this disclosure provides methods for preparing the compounds of this disclosure.

[0935] In some aspects, this disclosure provides methods for compounding compounds, comprising one or more steps as described herein.

[0936] In some aspects, this disclosure provides compounds that can be obtained by, or are obtained by, or are directly obtained by, methods for preparing compounds as described herein.

[0937] In some aspects, this disclosure provides intermediates as described herein that are suitable for use in methods for preparing compounds as described herein.

[0938] The compounds of this disclosure can be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further described in the attached examples.

[0939] It should be understood that in the descriptions of the synthetic methods described herein, and in any reference synthetic methods used to prepare the starting materials, all proposed reaction conditions, including the selection of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and work-up procedure, can be selected by those skilled in the art.

[0940] Those skilled in the art of organic synthesis will understand that the functional groups present in various parts of a molecule must be compatible with the reagents and reaction conditions used.

[0941] It will be understood that during the synthesis of the compounds of this disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain groups of substituents to prevent undesirable reactions. Experienced chemists will understand when such protection is needed and how to position and subsequently remove such protecting groups. For examples of protecting groups, see one of the many general publications on this subject, e.g., 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to experienced chemists, suitable for the removal of the protecting group in question, and such method should be selected so that the removal of the protecting group is achieved with minimal interference to other groups in the molecule. Thus, if the reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect those groups in some of the reactions listed herein.

[0942] For example, suitable protecting groups for amino or alkylamino groups include acyl groups, e.g., alkanoyl groups (e.g., acetyl), alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups), arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl), or aroyl groups (e.g., benzoyl). The deprotection conditions for the above protecting groups will inevitably vary depending on the protecting group selected. Therefore, for example, acyl groups such as alkanoyl or alkoxycarbonyl groups, or aroyl groups, may be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide (e.g., lithium or sodium hydroxide). Alternatively, acyl groups such as tert-butoxycarbonyl groups may be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups may be removed by hydrogenation on a catalyst such as palladium carbon, or by treatment with a Lewis acid such as tris(trifluoroacetic acid)boron. A suitable alternative protecting group for primary amino groups is a phthaloyl group, which can be removed by treatment with an alkylamine such as dimethylaminopropylamine, or by treatment with hydrazine.

[0943] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, such as alkanoyl groups (e.g., acetyl), alloyl groups (e.g., benzoyl), or arylmethyl groups (e.g., benzyl). The deprotection conditions for the above protecting groups will inevitably vary depending on the protected group selected. For example, acyl groups such as alkanoyl or alloyl groups may be removed by hydrolysis with a suitable base such as alkali metal hydroxides (e.g., lithium sodium hydroxide) or ammonia. Alternatively, arylmethyl groups such as benzyl groups may be removed by hydrogenation on a catalyst such as palladium carbon.

[0944] Suitable protecting groups for carboxyl groups include, for example, esterifying groups such as methyl or ethyl groups (which can be removed by hydrolysis with a base such as sodium hydroxide), or, for example, tert-butyl groups (which can be removed by treatment with an acid, such as an organic acid such as trifluoroacetic acid), or, for example, benzyl groups (which can be removed by hydrogenation on a catalyst such as palladium-carbon).

[0945] Once a compound of formula (I'), formula (I), formula (II), or formula (III) has been synthesized by any one of the processes defined herein, the process may then further include: (i) removing any protecting groups present; (ii) converting a compound of formula (I'), formula (I), formula (II), or formula (III) into another compound represented by formula (I'), formula (I), formula (II), or formula (III); (iii) forming a pharmaceutically acceptable salt, hydrate, or solvate thereof; and / or (iv) forming a prodrug thereof.

[0946] The resulting compounds of formula (I'), formula (I), formula (II), or formula (III) can be isolated and purified using techniques well known in the art.

[0947] Conveniently, the reaction of the compounds is preferably carried out in the presence of a suitable solvent that is inert under the respective reaction conditions. Examples of suitable solvents include hydrocarbons, e.g., hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, e.g., trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, e.g., diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, Examples include, but are not limited to, ethylene glycol monomethyl or monoethyl ether, or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methyl isobutyl ketone (MIBK), or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF), or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the aforementioned solvents or mixtures with water.

[0948] The reaction temperature is preferably about -100°C to 300°C, depending on the reaction process and conditions used.

[0949] The reaction time generally ranges from a few minutes to several days, depending on the reactivity of each compound and the respective reaction conditions. A suitable reaction time can be easily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperature given above, a suitable reaction time generally ranges from 10 minutes to 48 hours.

[0950] Furthermore, additional compounds of this disclosure can be readily prepared by using the procedures described herein in conjunction with ordinary skills in the art. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparation procedures can be used to prepare these compounds.

[0951] As will be understood by those skilled in the art of organic synthesis, the compounds of this disclosure are readily attainable through a variety of synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will readily recognize what kinds of reagents and reaction conditions should be used to obtain the compounds of this disclosure, and how these should be applied and adapted in any particular case (wherever necessary or useful). Furthermore, some of the compounds of this disclosure can be readily synthesized by reacting other compounds of this disclosure under suitable conditions, for example, by converting a particular functional group present in the compound of this disclosure or a suitable precursor molecule to another by applying standard synthetic methods such as reduction, oxidation, addition, or substitution reactions; such methods are well known to those skilled in the art. Similarly, those skilled in the art will be able to apply protective groups in synthesis (whenever necessary or useful); suitable protecting groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis, for example, in PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0952] A general route for preparing the compounds of this application is described in Scheme 1 of this specification.

[0953] Compound I, which is a compound of formulas (I'), (I), (II), and (III) where Z=NH, can be produced from commercially available and known compound A by the method shown in Scheme 1 below. In the formulas, P1 is a protecting group and X represents various leaving groups known in the art. Examples of protecting groups P1 for amino groups include, but are not limited to, carbamate-type protecting groups (e.g., tert-butyl carbamate). Examples of leaving groups X include halogens, particularly bromine or iodine, or sulfonic acid esters such as methyl sulfonate.

[0954] Scheme 1 TIFF0007840517000165.tif60155

[0955] Compound C can be produced by subjecting compound A to a nucleophilic substitution reaction with compound B in the presence of a base. Examples of bases include, but are not limited to, lithium amides. Alternatively, compound C can also be produced by converting it 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, pyrrolidines.

[0956] Compound D can be produced by subjecting compound C to a reductive amination reaction. Examples of amines that can be used include, but are not limited to, ammonium salts such as ammonium formate. Examples of reducing agents include, but are not limited to, sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, and formic acid. In addition, a metal catalyst may be added to the reaction system. Examples of catalysts that should be used include, but are not limited to, iridium catalysts.

[0957] Compound F can be produced by subjecting compound D to a sulfonamidate reaction with compound E in the presence of a base. Compound E can be commercially available or produced by known methods. Examples of bases to be used include, but are not limited to, organic bases, such as tertiary alkylamines like N,N-diisopropylethylamine.

[0958] 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 protecting group selected. For example, if P1 is a tert-butylcarbamate, deprotection can be achieved by treatment with an acid such as hydrochloric acid or trifluoroacetic acid.

[0959] Compound I can be prepared by subjecting Compound G and Compound H to a condensation reaction. Examples of Compound H include, but are not limited to, acyl halides, e.g., acid chlorides, alkyl chloroformates, carbamoyl chlorides; and activated carboxylic acids, e.g., acid anhydrides, activated esters. Examples of activators for carboxylic acids include, but are not limited to, carbodiimide condensing agents, carbonate ester condensing agents, e.g., 1,1-carbonyldiimidazole (CDI); benzotriazole-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent), alkyl chloroformate; and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), etc. When a condensing agent is used, additives such as 1-hydroxybenzotriazole (HOBt) or dimethylaminopyridine (DMAP) may be added to the reaction system.

[0960] Compound I obtained by the methods described above can be isolated and purified by known means (e.g., solvent extraction, phase transfer, crystallization, chromatography, etc.).

[0961] If compound I contains optical isomers, stereoisomers, and rotational isomers, these compounds are also included in compound I and can be obtained by synthesis or separation, respectively. For example, if optical isomers are present in compound I, the optical isomers separated from the compound are also included in compound I.

[0962] Biological assays Compounds designed, selected, and / or optimized by the methods described above can be characterized at the time of generation using various assays known to those skilled in the art to determine whether the compound is biologically active. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they have the predicted activity, binding activity, and / or binding specificity.

[0963] Furthermore, high-throughput screening can be used to accelerate analysis using such assays. As a result, it may be possible to rapidly screen the molecules described herein for activity using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays may use one or more different assay techniques, including but not limited to those described below.

[0964] Various in vitro or in vivo biological assays may be suitable for determining the effects of the compounds disclosed herein. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell survival assays, and assays described herein.

[0965] In NT1, despite the loss of orexin cells and reduced orexin peptides in the cerebrospinal fluid, orexin receptors on postsynaptic neurons remain intact, making them a suitable target for pharmacotherapy intervention. Orexin peptides A and B (OXA and OXB) can be cleaved from a single precursor molecule (prepro-orexin) produced exclusively in the lateral hypothalamus. Both orexin peptides bind to OX2R with similar high affinity, although OXA may preferentially bind to the orexin-1 receptor (OX1R). Postsynaptic excitation of these G protein-binding orexin receptors can stimulate the release of monoaminergic and cholinergic neurotransmitters that promote wakefulness and inhibitory neurotransmitters that suppress REM sleep atony.

[0966] In some embodiments, biological assays are described in the examples herein.

[0967] The biological activity of the compounds disclosed herein can be determined in cells that stably express either the orexin type 2 or orexin type 1 receptor. Activity can be measured in cells administered with the compounds disclosed herein (e.g., Chinese hamster ovary (CHO) cells expressing human orexin type 2 receptor (hOX2R) or human orexin type 2 receptor (hOX1R)). The agonist activity of the compounds disclosed herein can be determined by fluorescence emission.

[0968] The wakefulness-promoting effects of the compounds disclosed herein can be evaluated in models (e.g., NT1 B6.Cg-Tg(HCRT-MJD)1Stak / J(Atax) mouse models and wild-type (WT) colonymates). Models (e.g., mouse models) can be monitored for rapid, non-invasive classification of sleep and wakefulness after administration of the compounds disclosed herein (e.g., oral administration) by unsupervised machine learning to physiologically relevant readouts such as body movements and respiratory rate.

[0969] Pharmaceutical composition In some aspects, the Disclosure provides pharmaceutical compositions comprising the compounds of the Disclosure as active ingredients. In some embodiments, the Disclosure provides pharmaceutical compositions comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the Disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1.

[0970] As used herein, the term “composition” is intended to encompass products containing a predetermined amount of the specified components, as well as any products resulting directly or indirectly from a predetermined combination of the specified components.

[0971] The compounds of this disclosure can be formulated for oral administration in the form of tablets, capsules (each including sustained-release or sustained-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of this disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., transdermal patches) administration, all in forms well known to those skilled in the pharmaceutical art.

[0972] The formulations of this disclosure may be in the form of aqueous solutions containing an aqueous medium. The aqueous medium components may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonic agents, viscosity / suspensioning agents, buffers and pH adjusters, and mixtures thereof.

[0973] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins, such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated β-cyclodextrin, ethylated β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated γ-cyclodextrin, and trimethyl-γ-cyclodextrin, as well as mixtures thereof, selected from the group.

[0974] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0975] Any suitable preservative can be used. Examples of preservatives include those selected from the group consisting of quaternary ammonium salts, such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, methylthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, as well as mixtures thereof.

[0976] Aqueous media may also contain isotonic agents to adjust their isotonicity (osmotic pressure). The isotonic agents can be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, and triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, as well as mixtures thereof.

[0977] Aqueous media may also contain viscosity / suspensioning agents. Suitable viscosity / suspensioning agents include those selected from the group consisting of cellulose derivatives, e.g., methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and crosslinked acrylic acid polymers (carbomers), e.g., polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycol (Carbopols, e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0978] To adjust the formulation to an acceptable pH (typically about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly in the 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 pH adjusters. pH adjusters are typically mineral acids or metal hydroxide bases, selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to the desired acceptable pH range. Therefore, it is not always necessary to use both an acid and a base; depending on the formulation, the addition of either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0979] Aqueous media may also contain buffers to stabilize the pH. When used, buffers are selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as salts thereof containing boric acid or disodium tetraborate), citrate buffers (such as salts thereof containing citric acid or sodium citrate), and ε-aminocaproic acid, as well as mixtures thereof.

[0980] The formulation may further contain a wetting agent. Suitable types of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylene-sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, as well as mixtures thereof.

[0981] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable food-grade carrier. These can be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a liquid carrier for use as an oral rinse, where the compound in the liquid carrier is applied orally, rinsed in the mouth, and then coughed up or swallowed. Pharmaceutically compatible binders and / or adjuvants may be included as part of the composition. These tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar properties: binders, e.g., microcrystalline cellulose, tragacanth gum, or gelatin; excipients, e.g., starch, or lactose; disintegrants, e.g., alginic acid, Primogel, or corn starch; lubricants, e.g., magnesium stearate or sterote; flow enhancers, e.g., colloidal silicon dioxide; sweeteners, e.g., sucrose, or saccharin; or flavoring agents, e.g., peppermint, methyl salicylate, or orange flavoring.

[0982] Further aspects of this disclosure provide pharmaceutical compositions comprising, as defined herein, a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in combination with a pharmaceutically acceptable diluent or carrier.

[0983] The compositions of this 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), in a form suitable for topical use (e.g., as creams, ointments, gels, or aqueous or oily liquids or suspensions), in a form suitable for administration by inhalation (e.g., as fine powders or liquid aerosols), in a form suitable for administration by blowing (e.g., as fine powders), or in a form suitable for parenteral administration (e.g., as sterile aqueous or oily liquids for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as suppositories for rectal administration).

[0984] The compositions of this disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Accordingly, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings and / or preservatives.

[0985] An effective amount of the compounds of this disclosure for therapeutic use is sufficient to treat or prevent, slow the progression of, and / or reduce the symptoms associated with, orexin-related conditions as described herein.

[0986] An effective amount of the compounds of this disclosure for use in treatment is sufficient to treat, slow the progression of, and / or the symptoms associated with the orexin-related conditions referred to herein.

[0987] The size of doses for the therapeutic or prophylactic use of compounds of formula (I'), formula (I), formula (II), or formula (III) will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of medicine.

[0988] How to use In some aspects, the present disclosure provides a method for modulating orexin receptor activity (e.g., in vitro or in vivo), comprising the step of contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0989] In some aspects, the present disclosure provides a method for modulating orexin-2 receptor activity (e.g., in vitro or in vivo), comprising the step of contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0990] In some aspects, the present disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject where such treatment is needed, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0991] In some aspects, the present disclosure provides a method for treating a disease or disorder disclosed herein in a subject where such treatment is needed, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically effective amount of a pharmaceutically effective composition of the present disclosure.

[0992] In some embodiments, a disease or disorder is associated with related orexin receptor activity. In some embodiments, a disease or disorder is a disease or disorder to which orexin receptor activity is associated.

[0993] In some embodiments, a disease or disorder is associated with related orexin-2 receptor activity. In some embodiments, a disease or disorder is a disease or disorder to which orexin-2 receptor activity is associated.

[0994] In some aspects, the disease or disorder is narcolepsy, hypersomnia, neurodegenerative disorder, symptoms of a rare genetic disorder, mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or complications upon waking from anesthesia.

[0995] In some aspects, the Disclosure provides a method for treating or preventing narcolepsy, hypersomnia, neurodegenerative disorders, symptoms of rare genetic disorders, mental health disorders, metabolic syndrome, osteoporosis, heart failure, coma, or complications upon awakening from anesthesia in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the compound of the Disclosure or a pharmaceu...

Claims

1. Compounds of formula (I'''), or pharmaceutically acceptable salts thereof: During the ceremony, X is -C(R X1 ) 3 , -OR X2 , or -N(R X2 ) 2 And; Y is -(C(R Y ) 2 ) m -, -O-(C(R Y ) 2 ) m -, -(C(R Y ) 2 ) m -O-, -N(R Y )-(C(R Y ) 2 ) m -, or -(C(R Y ) 2 ) m -N(R Y )-; Z is -O- or -NR Z -and; Each R X1 These are independently H, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-C 1 -C 6 Alkoxy, C 3 -C 6 It is a cycloalkyl or a 3- to 7-membered heterocycloalkyl, Or, two R's X1 These, together with the atoms to which they are bonded, C 3 -C 7 They form cycloalkyl or 3- to 7-membered heterocycloalkyl groups, where the cycloalkyl or heterocycloalkyl group is oxo, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It may also be substituted with an alkoxy. Or, the three R's X1 These, together with the atoms to which they are bonded, C 4 -C 10 A cycloalkyl is formed, where the cycloalkyl is a halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It is also acceptable if it is substituted with an alkoxy; Each R X2 is, independently, H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl,C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 3- to 7-membered heterocycloalkyl, where the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more halogen, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 3- to 7-membered heterocycloalkyl, and may be substituted Or, two R's X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl group, where the heterocycloalkyl group comprises one or more halogens, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It is also acceptable if it is substituted with an alkoxy; Each R Y These are independently H, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; Each R Z H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 It is a haloalkyl; Ar 1 C 6 -C 10 It is an aryl or a 5- to 10-membered heteroaryl, where C 6 -C 10 Aryl or 5- to 10-membered heteroaryls are one or more R 3 It is also fine if it is replaced with; R 1 is, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -N(C 1 -C 6 Alkyl)(C 3 -C 10 Cycloalkyl), -S(C 1 -C 6 Alkyl), -S(C 6 -C 10 Ariel), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5-10 member heteroaryl), -O-(C 3 -C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C 3 -C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 1S It is also fine if it is replaced with; Each R 1S These are independently oxo, halogen, -CN, -OH, -O-(CH 2 ) 2 -OC 1 -C 6 Alkyl, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 3 -C 7 They are cycloalkyl or 3- to 7-membered heterocycloalkyl groups; R 2 These are halogens, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 -SH, -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), -S(C 6 -C 10 Aryl), -SO 2 (C 6 -C 10 Ariel), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5-10 member heteroaryl), -O-(C 3 -C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C 3 -C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It is also fine if it is replaced with; Each R 2S These are independently oxo, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 3 -C 7 They are cycloalkyl or 3- to 7-membered heterocycloalkyl groups; Each R 3 These are, independently, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; R 4a H, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; R 4b H, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; n is 0, 1, 2, or 3; and m is 0, 1, 2, 3, 4, or 5.

2. The compound according to claim 1, which is a compound of formula (I'') or a pharmaceutically acceptable salt thereof: During the ceremony, X is -C(R X1 ) 3 , -OR X2 , or -N(R X2 ) 2 And; Y is -(C(R Y ) 2 ) m -, -O-(C(R Y ) 2 ) m -,-(C(R Y ) 2 ) m -O-, -N(R Y )-(C(R Y ) 2 ) m -, or -(C(R Y ) 2 ) m -N(R Y )-and; Z is -O- or -NR Z -and; Each R X1 These are independently H, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-C 1 -C 6 Alkoxy, or C 3 -C 6 Is it cycloalkyl? Or, two R's X1 These, together with the atoms to which they are bonded, C 3 -C 7 It forms a cycloalkyl or a 3- to 7-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl is a halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It may also be substituted with an alkoxy. Or, the three R's X1 These, together with the atoms to which they are bonded, C 4 -C 10 A cycloalkyl is formed, where the cycloalkyl is a halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It is also acceptable if it is substituted with an alkoxy; Each R X2 H and C are independent of each other. 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, C 3 -C 6 A cycloalkyl or 3- to 7-membered heterocycloalkyl, where alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocycloalkyl is one or more halogens, -CN, -OH, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 3 -C 6 They may be substituted with cycloalkyl groups or 3- to 7-membered heterocycloalkyl groups. Or, two R's X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl group, where the heterocycloalkyl group comprises one or more halogens, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It is also acceptable if it is substituted with an alkoxy; Each R Y These are independently H, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; Each R Z H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 It is a haloalkyl; Ar 1 C 6 -C 10 It is an aryl or a 5- to 10-membered heteroaryl, where C 6 -C 10 Aryl or 5- to 10-membered heteroaryls are one or more R 3 It is also fine if it is replaced with; R 1 is, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -N(C 1 -C 6 Alkyl)(C 3 -C 10 Cycloalkyl), -S(C 1 -C 6 Alkyl), -S(C 6 -C 10 Ariel), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5-10 member heteroaryl), -O-(C 3 -C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C 3 -C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 1S It is also fine if it is replaced with; Each R 1S These are independently oxo, halogen, -CN, -OH, -O-(CH 2 ) 2 -OC 1 -C 6 Alkyl, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 3 -C 7 They are cycloalkyl or 3- to 7-membered heterocycloalkyl groups; R 2 These are halogens, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 -SH, -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), -S(C 6 -C 10 Aryl), -SO 2 (C 6 -C 10 Ariel), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5-10 member heteroaryl), -O-(C 3 -C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C 3 -C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It is also fine if it is replaced with; Each R 2S These are independently oxo, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 3 -C 7 They are cycloalkyl or 3- to 7-membered heterocycloalkyl groups; Each R 3 These are, independently, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; R 4a H, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; R 4b H, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; n is 0, 1, 2, or 3; and m is 0, 1, 2, 3, 4, or 5.

3. The compound according to claim 1, which is a compound of formula (I') or a pharmaceutically acceptable salt thereof: During the ceremony, X is -C(R X1 ) 3 , -OR X2 , or -N(R X2 ) 2 And; Y is -(C(R Y ) 2 ) m -, -O-(C(R Y ) 2 ) m -,-(C(R Y ) 2 ) m -O-, -N(R Y )-(C(R Y ) 2 ) m -, or -(C(R Y ) 2 ) m -N(R Y )-and; Z is -O- or -NR Z -and; Each R X1 These are independently H, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It is either an alkoxy or two Rs X1 These, together with the atoms to which they are bonded, C 3 -C 7 A cycloalkyl or 3- to 7-membered heterocycloalkyl is formed, wherein the cycloalkyl or heterocycloalkyl is one or more halogens, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It is also acceptable if it is substituted with an alkoxy; Each R X2 H and C are independent of each other. 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 It is either a haloalkyl or two Rs. X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl group, where the heterocycloalkyl group comprises one or more halogens, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It is also acceptable if it is substituted with an alkoxy; Each R Y These are independently H, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; Each R Z H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 It is a haloalkyl; Ar 1 C 6 -C 10 It is an aryl or a 5- to 10-membered heteroaryl, where C 6 -C 10 Aryl or 5- to 10-membered heteroaryls are one or more R 3 It is also fine if it is replaced with; R 1 is, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -S(C 6 -C 10 Ariel), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5-10 member heteroaryl), -O-(C 3 -C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C 3 -C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 1S It is also fine if it is replaced with; Each R 1S These are independently oxo, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 3 -C 7 They are cycloalkyl or 3- to 7-membered heterocycloalkyl groups; R 2 These are halogens, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 -SH, -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), -S(C 6 -C 10 Aryl), -SO 2 (C 6 -C 10 Ariel), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5-10 member heteroaryl), -O-(C 3 -C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C 3 -C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It is also fine if it is replaced with; Each R 2S These are independently oxo, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 3 -C 7 They are cycloalkyl or 3- to 7-membered heterocycloalkyl groups; Each R 3 These are, independently, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; R 4a is H, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1-6 alkoxy; R 4b H, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; n is 0, 1, 2, or 3; and m is 0, 1, 2, 3, 4, or 5.

4. The compound according to claim 1, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof: During the ceremony, X is -C(R X1 ) 3 , -OR X2 , or -N(R X2 ) 2 And; Y is -(C(R Y ) 2 ) m -, -O-(C(R Y ) 2 ) m -,-(C(R Y ) 2 ) m -O-, -N(R Y )-(C(R Y ) 2 ) m -, or -(C(R Y ) 2 ) m -N(R Y )-and; Z is -O- or -NR Z -and; Each R X1 is, independently, H, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy; or two Rs X1 together with the atom to which they are attached form C 3 -C 7 cycloalkyl or 3- to 7-membered heterocycloalkyl, where the cycloalkyl or heterocycloalkyl is substituted with one or more halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy; and may be substituted; Each R X2 H and C are independent of each other. 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 It is either a haloalkyl or two Rs. X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl group, where the heterocycloalkyl group comprises one or more halogens, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It is also acceptable if it is substituted with an alkoxy; Each R Y These are independently H, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; Each R Z H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 It is a haloalkyl; R 1 is, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -S(C 6 -C 10 Ariel), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5-10 member heteroaryl), -O-(C 3 -C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C 3 -C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 1S It is also fine if it is replaced with; Each R 1S These are independently oxo, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 3 -C 7 They are cycloalkyl or 3- to 7-membered heterocycloalkyl groups; R 2 These are halogens, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 -SH, -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), -S(C 6 -C 10 Aryl), -SO 2 (C 6 -C 10 Ariel), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5-10 member heteroaryl), -O-(C 3 -C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C 3 -C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It is also fine if it is replaced with; Each R 2S These are independently oxo, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 3 -C 7 They are cycloalkyl or 3- to 7-membered heterocycloalkyl groups; Each R 3 These are, independently, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; R 4a H, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; R 4b H, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; n is 0, 1, 2, or 3; m is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, or 4.

5. The compound according to claim 1, which is a compound of formula (II) or a pharmaceutically acceptable salt thereof: During the ceremony, X is -C(R X1 ) 3 , -OR X2 , or -N(R X2 ) 2 And; Y is -(C(R Y ) 2 ) m -, -O-(C(R Y ) 2 ) m -,-(C(R Y ) 2 ) m -O-, -N(R Y )-(C(R Y ) 2 ) m -, or -(C(R Y ) 2 ) m -N(R Y )-and; Z is -O- or -NR Z -and; Each R X1 These are independently H, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It is either an alkoxy or two Rs X1 These, together with the atoms to which they are bonded, C 3 -C 7 A cycloalkyl or 3- to 7-membered heterocycloalkyl is formed, wherein the cycloalkyl or heterocycloalkyl is one or more halogens, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It is also acceptable if it is substituted with an alkoxy; Each R X2 H and C are independent of each other. 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 It is either a haloalkyl or two Rs. X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl group, where the heterocycloalkyl group comprises one or more halogens, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It is also acceptable if it is substituted with an alkoxy; Each R Y These are independently H, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; Each R Z H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 It is a haloalkyl; R 1 is, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -S(C 6 -C 10 Ariel), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5-10 member heteroaryl), -O-(C 3 -C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C 3 -C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 1S It is also fine if it is replaced with; Each R 1S These are independently oxo, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 3 -C 7 They are cycloalkyl or 3- to 7-membered heterocycloalkyl groups; R 2 These are halogens, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 -SH, -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), -S(C 6 -C 10 Aryl), -SO 2 (C 6 -C 10 Ariel), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5-10 member heteroaryl), -O-(C 3 -C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C 3 -C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It is also fine if it is replaced with; Each R 2S These are independently oxo, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 3 -C 7 They are cycloalkyl or 3- to 7-membered heterocycloalkyl groups; Each R 3 These are, independently, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; R 4a H, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; R 4b H, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; n is 0, 1, 2, or 3; m is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3.

6. The compound according to claim 1, which is a compound of formula (III) or a pharmaceutically acceptable salt thereof: During the ceremony, X is -C(R X1 ) 3 , -OR X2 , or -N(R X2 ) 2 And; Y is -(C(R Y ) 2 ) m -, -O-(C(R Y ) 2 ) m -,-(C(R Y ) 2 ) m -O-, -N(R Y )-(C(R Y ) 2 ) m -, or -(C(R Y ) 2 ) m -N(R Y )-and; Z is -O- or -NR Z -and; Each R X1 These are independently H, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It is either an alkoxy or two Rs X1 These, together with the atoms to which they are bonded, C 3 -C 7 A cycloalkyl or 3- to 7-membered heterocycloalkyl is formed, wherein the cycloalkyl or heterocycloalkyl is one or more halogens, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It is also acceptable if it is substituted with an alkoxy; Each R X2 H and C are independent of each other. 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 It is either a haloalkyl or two Rs. X2 These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl group, where the heterocycloalkyl group comprises one or more halogens, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 It is also acceptable if it is substituted with an alkoxy; Each R Y These are independently H, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; Each R Z H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 It is a haloalkyl; R 1 is, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -S(C 6 -C 10 Ariel), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5-10 member heteroaryl), -O-(C 3 -C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C 3 -C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 1S It is also fine if it is replaced with; Each R 1S These are independently oxo, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 3 -C 7 They are cycloalkyl or 3- to 7-membered heterocycloalkyl groups; R 2 These are halogens, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 -SH, -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), -S(C 6 -C 10 Aryl), -SO 2 (C 6 -C 10 Ariel), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5-10 member heteroaryl), -O-(C 3 -C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C 3 -C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group is one or more R groups. 2S It is also fine if it is replaced with; Each R 2S These are independently oxo, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Alkoxy, C 3 -C 7 They are cycloalkyl or 3- to 7-membered heterocycloalkyl groups; Each R 3 These are, independently, halogen, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; R 4a H, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; R 4b H, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 It is an alkoxy; n is 0, 1, 2, or 3; m is 0, 1, 2, 3, 4, or 5; and p is either 0 or 1.

7. Z, -NR Z - The compound according to any one of claims 1 to 6.

8. Z is -NH-, and R 1 However, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -NH-(C 3 -C 10 A cycloalkyl group, or an -NH-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group comprises one or more R groups. 1S It may be replaced with; and Each R 1S However, independently, halogen, -CN, -OH, or C 1 -C 6 It is an alkoxy. The compound according to any one of claims 1 to 7.

9. X is -C(R X1 ) 3 or -N(R X2 ) 2 The compound according to any one of claims 1 to 8.

10. X, -OR X2 The compound according to any one of claims 1 to 8.

11. X The compound according to any one of claims 1 to 8.

12. Y is -(C(R Y ) 2 ) m - The compound according to any one of claims 1 to 11.

13. Y is -O-(C(R Y ) 2 ) m -,-(C(R Y ) 2 ) m -O-, -N(R Y )-(C(R Y ) 2 ) m -, or -(C(R Y ) 2 ) m -N(R Y A compound according to any one of claims 1 to 11, wherein the compound is )-.

14. Y, -CH 2 -, -CH 2 -O-, -O-CH 2 -, -CF 2 -, -CH 2 -NH-, -NH-CH 2 -, -CH 2 -N(CH 2 CF 3 )-, or -N(CH 2 -CF 3 )-CH 2 - The compound according to any one of claims 1 to 13.

15. Each R X1 The compound according to any one of claims 1 to 14, wherein H is independently present.

16. Each R X1 However, independently, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A compound according to any one of claims 1 to 14, wherein it is an alkoxy.

17. Two R's X1 However, together with the atoms to which these are bonded, C 3 -C 7 A cycloalkyl or 3- to 7-membered heterocycloalkyl is formed, where the cycloalkyl or heterocycloalkyl is one or more halogens, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 The compound according to any one of claims 1 to 14, which may be substituted with an alkoxy.

18. Each R X2 The compound according to any one of claims 1 to 17, wherein H is independently present.

19. Each R X2 However, independently, C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 A compound according to any one of claims 1 to 17, wherein the compound is a haloalkyl compound.

20. Two R's X2 However, these atoms, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl group, where the heterocycloalkyl group contains one or more halogens, -CN, -OH, and -NH. 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 The compound according to any one of claims 1 to 17, which may be substituted with an alkoxy.

21. Each R Y The compound according to any one of claims 1 to 20, wherein each of the compounds is independently H.

22. Each R Y However, independently, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 A compound according to any one of claims 1 to 20, wherein it is an alkoxy compound.

23. R Z The compound according to any one of claims 1 to 22, wherein H is present.

24. R Z However, C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 A compound according to any one of claims 1 to 22, wherein it is a haloalkyl compound.

25. Ar 1 However, C 6 -Aryl or 5- or 6-membered heteroaryl, where the aryl or heteroaryl is one or more R 3 The compound according to any one of claims 1 to 24, which may be substituted with

26. R 1 However, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -S(C 6 -C 10 Ariel), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5-10 member heteroaryl), -O-(C 3 -C 10 Cycloalkyl), -O-(3-7 member heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5-10 member heteroaryl), -NH-(C 3 -C 10 The compound according to any one of claims 1 to 25, which is a cycloalkyl or -NH-(3-7 member heterocycloalkyl).

27. R 1 However, C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 A compound according to any one of claims 1 to 26, wherein it is a haloalkyl compound.

28. R 1 However, methyl, isopropyl, ethyl, -CF 3 , -CHF 2 CH 2 F, -CF 2 CH 3 -CF(CH 3 ) 2 The compound according to any one of claims 1 to 27, wherein the compound is cyclopropyl or fluorocyclopropyl.

29. Each R 1S However, independently, oxo, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 A compound according to any one of claims 1 to 28, wherein it is an alkoxy compound.

30. R 1S The compound according to any one of claims 1 to 29, wherein the compound is a halogen.

31. Each R 1S However, independently, C 3 -C 7 The compound according to any one of claims 1 to 29, wherein it is a cycloalkyl or a 3- to 7-membered heterocycloalkyl.

32. R 2 However, -CN, C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 7 Cycloalkyl, 3-7 member heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5-10 member heteroaryl), -O-(C 3 -C 10 A cycloalkyl group, or an -O-(3-7 member heterocycloalkyl group), where alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups comprise one or more R groups. 2S The compound according to any one of claims 1 to 31, which may be substituted with

33. R 2 However, one or more R 2S The compound according to any one of claims 1 to 32, wherein the phenyl is substituted with a phenyl compound.

34. R 2 but, The compound according to any one of claims 1 to 33.

35. Each R 2S However, independently, oxo, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 Alkyl) 2 , -S(C 1 -C 6 Alkyl), -SO 2 (C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 A compound according to any one of claims 1 to 34, wherein it is an alkoxy.

36. Each R 2S However, independently, C 3 -C 7 The compound according to any one of claims 1 to 34, wherein it is a cycloalkyl or a 3- to 7-membered heterocycloalkyl.

37. Each R 3 However, independently, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 Alkyl), or -N(C 1 -C 6 Alkyl) 2 The compound according to any one of claims 1 to 35.

38. Each R 3 However, independently, C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, C 1 -C 6 Haloalkyl, or C 1-6 A compound according to any one of claims 1 to 34, wherein it is an alkoxy.

39. R 4a The compound according to any one of claims 1 to 38, wherein H is present.

40. R 4a However, C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 A compound according to any one of claims 1 to 38, wherein it is a haloalkyl compound.

41. R 4b The compound according to any one of claims 1 to 40, wherein H is present.

42. R 4b However, C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 2 -C 6 Alkinyl, or C 1 -C 6 A compound according to any one of claims 1 to 40, wherein it is a haloalkyl compound.

43. The compound according to any one of claims 1 to 42, wherein n is 1 or 2.

44. The compound according to any one of claims 1 to 43, wherein m is 0, 1, or 2.

45. The compound according to claim 4, wherein p is 0, 1, or 2.

46. In the formulas (I-1), (I-1a), (I-1b), (I-1c), (I-2), (I-2a), (I-2b), (I-2c), (I-3), (I-3a), (I-3b), (I-3c), (II-1), (II-1a), (II-1b), (II-1c), (III-1), (III-1a), (III-1b), or (III-1c): The compound according to any one of claims 1 to 45, which is a compound of the same, or a solvate or pharmaceutically acceptable salt thereof. 【Request Item 47】 【Chemistry 1】 A compound according to any one of claims 1 to 46, selected from a pharmaceutically acceptable salt thereof.

48. A pharmaceutical composition comprising a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

49. The aforementioned compound, 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] A pharmaceutical composition according to claim 48, selected from the above.

50. A composition for use in a method for modulating orexin-2 receptor activity, comprising a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, wherein the method comprises the step of contacting a cell with the compound or a pharmaceutically acceptable salt thereof; optionally, the activity of the composition is in vitro or in vivo activity.

51. A composition comprising a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48 or claim 49, for treating or preventing a disease or disorder in a subject who needs treatment or prevention of a disease or disorder.

52. A composition comprising a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48 or 49, for use in modulating orexin-2 receptor activity; optionally, the composition or pharmaceutical composition wherein the activity is in vitro or in vivo activity.

53. A composition comprising a compound according to any one of claims 1 to 47, or a pharmaceutical composition according to claim 48 or claim 49, for use in treating or preventing a disease or disorder.

54. The composition or pharmaceutical composition according to claim 53, wherein the disease or disorder is related to an associated orexin receptor.

55. The composition or pharmaceutical composition according to claim 53, wherein the disease or disorder is related to an associated orexin-2 receptor.

56. The composition or pharmaceutical composition according to claim 53, wherein the disease or disorder is narcolepsy, hypersomnia, neurodegenerative disorder, neurological disorder, symptoms of a rare genetic disorder, psychiatric disorder, mental health disorder, circadian rhythm disorder, metabolic syndrome, osteoporosis, heart failure, coma, or acceleration of awakening from anesthesia.

57. The composition or pharmaceutical composition according to claim 53, wherein the disease or disorder is narcolepsy, idiopathic hypersomnia, or sleep apnea.

58. The use of a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for modulating orexin-2 receptor activity; optionally, the use wherein the activity is in vitro or in vivo activity.

59. Use of a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for the treatment or prevention of a disease or disorder.

60. The use according to claim 59, wherein the disease or disorder is related to the associated orexin receptor.

61. The use according to claim 59, wherein the disease or disorder is related to the associated orexin-2 receptor.

62. The use according to claim 59, wherein the disease or disorder is narcolepsy, hypersomnia, neurodegenerative disorder, neurological disorder, symptoms of a rare genetic disorder, psychiatric disorder, mental health disorder, circadian rhythm disorder, metabolic syndrome, osteoporosis, heart failure, coma, or acceleration of awakening from anesthesia.

63. The use according to claim 59, wherein the disease or disorder is narcolepsy, idiopathic hypersomnia, or sleep apnea.

64. The aforementioned compound is as follows: 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

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