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

Abstract

The present disclosure relates to compounds of Formula (I'), and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods of preparation. The compounds disclosed herein are useful for modulating orexin receptor activity, and can be used to treat disorders in which orexin receptor activity is implicated, such as narcolepsy, excessive sleepiness disorders, neurodegenerative disorders, symptoms of rare genetic disorders, mental health disorders, metabolic syndrome, osteoporosis, heart failure, coma, or complications of anesthesia emergence.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 074,216, filed September 3, 2020, the entire contents of which are incorporated herein by reference.

[0003] background

[0004] This disclosure relates to small-molecule, potent agonists of the orexin-2 receptor (OX2R) designed for the treatment of narcolepsy and other disorders associated with orexin deficiency and / or excessive sleepiness. Narcolepsy affects approximately 1 in 2,000 people worldwide. Onset can occur during adolescence and last a lifetime, negatively impacting quality of life. Narcolepsy type 1 (NT1) is caused by the loss of neurons in the brain that produce orexin neuropeptides. There is no known cure, and currently approved treatments are symptomatic. Therefore, developing pharmaceutical agents to restore lost orexin signaling is crucial for treating the underlying cause of NT1.

[0005] In type 1 narcolepsy (NT1), the sole group of neurons producing orexin A and B (also known as hypothalamic-peptides-1 and 2) is disrupted by an immune mechanism that causes dysfunction of the arousal boundary. Mouse models of NT1 recreate the loss of orexin neurons and the two main symptoms observed in NT1 patients: excessive daytime sleepiness and cataplexy. Common symptoms of both type 1 and type 2 narcolepsy can include excessive daytime sleepiness, nighttime sleep disturbances and inappropriately timed rapid eye movement (REM) sleep, as well as sleep paralysis and hallucinations. Cataplexy is a sudden, reversible loss of tone (atonicity during REM sleep) invading the waking state in response to emotional stimuli and is a specific symptom of NT1.

[0006] The two main symptoms of type 1 narcolepsy, excessive daytime sleepiness and cataplexy, can be reduced by reactivating orexin neurotransmission at OX2R in a mouse model. In mice, reversal of cataplexy-like events and sleep / wake splits has been achieved by locally restoring OX2R signaling in the dorsal pontine nucleus and the mammillary nucleus of the hypothalamus, respectively, in regions otherwise lacking orexin receptors. Intraventricular (ICV) administration of orexin A (OXA) has been shown to increase wakefulness and reduce cataplexy-like behavior in orexin-neuronal resection mice. In the NT1 mouse model, intraperitoneal or ICV administration of the selective OX2R agonist YNT-185 moderately increased wakefulness in wild-type (WT) and orexin ligand-deficient mice and reduced the REM sleep onset phase and cataplexy-like events. Subcutaneous administration of the selective OX2R agonist TAK-925 moderately increased wakefulness in WT mice but not in OX2R knockout mice. Brain-penetrating and stable OX2R agonists would offer improvements to current treatment for NT1 patients. These OX2R agonists are bioavailable after alternative routes of administration (including, but not limited to, oral, intranasal, transmucosal, and transdermal) and bind with high affinity to effectively stimulate neurons regulating arousal. Indeed, preliminary clinical studies reported on TAK-925 have shown a trend toward significantly increased alertness and reduced cataplexy in NT1 individuals. Activation of OX1R is associated with mood regulation and reward behavior and may also contribute to arousal.

[0007] Orexin receptor agonists can also be used for other indications characterized by some degree of orexin neurodegeneration and excessive daytime sleepiness, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, and traumatic brain injury. Because OX2R stimulation promotes wakefulness in orexin-intact animals, orexin receptor agonists can treat excessive daytime sleepiness in patients with normal orexin levels, including type 2 narcolepsy, idiopathic hypersomnia, or sleep apnea. Similarly, orexin receptor agonists can provide wakefulness-promoting benefits in recurrent hypersomnia (such as Clayton-Ray syndrome) or inappropriate sleep timing (i.e., circadian rhythm sleep disorders) such as delayed or advanced sleep phase disorders, shift work disorders, and jet lag. Abnormal daytime sleepiness, REM sleep onset, and cataplexy-like symptoms in rare genetic disorders (e.g., ADCA-DN, Kohl's syndrome, Möbius syndrome, Norrie disease, Niemann-Pick disease type C, and Prad-Willi syndrome) can be relieved with orexin receptor agonists. Other indications for which orexin receptor agonists are considered beneficial include attention deficit hyperactivity disorder, age-related cognitive impairment, metabolic syndrome and obesity, osteoporosis, heart failure, coma, and recovery from anesthesia.

[0008] This disclosure stems from the need to provide other compounds with improved therapeutic potential for modulating orexin receptor activity (including activation of orexin-2 receptors) in the brain. In particular, compounds with improved physicochemical, pharmacological, and pharmaceutical properties compared to existing compounds are desired.

[0009] Overview

[0010] In some respects, this disclosure provides compounds of formula (I”'):

[0011]

[0012] Or its pharmaceutically acceptable salt, wherein:

[0013] X is -C(R) X1 3. -OR X2 or -N(R) X2 )2;

[0014] 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 )-;

[0015] Z is either -O- or -NR Z -;

[0016] Each R X1 Independently, it can be 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 membered heterocyclic alkyl.

[0017] Or two Rs X1Together with the atoms they are attached to, they form C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally 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 groups.

[0018] Or three Rs X1 Together with the atoms they are attached to, they form C4-C 10 Cycloalkyl, wherein the cycloalkyl group is optionally 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.

[0019] Each R X2 Independently, it is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocyclic alkyl is optionally substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic alkyl.

[0020] Or two Rs X2 Together with the atoms to which they are attached, they form 3-7 membered heterocyclic alkyl groups, wherein the heterocyclic alkyl groups are optionally 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;

[0021] Each R Y Independently, it is 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 Alkoxy;

[0022] Each R Z It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl;

[0023] Ar1 is C6-C 10 aryl or 5-10 heteroaryl, wherein the C6-C 10The aryl or 5-10 heteroaryl group is optionally substituted by one or more R3 groups;

[0024] 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 heteroaryl), -O-(C3-C 10 -cycloalkyl), -O- (3-7 membered heterocycloalkyl), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 Cycloalkyl) or -NH- (3-7 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally surrounded by one or more R 1S replace;

[0025] Each R 1S Independently, it is 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 alkoxy, C3-C7 cycloalkyl, or 3-7 membered heterocyclic alkyl;

[0026] 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 aryl), -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 heteroaryl), -O-(C3-C 10 -cycloalkyl), -O- (3-7 membered heterocycloalkyl), -NH- (C6-C 10aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 Cycloalkyl) or -NH- (3-7 membered heterocycloalkyl), wherein the alkyl, alkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally represented by one or more R 2S replace;

[0027] Each R 2S Independently, it is 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 alkoxy, C1-C6 haloalkyl, C3-C7 cycloalkyl, or 3-7 membered heterocyclic alkyl;

[0028] 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 ynyl, C1-C6 haloalkyl, or C 1-6 Alkoxy;

[0029] R 4a It is 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 Alkoxy;

[0030] R 4b It is 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 Alkoxy;

[0031] n is 0, 1, 2, or 3; and

[0032] m can be 0, 1, 2, 3, 4, or 5.

[0033] In some respects, this disclosure provides compounds that are obtainable or acquired by methods for preparing compounds as described herein (e.g., methods comprising one or more steps described in Scheme 1).

[0034] In some aspects, this disclosure provides a pharmaceutical composition comprising a compound of this disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0035] In some respects, this disclosure provides intermediates as described herein that are suitable for use in methods for preparing compounds as described herein (e.g., the intermediates are selected from those described in Examples 1-82).

[0036] In some respects, this disclosure provides a method for modulating orexin receptor activity (e.g., in vitro or in vivo), the method comprising contacting cells with an effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0037] In some respects, this disclosure provides a method for modulating orexin-2 receptor activity (e.g., in vitro or in vivo), the method comprising contacting cells with an effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0038] In some respects, this disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

[0039] In some respects, this disclosure provides a method for treating a disease or disorder disclosed herein in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

[0040] In some respects, this disclosure provides compounds of this disclosure or pharmaceutically acceptable salts thereof for modulating orexin receptor activity (e.g., in vitro or in vivo).

[0041] In some respects, this disclosure provides compounds of this disclosure or pharmaceutically acceptable salts thereof for modulating orexin-2 receptor activity (e.g., in vitro or in vivo).

[0042] In some respects, this disclosure provides compounds of this disclosure or pharmaceutically acceptable salts thereof for the treatment or prevention of the diseases or disorders disclosed herein.

[0043] In some respects, this disclosure provides compounds of this disclosure or pharmaceutically acceptable salts thereof for the treatment of diseases or disorders disclosed herein.

[0044] In some respects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the preparation of medicaments for modulating orexin receptor activity (e.g., in vitro or in vivo).

[0045] In some respects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the preparation of medicaments for modulating orexin-2 receptor activity (e.g., in vitro or in vivo).

[0046] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of the diseases or disorders disclosed herein.

[0047] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of the diseases or disorders disclosed herein.

[0048] In some respects, this disclosure provides a method for preparing the compounds of this disclosure.

[0049] In some aspects, this disclosure provides a method for preparing a compound, the method comprising one or more steps described herein.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In this specification, singular forms also include plural forms unless the context clearly indicates otherwise. Although similar or equivalent methods and materials to those described herein may be used in the practice or experimentation of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not recognized as prior art to the claimed invention. In case of conflict, this specification (including definitions) shall prevail. Furthermore, the materials, methods, and examples described are merely exemplary and are not intended to be limiting. In case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structure shall prevail.

[0051] Other features and advantages of this disclosure will become apparent from the following detailed description and claims.

[0052] Detailed description

[0053] This disclosure relates to spiroheterocyclic derivatives, their prodrugs, and pharmaceutically acceptable salts, which can modulate orexin-2 receptor activity and are therefore used to treat humans or animals. This disclosure also relates to methods for preparing these compounds, pharmaceutical compositions comprising them, and their use in treating disorders involving orexin-2 receptors, such as neurodegenerative disorders, neurological disorders, symptoms of rare genetic disorders, psychiatric disorders, mental health disorders, circadian rhythm disorders, metabolic syndrome, osteoporosis, heart failure, coma, or complications of anesthesia recovery.

[0054] definition

[0055] Unless otherwise stated, the following terms used in this specification and claims shall have the meanings set forth below.

[0056] As used herein, the terms "alkyl," "C1, C2, C3, C4, C5, or C6 alkyl," or "C1-C6 alkyl" are intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl groups include portions having 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl. In some embodiments, the straight-chain or branched alkyl group has 6 or fewer carbon atoms (e.g., C1-C6 for straight-chain and C3-C6 for branched-chain), and in another embodiment, the straight-chain or branched alkyl group has 4 or fewer carbon atoms.

[0057] As used herein, the term "optionally substituted alkyl" means an unsubstituted alkyl or an alkyl with a specified substituent that replaces one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbamoyloxy, arylcarbamoyloxy, alkoxycarbamoyloxy, aryloxycarbamoyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkylamino carbonyl, dialkylamino carbonyl, alkylthiocarbonyl, alkoxy, phosphate ester, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amidoyl, imino, mercapto, alkylthio, arylthio, thiocarbamate, sulfate, alkylsulfinyl, sulfonato, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl or aromatic or heteroaromatic moiety.

[0058] As used herein, the term "alkenyl" includes unsaturated aliphatic groups that are similar in length and possible substitutions to the aforementioned alkyl groups but contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In some embodiments, the straight-chain or branched alkenyl groups have six or fewer carbon atoms in their backbone (e.g., C2-C6 for straight chains and C3-C6 for branched chains). The term "C2-C6" includes alkenyl groups containing 2-6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3-6 carbon atoms.

[0059] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl with a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbamoyloxy, arylcarbamoyloxy, alkoxycarbamoyloxy, aryloxycarbamoyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkylamino carbonyl, dialkylamino carbonyl, alkylthiocarbonyl, alkoxy, phosphate ester, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarbamate, sulfate, alkylsulfinyl, sulfonato, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclic, alkylaryl or aromatic or heteroaromatic moiety.

[0060] As used herein, the term "alkynyl" includes unsaturated aliphatic groups that are similar in length and possible substitutions to the alkyl groups described above, but contain at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, penynyl, hexynyl, hepynyl, octyynyl, nonynyl, decanynyl) and branched-chain alkynyl groups. In some embodiments, the straight-chain or branched alkynyl group has six or fewer carbon atoms in its main chain (e.g., C2-C6 for straight chains and C3-C6 for branched chains). The term "C2-C6" includes alkynyl groups containing 2-6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3-6 carbon atoms. The terms "C2-C6 alkenyl linker" or "C2-C6 alkenyl linker" as used herein are intended to include C2, C3, C4, C5, or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2-C6 sub-olefinic linkers are intended to include C2, C3, C4, C5 and C6 sub-olefinic linkers.

[0061] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl with a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbamoyloxy, arylcarbamoyloxy, alkoxycarbamoyloxy, aryloxycarbamoyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkylamino carbonyl, dialkylamino carbonyl, alkylthiocarbonyl, alkoxy, phosphate ester, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amidoyl, imino, mercapto, alkylthio, arylthio, thiocarbamate, sulfate, alkylsulfinyl, sulfonato, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl or aromatic or heteroaromatic moiety.

[0062] Other optionally substituted portions (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups) include unsubstituted portions and portions having one or more specified substituents. For example, substituted heterocycloalkyl groups include those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0063] As used in this article, the term "cycloalkyl group" refers to a group having 3-30 carbon atoms (e.g., C3-C4). 12 C3-C 10 Cyclic hydrocarbons (C3-C8) are monocyclic or polycyclic (e.g., fused rings, bridged rings, or spirocyclic) systems of saturated or partially unsaturated hydrocarbons. Examples of cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl, and adamantyl. In the case of polycyclic cyclic hydrocarbon groups, only one ring in the cyclic hydrocarbon group needs to be non-aromatic.

[0064] As used herein, the term "heterocyclic hydrocarbon group" refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spirocyclic), or 11-14 membered tricyclic (fused, bridged, or spirocyclic) ring system having one or more heteroatoms (such as O, N, S, P, or Se), for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example, 1, 2, 3, 4, 5, or 6 heteroatoms, said heteroatoms being independently selected from nitrogen, oxygen, and sulfur, unless otherwise stated. Examples of heterocyclic hydrocarbon groups include, but are not limited to, piperidinyl, piperazine, pyrrolyl, dioxazolidinyl, tetrahydrofuranyl, isoindololinyl, indololinyl, imidazoalkyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxacyclopropyl, aziridine, oxacyclobutyl, thiohexacyclobutyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiaranyl, 1,4-diazacycloheptyl, 1,4-oxazacycloheptyl, 2-oxa-5- Azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-yl, 7′H-spiro[cyclohexane-1,5 ′-furano[3,4-b]pyridinyl]-yl, 3′H-spiro[cyclohexane-1,1′-furano[3,4-c]pyridinyl]-yl, 3-azabicyclo[3.1.0]hexyl, 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-pyrazololo[3,4-c]pyridinyl, 5,6,7,8- Tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]octane-6-yl, 5,6-dihydro-4H-cyclopentadien[b]thiophene, etc. In the case of polycyclic heterocyclic alkyl groups, only one ring in the heterocyclic alkyl group needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0065] As used herein, the term "aryl" includes aromatic groups, including "conjugated" or polycyclic systems having one or more aromatic rings and containing no heteroatoms in the ring structure. The term aryl includes both monovalent and divalent groups. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, etc. Conveniently, aryl is phenyl.

[0066] 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, the ring consisting of a carbon atom and one or more heteroatoms, for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example, 1, 2, 3, 4, 5, or 6 heteroatoms, said heteroatoms being independently selected from nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)). p (where p = 1 or 2). It should be noted that the total number of S and O atoms in an aromatic heterocycle does not exceed one. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetraazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. Heteroaryl groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic groups to form polycyclic systems (e.g., 4,5,6,7-tetrahydrobenzo[c]isooxazolyl). In some embodiments, the heteroaryl group is thiophene or benzothiophene. In some embodiments, the heteroaryl group is thiophene. In some embodiments, the heteroaryl group is benzothiophene.

[0067] In addition, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl, such as tricyclic and bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazolium, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, denitropurine, and indazine.

[0068] The cyclic hydrocarbon group, heterocyclic hydrocarbon group, aryl or heteroaryl ring may be substituted at one or more ring positions (e.g., the carbon or heteroatom forming the ring, such as N) with substituents such as those described above, such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid ester, alkyl carbonyl, alkylamino carbonyl, aralkylamino carbonyl, alkenylamino carbonyl, alkyl carbonyl, aryl carbonyl, aralkyl carbonyl, alkenyl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl thiocarbonyl, phosphate ester, phosphonate ester (phosphonato), phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarbamate, sulfate, alkylsulfinyl, sulfonato, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moieties. Aryl and heteroaromatic groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic groups to form polycyclic systems (e.g., tetrahydronaphthalene, methylenedioxyphenyl such as benzo[d][1,3]dioxacyclopenten-5-yl).

[0069] As used herein, the term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by an option of a specified group, provided that the substitution does not exceed the normal valence of the specified atom and that the substitution produces a stable compound. When the substituent is an oxo or ketone (i.e., =O), then two hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Cyclic double bonds as used herein are double bonds formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" are intended to mean a compound that is robust enough to withstand separation from the reaction mixture (RM) to a useful purity and formulation into an effective therapeutic agent.

[0070] When the bond to a substituent is shown to be an intersecting bond with two atoms in the linking ring, then such a substituent can bond to any atom in the ring. When a substituent is listed without specifying which atom it bonds to the rest of the compound in the given formula, then such a substituent can bond to any atom in the formula. Combinations of substituents and / or variables are permitted, provided that such combinations produce a stable compound.

[0071] When any variable (e.g., R) appears more than once in any component or formula of a compound, its definition for each occurrence is independent of its definition for every other occurrence. Thus, for example, if a group is shown to be substituted by 0-2 R moieties, then that group may optionally be substituted by at most two R moieties, and R is independently selected from the definition of R each time it appears. Furthermore, combinations of substituents and / or variables are permitted, provided that such combinations produce a stable compound.

[0072] The term "hydroxyl" or "hydroxyl" as used herein includes those having -OH or -O. - . group.

[0073] The term “halogenated” or “halogen” as used in this article refers to fluorine, chlorine, bromine, and iodine.

[0074] The terms “halogenated alkyl” or “halogenated alkoxy” refer to alkyl or alkoxy groups that are substituted with one or more halogen atoms.

[0075] As used herein, the term "optionally substituted haloalkyl" means an unsubstituted haloalkyl or a haloalkyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carboxyloxy, aryl carboxyloxy, alkoxy carboxyloxy, aryloxy carboxyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonato, phosphinato, amino (including alkyl amino, dialkyl amino, aryl amino, diaryl amino and alkyl aryl amino), acyl amino (including alkyl carbonyl amino, aryl carbonyl amino, carbamoyl and urea), amido, imino, mercapto, alkyl thio, aryl thio, thiocarbamate, sulfate, alkyl sulfinyl, sulfonato, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl or aromatic or heteroaromatic moiety.

[0076] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently attached to an oxygen atom. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy. Examples of substituted alkoxy groups include haloalkoxy groups. The alkoxy group may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkylamino carbonyl, dialkylamino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarbamate, sulfate, alkylsulfinyl, sulfonato, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl or aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0077] The expressions “one or more of A, B or C”, “one or more A, B or C”, “one or more of A, B and C”, “one or more A, B and C”, “choose from the group consisting of A, B and C”, “select from A, B and C”, etc., used interchangeably in this document, and all mean an option from the group consisting of A, B and / or C, that is, one or more A, one or more B, one or more C or any combination thereof, unless otherwise indicated.

[0078] It should be understood that this disclosure provides methods for synthesizing compounds of any formula described herein. This disclosure also provides detailed methods for synthesizing the various disclosed compounds according to the following schemes and those shown in the examples.

[0079] It should be understood that throughout this specification, when a composition is described as having, including, or comprising specific components, it is assumed that the composition is also substantially composed of or consisting of the listed components. Similarly, when a method or process is described as having, including, or comprising specific process steps, the process is also substantially composed of or consisting of the listed processing steps. Furthermore, it should be understood that the order of the steps or the sequence of certain actions is not important, as long as the invention remains operable. Moreover, two or more steps or actions may be performed simultaneously.

[0080] It should be understood that the synthetic methods of this disclosure can allow for a variety of functional groups, and therefore a wide range of substituted starting materials can be used. The methods typically provide the desired final compound at or near the end of the process, although it may be desirable in some cases to further convert the compound into its pharmaceutically acceptable salt.

[0081] 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 from readily prepared intermediates using standard synthetic methods and procedures known to those skilled in the art, or which will be apparent to those skilled in the art from the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules, as well as for functional group transformations and manipulations, are available from relevant scientific literature or standard textbooks in the art. Although not limited to any one or a few sources, classic texts such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) (incorporated herein by reference) are known and widely accepted reference textbooks on organic synthesis to those skilled in the art.

[0082] Those skilled in the art will notice that the order of certain steps, such as the introduction and removal of protecting groups, can be altered in the reaction sequence and synthetic scheme described herein. They will also recognize that certain groups may require protection from the effects of reaction conditions by using protecting groups. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups and how to introduce and remove them can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons: New York, 1999.

[0083] It should be understood that, unless otherwise stated, any description of a treatment or prevention method includes the use of the said compound to provide such treatment or prevention, as described herein. It should be further understood that, unless otherwise stated, any description of a treatment or prevention method includes the use of the said compound to prepare a medicament for treating or preventing such a condition. The treatment or prevention includes treating or preventing human or non-human animals, including rodents and other disease models.

[0084] It should be understood that, unless otherwise stated, any description of a treatment method includes the use of the said compounds to provide such treatment, as described herein. It should be further understood that, unless otherwise stated, any description of a treatment method includes the use of the said compounds to prepare a drug for treating such a condition. The treatment includes treatment of humans or non-human animals, including rodents and other disease models used herein.

[0085] As used herein, the term "object" includes humans and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the object is a mammal. The mammal may be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The object may also be a bird or poultry. In some embodiments, the object is a human.

[0086] As used herein, the term "object in need" refers to an object suffering from a disease or an object with an increased risk of developing a disease. "Object" includes mammals. The mammal may be, for example, a human or a suitable non-human mammal such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The object may also be a bird or poultry. In one embodiment, the mammal is a human. An object in need may be an object previously diagnosed or identified as suffering from a disease or disorder disclosed herein. An object in need may also be an object suffering from a disease or disorder disclosed herein. Alternatively, an object in need may be an object with an increased risk of developing such a disease or disorder relative to the general population (i.e., an object predisposed to developing such a disorder relative to the general population). An object in need may suffer from a treatment-resistant or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that is unresponsive to treatment or has not yet responded to treatment). The object may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, the object in need has received all known effective therapies for the disease or disorder disclosed herein and these have failed. In some implementations, the subject in need has received at least one prior therapy.

[0087] As used herein, the term “treatment” describes the management and care of a patient in order to combat a disease, symptom, or disorder, and includes the administration of compounds of this disclosure or their pharmaceutically acceptable salts, polymorphs, or solvates to alleviate or eliminate symptoms or complications of the disease, symptom, or disorder. The term “treatment” may also include treatment of in vitro cell or animal models. It should be understood that references to “treatment” include the reduction of existing symptoms of a condition. Thus, “treatment” for a state, disorder, or symptom includes: (1) preventing or delaying the onset of clinical symptoms of a state, disorder, or symptom occurring in a person who may have or is susceptible to the state, disorder, or symptom but has not yet experienced or displayed clinical or subclinical symptoms of the state, disorder, or symptom; (2) suppressing the state, disorder, or symptom, i.e., preventing, reducing, or delaying the development of the disease or its recurrence (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms; or (3) alleviating or reducing the disease, i.e., causing the disappearance of at least one of the state, disorder, or symptom or its clinical or subclinical symptoms.

[0088] It should be understood that the compounds of this disclosure or their pharmaceutically acceptable salts, polymorphs or solvates may or may not be used for the prevention of related diseases, symptoms or disorders, or for the identification of suitable candidates for such purposes.

[0089] The terms “prevention,” “stopping,” or “protection from” used in this article describe reducing or eliminating the onset of symptoms or complications of such a disease, condition, or disorder.

[0090] It should be understood that those skilled in the art may refer to general reference texts for a detailed description of the known or equivalent techniques discussed herein. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd Edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th Edition (1990). Of course, these texts may also be referenced when making or using any aspect of this disclosure.

[0091] It should be understood that this disclosure also provides pharmaceutical compositions comprising any of the compounds described herein and at least one pharmaceutically acceptable excipient or carrier.

[0092] As used herein, the term "pharmaceutical composition" refers to a formulation containing the compounds of this disclosure, in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. Unit dosage form can be any of a variety of forms, including, for example, capsules, intravenous infusion bags, tablets, a single pump on an aerosol inhaler, or a tubular bottle. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salts, hydrates, solvates, or isomers) in a unit dosage composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will understand that, depending on the patient's age and condition, it may sometimes be necessary to make routine variations in dosage. Dosage will also depend on the route of administration. A variety of routes are considered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, sublingual, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal application of the compounds used in this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and with any desired preservatives, buffers, or propellants.

[0093] As used herein, the term "pharmaceutically acceptable" means a compound, anion, cation, material, composition, carrier, and / or dosage form that, to a reasonable extent of medical judgment, is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0094] As used herein, the term "pharmaceuticalally acceptable excipient" refers to an excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients acceptable for both veterinary and human pharmaceutical applications. As used in this specification and claims, "pharmaceuticalally acceptable excipient" includes one or more such excipients.

[0095] It should be understood that the pharmaceutical compositions of this disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous application may include the following components: sterile diluents such as water for injection, saline solution, non-volatile oils, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and agents for adjusting the pH such as sodium chloride or dextrose. The pH may be adjusted with an acid or base (such as hydrochloric acid or sodium hydroxide). Parenteral preparations may be packaged in ampoules, disposable syringes, or multiple-dose tubular vials made of glass or plastic.

[0096] It should be understood that the compounds or pharmaceutical compositions of this disclosure can be administered to the subject using many well-known methods currently used for chemotherapeutic treatments. For example, the compounds of this disclosure can be injected into the bloodstream or body cavity, administered orally, or applied through the skin as a patch. The selected dose should be sufficient to constitute an effective treatment, but not high enough to cause unacceptable side effects. The condition of the disease (e.g., the disease or disorder disclosed herein) and the patient's health should preferably be closely monitored during treatment and for a reasonable period after treatment.

[0097] As used herein, the term "therapeutic effective amount" refers to the amount of a pharmaceutical agent used to treat, improve, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, body type, and health; the nature and severity of the condition; and the therapeutic agent or combination of therapeutic agents chosen for administration. A therapeutically effective amount for a given situation can be determined through routine experiments within the skill and judgment of a clinician.

[0098] As used herein, the term "therapeutic effective amount" refers to the amount of a pharmaceutical agent used to treat or improve an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, body type, and health; the nature and severity of the condition; and the therapeutic agent or combination of therapeutic agents chosen for administration. A therapeutic effective amount for a given situation can be determined through routine experiments within the skill and judgment of a clinician.

[0099] It should be understood that for any compound, the therapeutically effective dose can initially be estimated in a cell culture assay (e.g., a culture assay of proliferative cells) or in an animal model (typically rat, mouse, rabbit, dog, or pig). The animal model can also be used to determine the appropriate concentration range and route of administration. This information can then be used to determine the useful dose and route of administration in humans. Therapeutic / prophylactic efficacy and toxicity, e.g., ED, can be determined using standard pharmaceutical procedures in cell culture or laboratory animals. 50 (the therapeutically effective dose in 50% of the population) and LD 50 (The dose that would be lethal to 50% of the population). The dose ratio between toxic effects and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50. 50 / ED 50 Pharmaceutical compositions exhibiting a high therapeutic index are preferred. Dosage can vary within this range, depending on the dosage form used, patient sensitivity, and route of administration.

[0100] Adjust the dosage and administration to provide adequate levels of active agent or maintain the desired effect. Factors to consider include the severity of the condition, the subject's general health, age, weight and sex, diet, timing and frequency of administration, drug combination, sensitivity to response, and tolerance / response to therapy. Depending on the half-life and clearance rate of the specific formulation, long-acting drug combinations may be administered every 3 to 4 days, weekly, or bi-weekly.

[0101] Pharmaceutical compositions containing the active compounds of this disclosure can be prepared in ways commonly known, such as by means of conventional mixing, dissolving, granulation, pelleting, grinding, emulsification, encapsulation, embedding, or lyophilization processes. Pharmaceutical compositions can 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 compound into articles suitable for pharmaceutical use. Of course, appropriate formulations depend on the chosen route of administration.

[0102] Suitable pharmaceutical compositions for injection include sterile aqueous solutions (in the water-soluble case) or dispersions, and sterile powders for immediate preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, and Cremophor EL. TM(BASF, Parsippany, NJ) or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be fluid enough to be easily injected. It must be stable under the conditions of preparation and storage and must be preserved 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, etc.), and suitable mixtures thereof. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size (in the case of dispersions), and by using surfactants. Inhibition of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include an isotonic agent in the composition, such as sugars, polyols such as mannitol and sorbitol, and sodium chloride. The absorption of the injectable composition can be prolonged by including an absorption-delaying agent in the composition, such as aluminum monostearate and gelatin.

[0103] Sterile injectable solutions can be prepared by incorporating the desired amount of the active compound, along with one or more of the components listed above, into a suitable solvent, followed by filtration and sterilization. Dispersions are typically prepared by incorporating the active compound into a sterile medium containing a base dispersion medium and any other desired components from those listed above. For sterile powders used to prepare sterile injectable solutions, preparation methods include vacuum drying and freeze-drying, which produce a powder containing the active ingredient plus any other desired components from its previously sterile filtered solution.

[0104] Oral compositions typically include an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be mixed with excipients and administered in tablet, lozenge, or capsule form. Oral compositions may also be prepared using a liquid carrier for use as a mouthwash, wherein the compound in the fluid carrier is administered orally and by rinsing and spitting or swallowing. Pharmaceutically compatible binders and / or excipients may be included as part of the composition. The tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginate, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; gliding agents such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0105] For administration by inhalation, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser (containing a suitable propellant, such as a gas such as carbon dioxide) or a sprayer.

[0106] Systemic application can also be achieved via transmucosal or transdermal routes. For transmucosal or transdermal application, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are generally known in the art and include, for example, detergents, bile salts, and fusidic acid derivatives for transmucosal application. Transmucosal application can be accomplished by using nasal sprays or suppositories. For transdermal application, the active compound is formulated into ointments, creams, gels, or lotions generally known in the art.

[0107] Active compounds can be prepared together with pharmaceutically acceptable carriers that protect the compounds from rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene-vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be understood by those skilled in the art. The materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes targeting infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0108] Of particular advantage is that, for ease of administration and uniform dosage, oral or parenteral compositions are formulated in dosage units. The dosage unit form used herein refers to a physically discrete unit suitable as a unit dose for the object to be treated; each unit contains a predetermined amount of active compound, calculated to produce the desired therapeutic effect, in combination with the desired pharmaceutical carrier. The specifications of the dosage unit form of this disclosure depend on and are directly dependent on the unique characteristics of the active compound and the specific therapeutic effect to be achieved.

[0109] In therapeutic applications, the dosage of the pharmaceutical composition used according to this disclosure varies with the pharmaceutical agent, the age, weight, and clinical condition of the receiving patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dosage should be sufficient to cause a slowing and preferably remission of the symptoms of the disease or disorder disclosed herein, and preferably also to cause complete remission of the disease or disorder. Dosages can range from about 0.01 mg / kg / day to about 5000 mg / kg / day. An effective amount of a pharmaceutical agent is the amount that provides an objectively identifiable improvement noticeable to a clinician or other qualified observer. Improvement in survival and growth indicates remission. As used herein, the term "dosage-effective manner" refers to the amount of active compound that produces the desired biological effect in the subject or cells.

[0110] It should be understood that the pharmaceutical composition may be included in a container, packet or dispenser together with the instructions for use.

[0111] It should be understood that all these forms are also considered within the scope of the claimed disclosure for compounds of this disclosure that are capable of further forming salts.

[0112] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the compounds of this disclosure, wherein the parent compound is modified by preparing its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali metal or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetate, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, hydroxyacetic acid, hydroxyacetaminophenarsic acid, hexylresorcinic acid, hydroabamic acid, hydrogen... Bromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthyl carboxylic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, primordial acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, hypoacetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and common amino acids such as glycine, alanine, phenylalanine, and arginine.

[0113] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, N,N′-dibenzylethylenediamine salt (benzathine salt), tromethamine salt, ammonium salt, arginine salt, or lysine salt.

[0114] Other pharmaceutically acceptable examples of 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]-oct-2-en-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, mucoconic acid, etc. This disclosure also includes salts formed when the acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion); or salts formed when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc. In salt form, it should be understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0115] It should be understood that all references to pharmaceutically acceptable salts include the same salt in its solvation form (solvent) or crystalline form (polymorph) as defined herein.

[0116] The compound or its pharmaceutically acceptable salts may be administered orally, nasally, transdermally, pulmonaryly, by inhalation, sublingually, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, or parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0117] The dosing regimen for the compound is selected based on a number of factors, including patient type, race, age, weight, sex, and medical condition; the severity of the condition to be treated; route of administration; patient's renal and hepatic function; and the specific compound or its salt used. A general practitioner or veterinarian can readily determine and prescribe an effective amount of the drug required to prevent, counteract, or halt the progression of the disease.

[0118] Techniques for formulating and administering the disclosed compounds of this disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein, and their pharmaceutically acceptable salts, are combined with a pharmaceutically acceptable carrier or diluent for use in a pharmaceutical article. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dose within the range described herein.

[0119] Unless otherwise stated, all percentages and ratios used herein are by weight. Other features and advantages of this disclosure will become apparent from the various embodiments. The provided embodiments illustrate different components and methods that can be used to practice this disclosure. The embodiments do not limit the claimed disclosure. Based on this disclosure, those skilled in the art can identify and employ other components and methods that can be used to practice this disclosure.

[0120] In the synthetic schemes described herein, compounds may be drawn using a specific configuration for simplicity. Such a specific configuration should not be construed as limiting the disclosure to one or more isomers, tautomers, positional isomers, or stereoisomers, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers; however, it should be understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0121] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document were expressly and individually identified as incorporated herein by reference. The citation of publications and patent documents is not intended to acknowledge that any of them is prior art, nor does it constitute any admission of their content or date. The invention has now been described in writing, and those skilled in the art will recognize that the invention can be practiced in a variety of embodiments, and that the foregoing description and the following examples are for illustrative purposes and not for limiting the scope of the following claims.

[0122] As used herein, the phrase "compounds of this disclosure" refers to those compounds disclosed herein, both generally and specifically.

[0123] The compounds disclosed herein

[0124] In some respects, this disclosure provides compounds of formula (I”'):

[0125]

[0126] Or its pharmaceutically acceptable salt, wherein:

[0127] X is -C(R) X1 3. -OR X2 or -N(R) X2 )2;

[0128] 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 )-;

[0129] Z is either -O- or -NR Z -;

[0130] Each R X1 Independently, it can be 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 membered heterocyclic alkyl group.

[0131] Or two Rs X1 Together with the atoms they are attached to, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon group or heterocyclic hydrocarbon group is optionally 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 groups.

[0132] Or three Rs X1 Together with the atoms they are attached to, they form C4-C 10 Cycloalkyl group, wherein the cycloalkyl group is optionally substituted by 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.

[0133] Each RX2 Independently, it is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic hydrocarbon group, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocyclic hydrocarbon group is optionally substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic hydrocarbon group.

[0134] Or two Rs X2 Together with the atoms to which they are attached, they form 3-7 membered heterocyclic hydrocarbon groups, wherein the heterocyclic hydrocarbon groups are optionally 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.

[0135] Each R Y Independently, it is 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 Alkoxy;

[0136] Each R Z It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl;

[0137] Ar1 is C6-C 10 aryl or 5-10 heteroaryl, wherein the C6-C 10 The aryl or 5-10 heteroaryl group is optionally substituted by one or more R3 groups;

[0138] R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -N(C1-C6 alkyl)(C3-C 10 -Cyclohydryl group), -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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S replace;

[0139] Each R 1S Independently, it is an 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 alkoxy, C3-C7 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon;

[0140] 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 aryl), -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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 2S replace;

[0141] Each R 2S Independently, it is an 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 alkoxy, C1-C6 haloalkyl, C3-C7 cycloalkyl or 3-7 membered heterocyclic alkyl;

[0142] 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 ynyl, C1-C6 haloalkyl, or C 1-6 Alkoxy;

[0143] R 4a It is 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 Alkoxy;

[0144] R 4b It is 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 Alkoxy;

[0145] n is 0, 1, 2, or 3; and

[0146] m can be 0, 1, 2, 3, 4, or 5.

[0147] In some respects, this disclosure provides compounds of formula (I”):

[0148]

[0149] Or its pharmaceutically acceptable salt, wherein:

[0150] X is -C(R) X1 3. -OR X2 or -N(R) X2 )2;

[0151] 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 )-;

[0152] Z is either -O- or -NR Z -;

[0153] Each RX1 Independently, it can be 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 cyclic hydrocarbon.

[0154] Or two Rs X1 Together with the atoms they are attached to, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon group or heterocyclic hydrocarbon group is optionally 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.

[0155] Or three Rs X1 Together with the atoms they are attached to, they form C4-C 10 Cycloalkyl group, wherein the cycloalkyl group is optionally substituted by 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.

[0156] Each R X2 Independently, it is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic hydrocarbon group, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocyclic hydrocarbon group is optionally substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic hydrocarbon group.

[0157] Or two Rs X2 Together with the atoms to which they are attached, they form 3-7 membered heterocyclic hydrocarbon groups, wherein the heterocyclic hydrocarbon groups are optionally 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.

[0158] Each R Y Independently, it is 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 Alkoxy;

[0159] Each R Z It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl;

[0160] Ar1 is C6-C 10 aryl or 5-10 heteroaryl, wherein the C6-C 10 The aryl or 5-10 heteroaryl group is optionally substituted by one or more R3 groups;

[0161] R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -N(C1-C6 alkyl)(C3-C 10 -Cyclohydryl group), -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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S replace;

[0162] Each R 1S Independently, it is an 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 alkoxy, C3-C7 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon;

[0163] 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 aryl), -SO2(C6-C 10 aryl), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C10 Aryl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 2S replace;

[0164] Each R 2S Independently, it is an 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 alkoxy, C1-C6 haloalkyl, C3-C7 cycloalkyl or 3-7 membered heterocyclic alkyl;

[0165] 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 ynyl, C1-C6 haloalkyl, or C 1-6 Alkoxy;

[0166] R 4a It is 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 Alkoxy;

[0167] R 4b It is 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 Alkoxy;

[0168] n is 0, 1, 2, or 3; and

[0169] m can be 0, 1, 2, 3, 4, or 5.

[0170] In some respects, this disclosure provides compounds of formula (I'):

[0171]

[0172] Or its pharmaceutically acceptable salt, wherein:

[0173] X is -C(R) X1 3. -OR X2 or -N(R) X2 )2;

[0174] 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 )-;

[0175] Z is either -O- or -NR Z -;

[0176] Each R X1 Independently, it is 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 Together with the atoms to which they are attached, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon groups or heterocyclic hydrocarbon groups are optionally substituted by 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;

[0177] Each R X2 It is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or two R X2 Together with the atoms to which they are attached, they form 3-7 membered heterocyclic hydrocarbon groups, wherein the heterocyclic hydrocarbon groups are optionally 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.

[0178] Each R YIndependently, it is 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 Alkoxy;

[0179] Each R Z It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl;

[0180] Ar1 is C6-C 10 aryl or 5-10 heteroaryl, wherein the C6-C 10 The aryl or 5-10 heteroaryl group is optionally substituted by one or more R3 groups;

[0181] 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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S replace;

[0182] Each R 1S Independently, it is an 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 alkoxy, C3-C7 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon;

[0183] 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 aryl), -SO2(C6-C 10aryl), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 2S replace;

[0184] Each R 2S Independently, it is an 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 alkoxy, C3-C7 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon;

[0185] 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 ynyl, C1-C6 haloalkyl, or C 1-6 Alkoxy;

[0186] R 4a It is 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 Alkoxy;

[0187] R 4b It is 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 Alkoxy;

[0188] n is 0, 1, 2, or 3; and

[0189] m can be 0, 1, 2, 3, 4, or 5.

[0190] In some respects, this disclosure provides compounds of formula (I):

[0191]

[0192] Or its pharmaceutically acceptable salt, wherein:

[0193] X is -C(R) X1 3. -OR X2 or -N(R) X2 )2;

[0194] 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 )-;

[0195] Z is either -O- or -NR Z -;

[0196] Each R X1 Independently, it is 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 Together with the atoms to which they are attached, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon groups or heterocyclic hydrocarbon groups are optionally substituted by 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;

[0197] Each R X2 It is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or two R X2 Together with the atoms to which they are attached, they form 3-7 membered heterocyclic hydrocarbon groups, wherein the heterocyclic hydrocarbon groups are optionally 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] Each R Y Independently, it is 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 Alkoxy;

[0199] Each R Z It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl;

[0200] 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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S replace;

[0201] Each R 1S Independently, it is an 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 alkoxy, C3-C7 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon;

[0202] 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 aryl), -SO2(C6-C 10 aryl), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10Aryl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 2S replace;

[0203] Each R 2S Independently, it is an 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 alkoxy, C3-C7 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon;

[0204] 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 ynyl, C1-C6 haloalkyl, or C 1-6 Alkoxy;

[0205] R 4a It is 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 Alkoxy;

[0206] R 4b It is 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 Alkoxy;

[0207] n is 0, 1, 2, or 3;

[0208] m is 0, 1, 2, 3, 4, or 5; and

[0209] p can be 0, 1, 2, 3, or 4.

[0210] In some respects, this disclosure provides compounds of formula (II):

[0211]

[0212] Or its pharmaceutically acceptable salt, wherein:

[0213] X is -C(R) X1 3. -OR X2 or -N(R) X2 )2;

[0214] 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 )-;

[0215] Z is either -O- or -NR Z -;

[0216] Each R X1 Independently, it is 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 Together with the atoms to which they are attached, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon groups or heterocyclic hydrocarbon groups are optionally substituted by 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;

[0217] Each R X2 It is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or two R X2 Together with the atoms to which they are attached, they form 3-7 membered heterocyclic hydrocarbon groups, wherein the heterocyclic hydrocarbon groups are optionally 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] Each R YIndependently, it is 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 Alkoxy;

[0219] Each R Z It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl;

[0220] 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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S replace;

[0221] Each R 1S Independently, it is an 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 alkoxy, C3-C7 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon;

[0222] 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 aryl), -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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 2S replace;

[0223] Each R 2S Independently, it is an 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 alkoxy, C3-C7 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon;

[0224] 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 ynyl, C1-C6 haloalkyl, or C 1-6 Alkoxy;

[0225] R 4a It is 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 Alkoxy;

[0226] R 4b It is 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 Alkoxy;

[0227] n is 0, 1, 2, or 3;

[0228] m is 0, 1, 2, 3, 4, or 5; and

[0229] p is 0, 1, 2 or 3.

[0230] In some respects, this disclosure provides compounds of formula (III):

[0231]

[0232] Or its pharmaceutically acceptable salt, wherein:

[0233] X is -C(R) X1 3. -OR X2 or -N(R) X2 )2;

[0234] 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 )-;

[0235] Z is either -O- or -NR Z -;

[0236] Each R X1 Independently, it is 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 Together with the atoms to which they are attached, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon groups or heterocyclic hydrocarbon groups are optionally substituted by 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;

[0237] Each R X2 It is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or two R X2 Together with the atoms to which they are attached, they form 3-7 membered heterocyclic hydrocarbon groups, wherein the heterocyclic hydrocarbon groups are optionally 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.

[0238] Each R YIndependently, it is 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 Alkoxy;

[0239] Each R Z It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl;

[0240] 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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S replace;

[0241] Each R 1S Independently, it is an 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 alkoxy, C3-C7 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon;

[0242] 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 aryl), -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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 2S replace;

[0243] Each R 2S Independently, it is an 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 alkoxy, C3-C7 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon;

[0244] Each R3 is 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 Alkoxy;

[0245] R 4a It is 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 Alkoxy;

[0246] R 4b It is 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 Alkoxy;

[0247] n is 0, 1, 2, or 3;

[0248] m is 0, 1, 2, 3, 4, or 5; and

[0249] p is 0 or 1.

[0250] In some respects, this disclosure provides compounds of formula (I') or pharmaceutically acceptable salts thereof, wherein:

[0251] Z is -NR Z -;and

[0252] 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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S replace.

[0253] In some respects, this disclosure provides compounds of formula (I') or pharmaceutically acceptable salts thereof, wherein:

[0254] Z is -NR Z -;and

[0255] R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon, 3-7 membered heterocyclic hydrocarbon, -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S Replace; and

[0256] Each R 1S It is independently a halogen, -CN, -OH, or C1-C6 alkoxy group.

[0257] In some respects, this disclosure provides compounds of formula (I') or pharmaceutically acceptable salts thereof, wherein:

[0258] Z is -NH-; and

[0259] R1 is a C1-C6 alkyl group.

[0260] In some respects, this disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein:

[0261] Z is -NR Z -;and

[0262] 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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S replace.

[0263] In some respects, this disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein:

[0264] Z is -NR Z -;and

[0265] R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon, 3-7 membered heterocyclic hydrocarbon, -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S Replace; and

[0266] Each R 1S It is independently a halogen, -CN, -OH, or C1-C6 alkoxy group.

[0267] In some respects, this disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein:

[0268] Z is -NH-; and

[0269] R1 is a C1-C6 alkyl group.

[0270] In some respects, this disclosure provides compounds of formula (II) or pharmaceutically acceptable salts thereof, wherein:

[0271] Z is -NR Z -;and

[0272] 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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S replace.

[0273] In some respects, this disclosure provides compounds of formula (II) or pharmaceutically acceptable salts thereof, wherein:

[0274] Z is -NR Z -;and

[0275] R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon, 3-7 membered heterocyclic hydrocarbon, -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S Replace; and

[0276] Each R 1S It is independently a halogen, -CN, -OH, or C1-C6 alkoxy group.

[0277] In some respects, this disclosure provides compounds of formula (II) or pharmaceutically acceptable salts thereof, wherein:

[0278] Z is -NH-; and

[0279] R1 is a C1-C6 alkyl group.

[0280] In some respects, this disclosure provides compounds of formula (III) or pharmaceutically acceptable salts thereof, wherein:

[0281] Z is -NR Z -;and

[0282] 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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S replace.

[0283] In some respects, this disclosure provides compounds of formula (III) or pharmaceutically acceptable salts thereof, wherein:

[0284] Z is -NR Z -;and

[0285] R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon, 3-7 membered heterocyclic hydrocarbon, -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S Replace; and

[0286] Each R 1S It is independently a halogen, -CN, -OH, or C1-C6 alkoxy group.

[0287] In some respects, this disclosure provides compounds of formula (III) or pharmaceutically acceptable salts thereof, wherein:

[0288] Z is -NH-; and

[0289] R1 is a C1-C6 alkyl group.

[0290] It should be understood that for compounds of formula (I”), (I’), (I), (II) or (III), X, Y, Z, R X1 R X2 R Y R Z Ar1, R1, R 1S R2, R2S R3, R 4a R 4b The radicals X, Y, Z, and R can each be selected from the groups described herein (where applicable), and the references to X, Y, Z, and R are as follows. X1 R X2 R Y R Z Ar1, R1, R 1S R2, R 2S R3, R 4a R 4b Any group described in this document with respect to X, Y, Z, R, n, m, or p can be related to the groups described in this document with respect to X, Y, Z, R. X1 R X2 R Y R Z Ar1, R1, R 1S R2, R 2S R3, R 4a R 4b Any combination of one or more of the remaining groups described in n, m, or p (where applicable).

[0291] In some implementations, X is -C(R) X1 3. -OR X2 or -N(R) X2 )2.

[0292] In some implementations, X is -OR X2 or -N(R) X2 )2.

[0293] In some implementations, X is -C(R) X1 3. In some implementations, X is -OR X2 In some implementations, X is -N(R) X2 )2.

[0294] In some implementations, X is -O (methyl)

[0295] In some implementations, X is

[0296] In some implementations, X is -O (methyl).

[0297] In some implementations, X is

[0298] In some implementations, X is

[0299] In some implementations, X is

[0300] In some implementations, X is

[0301] In some implementations, X is

[0302] In some implementations, X is

[0303] In some implementations, X is

[0304] In some implementations, X is

[0305] In some implementations, 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 )-.

[0306] In some implementations, 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 )-.

[0307] In some implementations, Y is -(C(R) Y )2) m -

[0308] In some implementations, Y is -O-(C(R) Y )2) m -or-(C(R) Y )2) m -O-.

[0309] In some implementations, Y is -O-(C(R) Y )2) m -. In some implementations, Y is -(C(R) Y )2) m -O-.

[0310] In some implementations, Y is -N(R) Y )-(C(R Y )2) m -or-(C(R) Y )2) m -N(R Y )-.

[0311] In some implementations, Y is -N(R) Y )-(C(R Y )2) m -. In some implementations, Y is -(C(R) Y )2) m -N(R Y )-.

[0312] In some implementations, Y is -CH2-, -CF2-, -CH2-O-, -O-CH2-, -CH2-NH-, -NH-CH2-, -CH2-N(CH2CF3)-, or -N(CH2-CF3)-CH2-.

[0313] In some implementations, Y is -CH2-.

[0314] In some implementations, Y is -CH2-O- or -O-CH2.

[0315] In some implementations, Y is -CH2-NH-, -NH-CH2-, -CH2-N(CH2CF3)-, or -N(CH2-CF3)-CH2-.

[0316] In some implementations, Y is -CH2-NH- or -NH-CH2-.

[0317] In some implementations, Y is -CH2-N(CH2CF3)- or -N(CH2-CF3)-CH2-.

[0318] In some implementations, Z is -O- or -NR. Z -

[0319] In some implementations, Z is -O-. In some implementations, Z is -NR. Z -

[0320] In some implementations, Z is -NH-.

[0321] In some implementations, each R X1 Independently, it can be 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 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon.

[0322] Or two Rs X1 Together with the atoms they are attached to, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon group or heterocyclic hydrocarbon group is optionally substituted by 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 groups, or

[0323] Three Rs X1 Together with the atoms they are attached to, they form C4-C 10 Cycloalkyl group, wherein the cycloalkyl group is optionally 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.

[0324] In some implementations, each R X1 Independently, it can be 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 cyclic hydrocarbon.

[0325] Or two Rs X1 Together with the atoms they are attached to, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon group or heterocyclic hydrocarbon group is optionally 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, or

[0326] Three Rs X1 Together with the atoms they are attached to, they form C4-C 10Cycloalkyl group, wherein the cycloalkyl group is optionally 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.

[0327] In some implementations, each R X1 Independently, it can be 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 cyclic hydrocarbon.

[0328] Or two Rs X1 Together with the atoms they are attached to, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon group or heterocyclic hydrocarbon group is optionally 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, or

[0329] Three Rs X1 Together with the atoms they are attached to, they form C4-C 10 Cycloalkyl group, wherein the cycloalkyl group is optionally 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.

[0330] In some implementations, each R X1 Independently, it can be 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 cyclic hydrocarbon.

[0331] Or two Rs X1 Together with the atoms to which they are attached, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon groups or heterocyclic hydrocarbon groups are optionally substituted by 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.

[0332] In some implementations, each RX1 Independently, it is 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.

[0333] Or two Rs X 1. Together with the atoms to which they are attached, they form a C3-C7 cyclic hydrocarbon group or a 3-7 membered heterocyclic hydrocarbon group, wherein the cyclic hydrocarbon group or heterocyclic hydrocarbon group is optionally substituted by 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.

[0334] In some implementations, each R X1 Independently, it is 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 cyclic hydrocarbon or 3-7 membered heterocyclic hydrocarbon.

[0335] In some implementations, each R X1 Independently, it is 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 cyclic hydrocarbon.

[0336] In some implementations, each R X1 Independently, it is 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.

[0337] In some implementations, each R X1 H stands alone.

[0338] In some implementations, each R X1 It 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 C1-C6 alkoxy.

[0339] In some implementations, each R X1It is independently a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0340] In some implementations, each R X1 It is a halogen on its own.

[0341] In some implementations, each R X1 It is independently F, Cl, Br, or I. In some implementations, each R X1 It is independently F, Cl, or Br. In some implementations, each R X1 It is either F or Cl on its own.

[0342] In some implementations, each R X1 Independently, it is F. In some implementations, each R X1 Independently, it is Cl. In some implementations, each R X1 Independently, it is Br. In some implementations, each R X1 I is independent.

[0343] In some implementations, each R X1 Independently, it is -CN.

[0344] In some implementations, each R X1 It is -OH on its own.

[0345] In some implementations, each R X1 It is independently -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0346] In some implementations, each R X1 It is -NH2 independently.

[0347] In some implementations, each R X1 Independently, it is -NH (C1-C6 alkyl).

[0348] In some implementations, each R X1 Independently, it is -NH (methyl). In some embodiments, each R X1 Independently, it is -NH(ethyl). In some embodiments, each R X1 Independently, it is -NH (propyl). In some embodiments, each R X1 Independently, it is -NH (butyl). In some embodiments, each R X1 Independently, it is -NH(pentyl). In some embodiments, each R X1 Independently, it is -NH (hexyl).

[0349] In some implementations, each R X1 It is independently -N(C1-C6 alkyl)2.

[0350] In some implementations, each R X1 It is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl or C1-C6 alkoxy.

[0351] In some implementations, each R X1 It is independently C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0352] In some implementations, each R X1 It is independently a C1-C6 alkyl group.

[0353] In some implementations, each R X1 Independently, it is methyl. In some embodiments, each R X1 It is ethyl independently. In some embodiments, each R X1 It is propyl, independently. In some embodiments, each R X1 It is butyl independently. In some implementations, each R X1 It is pentyl independently. In some embodiments, each R X1 It is independently a base. In some implementations, each R is... X1 Independently, it is isopropyl. In some embodiments, each R... X1 Independently, it is isobutyl. In some implementations, each R... X1 Independently, it is isopentyl. In some embodiments, each R... X1 Independently, it is a heterobase. In some implementations, each R... X1 It is independently sec-butyl. In some implementations, each R X1 Independently, it is sec-amyl. In some implementations, each R... X1 Independently, it is Zhongjiji. In some implementations, each R X1 It is tert-butyl independently.

[0354] In some implementations, each R X1 It is independently a C2-C6 alkenyl group.

[0355] In some implementations, each R X1 Independently, it is a C2 alkenyl group. In some embodiments, each R X1 It is independently a C3 alkenyl group. In some embodiments, each R X1 Independently, it is a C4 alkenyl group. In some embodiments, each R X1 It is independently a C5 alkenyl group. In some embodiments, each RX1 It is independently a C6 alkenyl group.

[0356] In some implementations, each R X1 It is independently a C2-C6 ynyl group.

[0357] In some implementations, each R X1 It is independently a C2 ynyl group. In some embodiments, each R X1 It is independently a C3 ynyl group. In some embodiments, each R X1 It is independently a C4 ynyl group. In some embodiments, each R X1 It is independently a C5 ynyl group. In some embodiments, each R X1 It is independently a C6 ynyl group.

[0358] In some implementations, each R X1 It is independently a C1-C6 haloalkyl or C1-C6 alkoxy.

[0359] In some implementations, each R X1 It is independently a C1-C6 haloalkyl group.

[0360] In some implementations, each R X1 Independently, it is a halomethyl group. In some embodiments, each R... X1 Independently, it is a haloethyl. In some embodiments, each R X1 Independently, it is a halopropyl group. In some embodiments, each R... X1 Independently, it is a halogenated butyl group. In some implementations, each R... X1 Independently, it is a halopentyl group. In some embodiments, each R... X1 It is a halogenated hexyl group on its own.

[0361] In some implementations, each R X1 Independently, it is a C1-C6 alkoxy group.

[0362] In some implementations, each R X1 It is independently a methoxyl group. In some embodiments, each R... X1 It is independently ethoxylated. In some embodiments, each R X1 It is propoxy-based independently. In some embodiments, each R... X1 It is independently butoxyl. In some embodiments, each R X1 It is independently pentoxygenated. In some embodiments, each R X1 It is independently an hexoxy group.

[0363] In some implementations, each R X1It is independently C1-C6 alkyl-C1-C6 alkoxy.

[0364] In some implementations, each R X1 Independently, it is a C1 alkyl-C1-C6 alkoxy group. In some embodiments, each R X1 Independently, it is a C2 alkyl-C1-C6 alkoxy group. In some embodiments, each R X1 Independently, it is a C3 alkyl-C1-C6 alkoxy group. In some embodiments, each R X1 Independently, it is a C4 alkyl-C1-C6 alkoxy group. In some embodiments, each R... X1 Independently, it is a C5 alkyl-C1-C6 alkoxy group. In some embodiments, each R X1 It is independently a C6 alkyl-C1-C6 alkoxy group.

[0365] In some implementations, each R X1 Independently, it is a C1-C6 alkyl-C1 alkoxy group. In some embodiments, each R X1 Independently, it is a C1-C6 alkyl-C2 alkoxy group. In some embodiments, each R X1 Independently, it is a C1-C6 alkyl-C3 alkoxy group. In some embodiments, each R X1 Independently, it is a C1-C6 alkyl-C4 alkoxy group. In some embodiments, each R X1 Independently, it is a C1-C6 alkyl-C5 alkoxy group. In some embodiments, each R X1 It is independently C1-C6 alkyl-C6 alkoxy.

[0366] In some implementations, each R X1 It is independently a C3-C6 cyclic hydrocarbon group.

[0367] In some implementations, each R X1 It is independently a C3 cyclic hydrocarbon group. In some embodiments, each R X1 It is independently a C4 cyclic hydrocarbon group. In some embodiments, each R X1 It is independently a C5 cyclic hydrocarbon group. In some embodiments, each R X1 It is independently a C6 cyclic hydrocarbon group.

[0368] In some implementations, each R X1 It is independently a 3-7 membered heterocyclic hydrocarbon group.

[0369] In some implementations, each R X1 It is independently a 3-membered heterocyclic hydrocarbon group. In some embodiments, each R X1 It is independently a 4-membered heterocyclic hydrocarbon group. In some embodiments, each RX1 It is independently a 5-membered heterocyclic hydrocarbon group. In some embodiments, each R X1 It is independently a 6-membered heterocyclic hydrocarbon group. In some embodiments, each R X1 It is independently a 7-membered heterocyclic hydrocarbon group.

[0370] In some implementations, two R X1 Together with the atoms to which they are attached, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon groups or heterocyclic hydrocarbon groups are optionally substituted by 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 groups.

[0371] In some implementations, two R X1 Together with the atoms to which they are attached, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon groups or heterocyclic hydrocarbon groups are optionally substituted by 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.

[0372] In some implementations, two R X1 Together with the atoms they are attached to, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups.

[0373] In some implementations, two R X1 Together with the atoms they are attached to, they form C3-C7 cyclic hydrocarbon groups.

[0374] In some implementations, two R X1 Together with the atoms to which they are attached, they form a C3-C7 cyclic hydrocarbon group, which may optionally 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 groups.

[0375] In some implementations, two R X1 Together with the atoms to which they are attached, they form a C3-C7 cyclic hydrocarbon group, which may optionally 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.

[0376] In some implementations, two R X1 Together with the atoms they are attached to, they form a C3-C7 cyclic hydrocarbon group, which is substituted by 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.

[0377] In some implementations, two R X1 Together with the atoms they are attached to, they form C3 cyclic hydrocarbon groups.

[0378] In some implementations, two R X1 Together with the atoms to which they are attached, they form a C3 cyclic hydrocarbon group, which may optionally 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.

[0379] In some implementations, two R X1 Together with the atoms they are attached to, they form a C3 cyclic hydrocarbon group, which is substituted by 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.

[0380] In some implementations, two R X1 Together with the atoms they are attached to, they form C4 cyclic hydrocarbon groups.

[0381] In some implementations, two R X1 Together with the atoms to which they are attached, they form a C4 cyclic hydrocarbon group, which may optionally 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.

[0382] In some implementations, two R X1 Together with the atoms they are attached to, they form a C4 cyclic hydrocarbon group, which is substituted by 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.

[0383] In some implementations, two R X1 Together with the atoms they are attached to, they form C5 cyclic hydrocarbon groups.

[0384] In some implementations, two R X1 Together with the atoms to which they are attached, they form a C5 cyclic hydrocarbon group, which may optionally 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.

[0385] In some implementations, two R X1 Together with the atoms they are attached to, they form a C5 cyclic hydrocarbon group, which is substituted by 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.

[0386] In some implementations, two R X1 Together with the atoms they are attached to, they form a C6 cyclic hydrocarbon group.

[0387] In some implementations, two R X1 Together with the atoms to which they are attached, they form a C6 cyclic hydrocarbon group, which may optionally 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.

[0388] In some implementations, two R X1 Together with the atoms they are attached to, they form a C6 cyclic hydrocarbon group, which is substituted by 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.

[0389] In some implementations, two R X1 Together with the atoms they are attached to, they form C7 cyclic hydrocarbon groups.

[0390] In some implementations, two R X1Together with the atoms to which they are attached, they form a C7 cyclic hydrocarbon group, which may optionally 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.

[0391] In some implementations, two R X1 Together with the atoms they are attached to, they form a C7 cyclic hydrocarbon group, which is substituted by 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.

[0392] In some implementations, two R X1 Together with the atoms they are attached to, they form 3-7 membered heterocyclic hydrocarbon groups.

[0393] In some implementations, two R X1 Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic hydrocarbon group, which may optionally 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 groups.

[0394] In some implementations, two R X1 Together with the atoms they are attached to, they form a 3-7 membered heterocyclic hydrocarbon group, which is substituted by 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 groups.

[0395] In some implementations, two R X1 Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic hydrocarbon group, which may optionally 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.

[0396] In some implementations, two R X1Together with the atoms they are attached to, they form a 3-7 membered heterocyclic hydrocarbon group, which is substituted by 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.

[0397] In some implementations, two R X1 Together with the atoms they are attached to, they form 3-membered heterocyclic hydrocarbon groups.

[0398] In some implementations, two R X1 Together with the atoms to which they are attached, they form a 3-membered heterocyclic hydrocarbon group, which may optionally 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.

[0399] In some implementations, two R X1 Together with the atoms they are attached to, they form a 3-membered heterocyclic hydrocarbon group, which is substituted by 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.

[0400] In some implementations, two R X1 Together with the atoms they are attached to, they form oxocyclic butyl groups.

[0401] In some implementations, two R X1 Together with the atoms to which they are attached, they form an oxocyclic butyl group, which may optionally 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.

[0402] In some implementations, two R X1 Together with the atoms they are attached to, they form an oxobutyl group, which is substituted by 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.

[0403] In some implementations, two R X1Together with the atoms they are attached to, they form a 4-membered heterocyclic hydrocarbon group.

[0404] In some implementations, two R X1 Together with the atoms to which they are attached, they form a 4-membered heterocyclic hydrocarbon group, which may optionally 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.

[0405] In some implementations, two R X1 Together with the atoms they are attached to, they form a 4-membered heterocyclic hydrocarbon group, which is substituted by 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.

[0406] In some implementations, two R X1 Together with the atoms they are attached to, they form a 5-membered heterocyclic hydrocarbon group.

[0407] In some implementations, two R X1 Together with the atoms to which they are attached, they form a 5-membered heterocyclic hydrocarbon group, which may optionally 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.

[0408] In some implementations, two R X1 Together with the atoms they are attached to, they form a 5-membered heterocyclic hydrocarbon group, which is substituted by 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.

[0409] In some implementations, two R X1 Together with the atoms they are attached to, they form a 6-membered heterocyclic hydrocarbon group.

[0410] In some implementations, two R X1Together with the atoms to which they are attached, they form a 6-membered heterocyclic hydrocarbon group, which may optionally 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.

[0411] In some implementations, two R X1 Together with the atoms they are attached to, they form a 6-membered heterocyclic hydrocarbon group, which is substituted by 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.

[0412] In some implementations, two R X1 Together with the atoms they are attached to, they form a 7-membered heterocyclic hydrocarbon group.

[0413] In some implementations, two R X1 Together with the atoms to which they are attached, they form a 7-membered heterocyclic hydrocarbon group, which may optionally 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.

[0414] In some implementations, two R X1 Together with the atoms they are attached to, they form a 7-membered heterocyclic hydrocarbon group, which is substituted by 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.

[0415] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form C4-C 10 Cyclic hydrocarbon group.

[0416] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form C4-C 10 Cyclic hydrocarbon group, which may optionally 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.

[0417] In some implementations, the three RsX1 Together with the atoms they are attached to, they form C4-C 10 Cyclic hydrocarbon group, which is substituted by 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.

[0418] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form C4 cyclic hydrocarbon groups.

[0419] In some implementations, the three Rs X1 Together with the atoms to which they are attached, they form a C4 cyclic hydrocarbon group, which may optionally 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.

[0420] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form a C4 cyclic hydrocarbon group, which is substituted by 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.

[0421] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form C5 cyclic hydrocarbon groups.

[0422] In some implementations, the three Rs X1 Together with the atoms to which they are attached, they form a C5 cyclic hydrocarbon group, which may optionally 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.

[0423] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form a C5 cyclic hydrocarbon group, which is substituted by 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.

[0424] In some implementations, the three Rs X1Together with the atoms they are attached to, they form a C6 cyclic hydrocarbon group.

[0425] In some implementations, the three Rs X1 Together with the atoms to which they are attached, they form a C6 cyclic hydrocarbon group, which may optionally 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.

[0426] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form a C6 cyclic hydrocarbon group, which is substituted by 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.

[0427] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form C7 cyclic hydrocarbon groups.

[0428] In some implementations, the three Rs X1 Together with the atoms to which they are attached, they form a C7 cyclic hydrocarbon group, which may optionally 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.

[0429] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form a C7 cyclic hydrocarbon group, which is substituted by 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.

[0430] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form C8 cyclic hydrocarbon groups.

[0431] In some implementations, the three Rs X1 Together with the atoms to which they are attached, they form a C8 cyclic hydrocarbon group, which may optionally 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.

[0432] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form a C8 cyclic hydrocarbon group, which is substituted by 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.

[0433] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form C9 cyclic hydrocarbon groups.

[0434] In some implementations, the three Rs X1 Together with the atoms to which they are attached, they form a C9 cyclic hydrocarbon group, which may optionally 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.

[0435] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form a C9 cyclic hydrocarbon group, which is substituted by 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.

[0436] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form C 10 Cyclic hydrocarbon group.

[0437] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form C 10 Cyclic hydrocarbon group, which may optionally 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.

[0438] In some implementations, the three Rs X1 Together with the atoms they are attached to, they form C 10Cyclic hydrocarbon group, which is substituted by 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.

[0439] In some implementations, each R X2 Independently, it is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic hydrocarbon group, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocyclic hydrocarbon group is optionally substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic hydrocarbon group.

[0440] Or two Rs X2 Together with the atoms to which they are attached, they form 3-7 membered heterocyclic hydrocarbon groups, wherein the heterocyclic hydrocarbon groups are optionally 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.

[0441] In some implementations, each R X2 It is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl or C1-C6 haloalkyl.

[0442] Or two Rs X2 Together with the atoms to which they are attached, they form 3-7 membered heterocyclic hydrocarbon groups, wherein the heterocyclic hydrocarbon groups are optionally 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.

[0443] In some implementations, each R X2 It is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or two R X2 Together with the atoms to which they are attached, they form 3-7 membered heterocyclic hydrocarbon groups, wherein the heterocyclic hydrocarbon groups are optionally 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.

[0444] In some implementations, each R X2 Independently, it is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic hydrocarbon, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocyclic hydrocarbon is optionally substituted by one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic hydrocarbon.

[0445] In some implementations, each R X2 It is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl or C1-C6 haloalkyl.

[0446] In some implementations, each R X2 H stands alone.

[0447] In some implementations, each R X2 It is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl.

[0448] In some implementations, each R X2 Independently, it is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl, wherein the alkyl, alkenyl, alkynyl, or haloalkyl is optionally substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic alkyl.

[0449] In some implementations, each R X2 It is independently C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0450] In some implementations, each R X2 It is independently a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted by one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic alkyl.

[0451] In some implementations, each R X2 It is independently a C1-C6 alkyl group.

[0452] In some implementations, each R X2Independently, it is a C1-C6 alkyl group, which may optionally be substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cyclic hydrocarbon or 3-7 membered heterocyclic hydrocarbon.

[0453] In some implementations, each R X2 It is independently a C1-C6 alkyl group, which is substituted by one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cyclic hydrocarbon or 3-7 membered heterocyclic hydrocarbon.

[0454] In some implementations, each R X2 Independently, it is methyl. In some embodiments, each R X2 It is ethyl independently. In some embodiments, each R X2 It is propyl, independently. In some embodiments, each R X2 It is butyl independently. In some implementations, each R X2 It is pentyl independently. In some embodiments, each R X2 It is independently a base. In some implementations, each R is... X2 Independently, it is isopropyl. In some embodiments, each R... X2 Independently, it is isobutyl. In some implementations, each R... X2 Independently, it is isopentyl. In some embodiments, each R... X2 Independently, it is a heterobase. In some implementations, each R... X2 It is independently sec-butyl. In some implementations, each R X2 Independently, it is sec-amyl. In some implementations, each R... X2 Independently, it is Zhongjiji. In some implementations, each R... X2 It is tert-butyl independently.

[0455] In some implementations, each R X2 It is independently a C2-C6 alkenyl group.

[0456] In some implementations, each R X2 Independently, it is a C2-C6 alkenyl group, which may optionally 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 heterocyclic alkyl groups.

[0457] In some implementations, each R X2It is independently a C2-C6 alkenyl group, which is substituted by one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cyclic hydrocarbon or 3-7 membered heterocyclic hydrocarbon.

[0458] In some implementations, each R X2 Independently, it is a C2 alkenyl group. In some embodiments, each R X2 It is independently a C3 alkenyl group. In some embodiments, each R X2 It is independently a C4 alkenyl group. In some embodiments, each R X2 It is independently a C5 alkenyl group. In some embodiments, each R X2 It is independently a C6 alkenyl group.

[0459] In some implementations, each R X2 It is independently a C2-C6 ynyl group.

[0460] In some implementations, each R X2 Independently, it is a C2-C6 alkynyl group, which may optionally be substituted by one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cyclic hydrocarbon or 3-7 membered heterocyclic hydrocarbon.

[0461] In some implementations, each R X2 It is independently a C2-C6 alkynyl group, which is substituted by one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cyclic hydrocarbon or 3-7 membered heterocyclic hydrocarbon.

[0462] In some implementations, each R X2 It is independently a C2 ynyl group. In some embodiments, each R X2 It is independently a C3 ynyl group. In some embodiments, each R X2 It is independently a C4 ynyl group. In some embodiments, each R X2 It is independently a C5 ynyl group. In some embodiments, each R X2 It is independently a C6 ynyl group.

[0463] In some implementations, each R X2 It is independently a C1-C6 haloalkyl group.

[0464] In some implementations, each R X2 Independently, it is a C1-C6 haloalkyl group, which may optionally be substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cyclic hydrocarbon or 3-7 membered heterocyclic hydrocarbon.

[0465] In some implementations, each R X2 It is independently a C1-C6 haloalkyl group, which is substituted by one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cyclic hydrocarbon or 3-7 membered heterocyclic hydrocarbon.

[0466] In some implementations, each R X2 Independently, it is a halomethyl group. In some embodiments, each R X2 Independently, it is a haloethyl. In some embodiments, each R X2 Independently, it is a halopropyl group. In some embodiments, each R... X2 Independently, it is a halogenated butyl group. In some embodiments, each R... X2 Independently, it is a halopentyl group. In some embodiments, each R... X2 It is a halogenated hexyl group on its own.

[0467] In some implementations, each R X2 It is independently a C3-C6 cyclic hydrocarbon group.

[0468] In some implementations, each R X2 Independently, it is a C3-C6 cyclic hydrocarbon group, which may optionally be substituted by one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cyclic hydrocarbon group or 3-7 membered heterocyclic hydrocarbon group.

[0469] In some implementations, each R X2 It is independently a C3-C6 cyclic hydrocarbon group, which is substituted by one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cyclic hydrocarbon group or 3-7 membered heterocyclic hydrocarbon group.

[0470] In some implementations, each R X2 It is independently a C3 cyclic hydrocarbon group. In some embodiments, each R X2 It is independently a C4 cyclic hydrocarbon group. In some embodiments, each R X2 It is independently a C5 cyclic hydrocarbon group. In some embodiments, each R X2 It is independently a C6 cyclic hydrocarbon group.

[0471] In some implementations, each R X2 It is independently a 3-7 membered heterocyclic hydrocarbon group.

[0472] In some implementations, each R X2Independently, it is a 3-7 membered heterocyclic hydrocarbon group, which may optionally be substituted by one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cyclic hydrocarbon or 3-7 membered heterocyclic hydrocarbon groups.

[0473] In some implementations, each R X2 It is independently a 3-7 membered heterocyclic hydrocarbon group, which is substituted by one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cyclic hydrocarbon or 3-7 membered heterocyclic hydrocarbon groups.

[0474] In some implementations, each R X2 It is independently a 3-membered heterocyclic hydrocarbon group. In some embodiments, each R X2 It is independently a 4-membered heterocyclic hydrocarbon group. In some embodiments, each R X2 It is independently a 5-membered heterocyclic hydrocarbon group. In some embodiments, each R X2 It is independently a 6-membered heterocyclic hydrocarbon group. In some embodiments, each R X2 It is independently a 7-membered heterocyclic hydrocarbon group.

[0475] In some implementations, two R X2 Together with the atoms they are attached to, they form 3-7 membered heterocyclic hydrocarbon groups.

[0476] In some implementations, two R X2 Together with the atoms to which they are attached, they form a 3-7 membered heterocyclic hydrocarbon group, which may optionally 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.

[0477] In some implementations, two R X2 Together with the atoms they are attached to, they form a 3-7 membered heterocyclic hydrocarbon group, which is substituted by 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.

[0478] In some implementations, two R X2 Together with the atoms they are attached to, they form 3-membered heterocyclic hydrocarbon groups.

[0479] In some implementations, two R X2Together with the atoms to which they are attached, they form a 3-membered heterocyclic hydrocarbon group, which may optionally 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.

[0480] In some implementations, two R X2 Together with the atoms they are attached to, they form a 3-membered heterocyclic hydrocarbon group, which is substituted by 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.

[0481] In some implementations, two R X2 Together with the atoms they are attached to, they form a 4-membered heterocyclic hydrocarbon group.

[0482] In some implementations, two R X2 Together with the atoms to which they are attached, they form a 4-membered heterocyclic hydrocarbon group, which may optionally 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.

[0483] In some implementations, two R X2 Together with the atoms they are attached to, they form a 4-membered heterocyclic hydrocarbon group, which is substituted by 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.

[0484] In some implementations, two R X2 Together with the atoms they are attached to, they form a 5-membered heterocyclic hydrocarbon group.

[0485] In some implementations, two R X2 Together with the atoms to which they are attached, they form a 5-membered heterocyclic hydrocarbon group, which may optionally 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.

[0486] In some implementations, two R X2Together with the atoms they are attached to, they form a 5-membered heterocyclic hydrocarbon group, which is substituted by 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.

[0487] In some implementations, two R X2 Together with the atoms they are attached to, they form a 6-membered heterocyclic hydrocarbon group.

[0488] In some implementations, two R X2 Together with the atoms to which they are attached, they form a 6-membered heterocyclic hydrocarbon group, which may optionally 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.

[0489] In some implementations, two R X2 Together with the atoms they are attached to, they form a 6-membered heterocyclic hydrocarbon group, which is substituted by 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.

[0490] In some implementations, two R X2 Together with the atoms they are attached to, they form a 7-membered heterocyclic hydrocarbon group.

[0491] In some implementations, two R X2 Together with the atoms to which they are attached, they form a 7-membered heterocyclic hydrocarbon group, which may optionally 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.

[0492] In some implementations, two R X2 Together with the atoms they are attached to, they form a 7-membered heterocyclic hydrocarbon group, which is substituted by 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.

[0493] In some implementations, each R YIndependently, it is 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 Alkyl group.

[0494] In some implementations, each R Y H stands alone.

[0495] In some implementations, each R Y Independently, it is 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 Alkyl group.

[0496] In some implementations, each R Y It is independently a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0497] In some implementations, each R Y It is a halogen on its own.

[0498] In some implementations, each R Y It is independently F, Cl, Br, or I. In some implementations, each R Y It is independently F, Cl, or Br. In some implementations, each R Y It is either F or Cl on its own.

[0499] In some implementations, each R Y Independently, it is F. In some implementations, each R Y Independently, it is Cl. In some implementations, each R Y Independently, it is Br. In some implementations, each R Y I is independent.

[0500] In some implementations, each R Y It is independently -CN, -OH, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0501] In some implementations, each R Y Independently, it is -CN.

[0502] In some implementations, each R Y It is -OH on its own.

[0503] In some implementations, each RY It is independently -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0504] In some implementations, each R Y It is -NH2 independently.

[0505] In some implementations, each R Y Independently, it is -NH (C1-C6 alkyl).

[0506] In some implementations, each R Y Independently, it is -NH (methyl). In some embodiments, each R Y Independently, it is -NH(ethyl). In some embodiments, each R Y Independently, it is -NH (propyl). In some embodiments, each R Y Independently, it is -NH (butyl). In some embodiments, each R Y Independently, it is -NH(pentyl). In some embodiments, each R Y Independently, it is -NH (hexyl).

[0507] In some implementations, each R Y It is independently -N(C1-C6 alkyl)2.

[0508] In some implementations, each R Y It is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl or C 1-6 Alkyl group.

[0509] In some implementations, each R Y It is independently C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0510] In some implementations, each R Y It is independently a C1-C6 alkyl group.

[0511] In some implementations, each R Y Independently, it is methyl. In some embodiments, each R Y It is ethyl independently. In some embodiments, each R Y It is propyl, independently. In some embodiments, each R Y It is butyl independently. In some implementations, each R Y It is pentyl independently. In some embodiments, each R Y It is independently a base. In some implementations, each R is... YIndependently, it is isopropyl. In some embodiments, each R... Y Independently, it is isobutyl. In some implementations, each R... Y Independently, it is isopentyl. In some embodiments, each R... Y Independently, it is a heterobase. In some implementations, each R... Y It is independently sec-butyl. In some implementations, each R Y Independently, it is sec-amyl. In some implementations, each R... Y Independently, it is Zhongjiji. In some implementations, each R Y It is tert-butyl independently.

[0512] In some implementations, each R Y It is independently a C2-C6 alkenyl group.

[0513] In some implementations, each R Y Independently, it is a C2 alkenyl group. In some embodiments, each R Y It is independently a C3 alkenyl group. In some embodiments, each R Y Independently, it is a C4 alkenyl group. In some embodiments, each R Y It is independently a C5 alkenyl group. In some embodiments, each R Y It is independently a C6 alkenyl group.

[0514] In some implementations, each R Y It is independently a C2-C6 ynyl group.

[0515] In some implementations, each R Y It is independently a C2 ynyl group. In some embodiments, each R Y It is independently a C3 ynyl group. In some embodiments, each R Y It is independently a C4 ynyl group. In some embodiments, each R Y It is independently a C5 ynyl group. In some embodiments, each R Y It is independently a C6 acetylene group.

[0516] In some implementations, each R Y Independently C1-C6 haloalkyl or C 1-6 Alkyl group.

[0517] In some implementations, each R Y It is independently a C1-C6 haloalkyl group.

[0518] In some implementations, each R Y Independently, it is a halomethyl group. In some embodiments, each R... YIndependently, it is a haloethyl. In some embodiments, each R Y Independently, it is a halopropyl group. In some embodiments, each R... Y Independently, it is a halogenated butyl group. In some implementations, each R... Y Independently, it is a halopentyl group. In some embodiments, each R... Y It is a halogenated hexyl group on its own.

[0519] In some implementations, each R Y C is independent 1-6 Alkyl group.

[0520] In some implementations, each R Y It is independently a methoxyl group. In some embodiments, each R... Y It is independently ethoxylated. In some embodiments, each R Y It is propoxy-based independently. In some embodiments, each R... Y It is independently butoxyl. In some embodiments, each R Y It is independently pentoxygenated. In some embodiments, each R Y It is independently an hexoxy group.

[0521] In some implementations, each R Z It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl.

[0522] In some implementations, R Z It is H.

[0523] In some implementations, R Z It is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl.

[0524] In some implementations, R Z It is a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0525] In some implementations, R Z It is a C1-C6 alkyl group.

[0526] In some implementations, R Z It is methyl. In some embodiments, R Z It is ethyl. In some embodiments, R Z It is propyl. In some embodiments, R Z It is butyl. In some implementations, R Z It is pentyl. In some implementations, R Z It is self-based. In some implementations, RZ It is isopropyl. In some embodiments, R Z It is isobutyl. In some implementations, R Z It is isopentyl. In some embodiments, R Z It is an allohexyl group. In some implementations, R Z It is sec-butyl. In some implementations, R Z It is sec-amyl. In some implementations, R Z It is Zhong Jiji. In some implementations, R Z It is tert-butyl.

[0527] In some implementations, R Z It is a C2-C6 alkenyl group.

[0528] In some implementations, R Z It is C2-alkenyl. In some embodiments, R Z It is a C3 alkenyl group. In some embodiments, R Z It is a C4 alkenyl group. In some embodiments, R Z It is C5 alkenyl. In some embodiments, R Z It is a C6 alkenyl group.

[0529] In some implementations, R Z It is a C2-C6 acetylene group.

[0530] In some implementations, R Z It is a C2 acetylene group. In some embodiments, R Z It is a C3 acetylene group. In some embodiments, R Z It is a C4 acetylene group. In some embodiments, R Z It is a C5 acetylene group. In some embodiments, R Z It is a C6 acetylene group.

[0531] In some implementations, R Z It is a C1-C6 haloalkyl group.

[0532] In some implementations, R Z It is a halomethyl group. In some embodiments, R Z It is a haloethyl. In some embodiments, R Z It is a halopropyl group. In some embodiments, R Z It is a halogenated butyl. In some implementations, R Z It is a halopentyl group. In some embodiments, R Z It is a halogenated hexyl group.

[0533] In some implementations, Ar1 is C6-C 10 Aryl or 5-10 heteroaryl compounds.

[0534] In some implementations, Ar1 is C6-C 10 aryl or 5-10 heteroaryl, wherein the C6-C 10 The aryl or 5-10 heteroaryl group is optionally substituted with one or more R3 groups.

[0535] In some implementations, Ar1 is C6-C 10 Aryl.

[0536] In some implementations, Ar1 is C6-C optionally replaced by one or more R3. 10 Aryl.

[0537] In some implementations, Ar1 is C6-C substituted with one or more R3s. 10 Aryl (e.g., phenyl).

[0538] In some implementations, Ar1 is C6-C replaced by an R3. 10 Aryl (e.g., phenyl). In some embodiments, Ar1 is a C6-C substituted with two R3 groups. 10 Aryl (e.g., phenyl). In some embodiments, Ar1 is a C6-C molecule substituted with three R3 groups. 10 Aryl (e.g., phenyl).

[0539] In some embodiments, Ar1 is a C6 aryl group (e.g., phenyl).

[0540] In some embodiments, Ar1 is a C6 aryl group (e.g., phenyl) optionally substituted with one or more R3 groups.

[0541] In some embodiments, Ar1 is a C6 aryl group substituted with one or more R3 groups (e.g., phenyl).

[0542] In some embodiments, Ar1 is a C6 aryl group substituted with one R3 (e.g., phenyl). In some embodiments, Ar1 is a C6 aryl group substituted with two R3s (e.g., phenyl). In some embodiments, Ar1 is a C6 aryl group substituted with three R3s (e.g., phenyl).

[0543] In some implementations, Ar1 is phenyl.

[0544] In some embodiments, Ar1 is a phenyl group optionally substituted with one or more R3 groups.

[0545] In some embodiments, Ar1 is a phenyl group substituted with one or more R3 groups.

[0546] In some embodiments, Ar1 is a phenyl group substituted with one R3. In some embodiments, Ar1 is a phenyl group substituted with two R3s. In some embodiments, Ar1 is a phenyl group substituted with three R3s.

[0547] In some embodiments, Ar1 is a phenyl group optionally substituted with one or more halogens (e.g., F, Cl, or Br).

[0548] In some embodiments, Ar1 is a phenyl group substituted with one or more halogens (e.g., F, Cl, or Br).

[0549] In some embodiments, Ar1 is a phenyl group substituted with one halogen (e.g., F, Cl, or Br). In some embodiments, Ar1 is a phenyl group substituted with two halogens (e.g., F, Cl, or Br). In some embodiments, Ar1 is a phenyl group substituted with three halogens (e.g., F, Cl, or Br).

[0550] In some implementations, Ar1 is C8 aryl.

[0551] In some implementations, Ar1 is a C8 aryl group optionally substituted with one or more R3 groups.

[0552] In some embodiments, Ar1 is a C8 aryl group substituted with one or more R3 groups (e.g., phenyl).

[0553] In some embodiments, Ar1 is a C8 aryl group substituted with one R3 (e.g., phenyl). In some embodiments, Ar1 is a C8 aryl group substituted with two R3s (e.g., phenyl). In some embodiments, Ar1 is a C8 aryl group substituted with three R3s (e.g., phenyl).

[0554] In some implementations, Ar1 is C 10 Aryl.

[0555] In some implementations, Ar1 is C, which is optionally replaced by one or more R3. 10 Aryl.

[0556] In some implementations, Ar1 is C replaced by one or more R3s. 10 Aryl (e.g., phenyl).

[0557] In some implementations, Ar1 is C replaced by an R3. 10 Aryl (e.g., phenyl). In some embodiments, Ar1 is a C-shaped compound substituted with two R3 groups. 10 Aryl (e.g., phenyl). In some embodiments, Ar1 is a C-shaped compound substituted with three R3 groups. 10 Aryl (e.g., phenyl).

[0558] In some implementations, Ar1 is a 5-10 membered heteroaryl group.

[0559] In some embodiments, Ar1 is a 5-10 membered heteroaryl group optionally substituted with one or more R3s.

[0560] In some implementations, Ar1 is a 5-10 heteroaryl group substituted with one or more R3s.

[0561] In some embodiments, Ar1 is a 5-10 membered heteroaryl group substituted with one R3. In some embodiments, Ar1 is a 5-10 membered heteroaryl group substituted with two R3s. In some embodiments, Ar1 is a 5-10 membered heteroaryl group substituted with three R3s.

[0562] In some implementations, Ar1 is a 5-membered heteroaryl group.

[0563] In some implementations, Ar1 is a 5-membered heteroaryl group optionally substituted with one or more R3 groups.

[0564] In some implementations, Ar1 is a 5-membered heteroaryl group substituted with one or more R3s.

[0565] In some embodiments, Ar1 is a 5-membered heteroaryl group substituted with one R3. In some embodiments, Ar1 is a 5-membered heteroaryl group substituted with two R3s. In some embodiments, Ar1 is a 5-membered heteroaryl group substituted with three R3s.

[0566] In some implementations, Ar1 is a thiazolyl group.

[0567] In some embodiments, Ar1 is a thiazolyl group optionally substituted with one or more R3 groups.

[0568] In some implementations, Ar1 is a thiazolyl group substituted with one or more R3 groups.

[0569] In some embodiments, Ar1 is a thiazolyl group substituted with one R3. In some embodiments, Ar1 is a thiazolyl group substituted with two R3s. In some embodiments, Ar1 is a thiazolyl group substituted with three R3s.

[0570] In some implementations, Ar1 is a 6-membered heteroaryl group.

[0571] In some implementations, Ar1 is a 6-membered heteroaryl group optionally substituted with one or more R3 groups.

[0572] In some implementations, Ar1 is a 6-membered heteroaryl group substituted with one or more R3s.

[0573] In some embodiments, Ar1 is a 6-membered heteroaryl group substituted with one R3. In some embodiments, Ar1 is a 6-membered heteroaryl group substituted with two R3s. In some embodiments, Ar1 is a 6-membered heteroaryl group substituted with three R3s.

[0574] In some implementations, Ar1 is pyridyl.

[0575] In some embodiments, Ar1 is a pyridyl group optionally substituted with one or more R3 groups.

[0576] In some implementations, Ar1 is a pyridyl group substituted with one or more R3 groups.

[0577] In some embodiments, Ar1 is a pyridinyl group substituted with one R3. In some embodiments, Ar1 is a pyridinyl group substituted with two R3s. In some embodiments, Ar1 is a pyridinyl group substituted with three R3s.

[0578] In some implementations, Ar1 is a 7-membered heteroaryl group.

[0579] In some implementations, Ar1 is a 7-membered heteroaryl group optionally substituted with one or more R3 groups.

[0580] In some implementations, Ar1 is a 7-membered heteroaryl group substituted with one or more R3s.

[0581] In some embodiments, Ar1 is a 7-membered heteroaryl group substituted with one R3. In some embodiments, Ar1 is a 7-membered heteroaryl group substituted with two R3s. In some embodiments, Ar1 is a 7-membered heteroaryl group substituted with three R3s.

[0582] In some implementations, Ar1 is an 8-membered heteroaryl group.

[0583] In some implementations, Ar1 is an 8-membered heteroaryl group optionally substituted with one or more R3s.

[0584] In some implementations, Ar1 is an 8-membered heteroaryl group substituted with one or more R3s.

[0585] In some embodiments, Ar1 is an 8-membered heteroaryl group substituted with one R3. In some embodiments, Ar1 is an 8-membered heteroaryl group substituted with two R3s. In some embodiments, Ar1 is an 8-membered heteroaryl group substituted with three R3s.

[0586] In some implementations, Ar1 is a 9-membered heteroaryl group.

[0587] In some implementations, Ar1 is a 9-membered heteroaryl group optionally substituted with one or more R3s.

[0588] In some implementations, Ar1 is a 9-membered heteroaryl group substituted with one or more R3s.

[0589] In some embodiments, Ar1 is a 9-membered heteroaryl group substituted with one R3. In some embodiments, Ar1 is a 9-membered heteroaryl group substituted with two R3s. In some embodiments, Ar1 is a 9-membered heteroaryl group substituted with three R3s.

[0590] In some implementations, Ar1 is a 10-membered heteroaryl group.

[0591] In some implementations, Ar1 is a 10-membered heteroaryl group optionally substituted with one or more R3 groups.

[0592] In some implementations, Ar1 is a 10-membered heteroaryl group substituted with one or more R3s.

[0593] In some embodiments, Ar1 is a 10-membered heteroaryl group substituted with one R3. In some embodiments, Ar1 is a 10-membered heteroaryl group substituted with two R3s. In some embodiments, Ar1 is a 10-membered heteroaryl group substituted with three R3s.

[0594] 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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group).

[0595] In some embodiments, R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -N(C1-C6 alkyl)(C3-C 10 -Cyclohydryl group), -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 10Aryl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group).

[0596] 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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S replace.

[0597] 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-C6 alkyl) 10 Aryl).

[0598] In some embodiments, R1 is -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -S (C1-C6 alkyl), or -S (C6-C6 alkyl). 10 Aryl).

[0599] In some embodiments, R1 is -NH2, -NH(C1-C6 alkyl)2, or -N(C1-C6 alkyl)2, or -N(C1-C6 alkyl)(C3-C 10 (cyclic hydrocarbon group).

[0600] In some embodiments, R1 is -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0601] In some implementations, R1 is -NH2.

[0602] In some embodiments, R1 is -NH (C1-C6 alkyl).

[0603] 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).

[0604] In some embodiments, R1 is -N(C1-C6 alkyl)2.

[0605] In some embodiments, R1 is -N(C1-C6 alkyl)(C3 ... 10 (cyclic hydrocarbon group).

[0606] In some embodiments, R1 is -N(C1-C6 alkyl)(C3 cyclic hydrocarbon group). In some embodiments, R1 is -N(C1-C6 alkyl)(C4 cyclic hydrocarbon group). In some embodiments, R1 is -N(C1-C6 alkyl)(C5 cyclic hydrocarbon group). In some embodiments, R1 is -N(C1-C6 alkyl)(C6 cyclic hydrocarbon group). In some embodiments, R1 is -N(C1-C6 alkyl)(C7 cyclic hydrocarbon group). In some embodiments, R1 is -N(C1-C6 alkyl)(C8 cyclic hydrocarbon group). In some embodiments, R1 is -N(C1-C6 alkyl)(C9 cyclic hydrocarbon group). In some embodiments, R1 is -N(C1-C6 alkyl)(C9 cyclic hydrocarbon group). 10 (cyclic hydrocarbon group).

[0607] In some embodiments, R1 is -S (C1-C6 alkyl) or -S (C6-C6 alkyl) 10 Aryl).

[0608] In some embodiments, R1 is -S (C1-C6 alkyl).

[0609] 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).

[0610] In some implementations, R1 is -S(C6-C10 Aryl).

[0611] In some embodiments, R1 is -S(C6 aryl). In some embodiments, R1 is -S(C8 aryl). In some embodiments, R1 is -S(C6 aryl). 10 Aryl).

[0612] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group).

[0613] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S replace.

[0614] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0615] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl, alkenyl, or alkynyl group is optionally surrounded by one or more R1 groups. 1S replace.

[0616] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl, alkenyl, or alkynyl group is influenced by one or more R1 groups. 1S replace.

[0617] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl, alkenyl, or alkynyl group is surrounded by an R1. 1S replace.

[0618] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl, alkenyl, or alkynyl group is separated by two R1 groups. 1S replace.

[0619] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl, alkenyl, or alkynyl group is surrounded by three R groups. 1S replace.

[0620] In some implementations, R1 is C 1- C6 alkyl.

[0621] 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.

[0622] In some implementations, R1 is optionally defined by one or more R 1S Substituted C1-C6 alkyl groups.

[0623] In some implementations, R1 is controlled by one or more R... 1S Substituted C1-C6 alkyl groups.

[0624] In some implementations, R1 is controlled by an R 1S Substituted C1-C6 alkyl groups.

[0625] In some implementations, R1 is controlled by two R... 1SSubstituted C1-C6 alkyl groups.

[0626] In some implementations, R1 is composed of three Rs. 1S Substituted C1-C6 alkyl groups.

[0627] In some implementations, R1 is a C2-C6 alkenyl group.

[0628] In some embodiments, R1 is a C2 alkenyl group. In some embodiments, R1 is a C3 alkenyl group. In some embodiments, R1 is a C4 alkenyl group. In some embodiments, R1 is a C5 alkenyl group. In some embodiments, R1 is a C6 alkenyl group.

[0629] In some implementations, R1 is optionally defined by one or more R 1S Substituted C2-C6 alkenyl groups.

[0630] In some implementations, R1 is controlled by one or more R... 1S Substituted C2-C6 alkenyl groups.

[0631] In some implementations, R1 is controlled by an R 1S Substituted C2-C6 alkenyl groups.

[0632] In some implementations, R1 is controlled by two R... 1S Substituted C2-C6 alkenyl groups.

[0633] In some implementations, R1 is composed of three Rs. 1S Substituted C2-C6 alkenyl groups.

[0634] In some implementations, R1 is a C2-C6 acetylene group.

[0635] In some embodiments, R1 is a C2 ynyl group. In some embodiments, R1 is a C3 ynyl group. In some embodiments, R1 is a C4 ynyl group. In some embodiments, R1 is a C5 ynyl group. In some embodiments, R1 is a C6 ynyl group.

[0636] In some implementations, R1 is optionally defined by one or more R 1S Substituted C2-C6 ynyl group.

[0637] In some implementations, R1 is controlled by one or more R... 1S Substituted C2-C6 ynyl group.

[0638] In some implementations, R1 is controlled by an R 1S Substituted C2-C6 ynyl group.

[0639] In some implementations, R1 is controlled by two R... 1SSubstituted C2-C6 ynyl group.

[0640] In some implementations, R1 is composed of three Rs. 1S Substituted C2-C6 ynyl group.

[0641] In some embodiments, R1 is a C1-C6 haloalkyl group.

[0642] In some embodiments, R1 is a halomethyl group. In some embodiments, R1 is a haloethyl group. In some embodiments, R1 is a halopropyl group. In some embodiments, R1 is a halobutyl group. In some embodiments, R1 is a halopentyl group. In some embodiments, R1 is a halohexyl group.

[0643] In some implementations, R1 is optionally defined by one or more R 1S Substituted C1-C6 haloalkyl groups.

[0644] In some implementations, R1 is controlled by one or more R... 1S Substituted C1-C6 haloalkyl groups.

[0645] In some implementations, R1 is controlled by an R 1S Substituted C1-C6 haloalkyl groups.

[0646] In some implementations, R1 is controlled by two R... 1S Substituted C1-C6 haloalkyl groups.

[0647] In some implementations, R1 is composed of three Rs. 1S Substituted C1-C6 haloalkyl groups.

[0648] In some embodiments, R1 is a C1-C6 alkoxy group.

[0649] 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.

[0650] In some implementations, R1 is optionally defined by one or more R 1S Substituted C1-C6 alkoxy groups.

[0651] In some implementations, R1 is controlled by one or more R... 1S Substituted C1-C6 alkoxy groups.

[0652] In some implementations, R1 is controlled by an R 1S Substituted C1-C6 alkoxy groups.

[0653] In some implementations, R1 is controlled by two R... 1S Substituted C1-C6 alkoxy groups.

[0654] In some implementations, R1 is composed of three Rs. 1S Substituted C1-C6 alkoxy groups.

[0655] In some implementations, R1 is C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon group or 3-7 membered heterocyclic hydrocarbon group.

[0656] In some implementations, R1 is C6-C 10 aryl, 5-10-membered heteroaryl, C3-C7 cyclic hydrocarbon, or 3-7-membered heterocyclic hydrocarbon, wherein the aryl, heteroaryl, cyclic hydrocarbon, and heterocyclic hydrocarbon are optionally surrounded by one or more R 1S replace.

[0657] In some implementations, R1 is C6-C 10 aryl, 5-10-membered heteroaryl, C3-C7 cyclic hydrocarbon or 3-7-membered heterocyclic hydrocarbon, wherein the aryl, heteroaryl, cyclic hydrocarbon and heterocyclic hydrocarbon are determined by one or more R 1S replace.

[0658] In some implementations, R1 is C6-C 10 aryl, 5-10-membered heteroaryl, C3-C7 cyclic hydrocarbon or 3-7-membered heterocyclic hydrocarbon, wherein the aryl, heteroaryl, cyclic hydrocarbon or heterocyclic hydrocarbon is determined by an R 1S Replacement.

[0659] In some implementations, R1 is C6-C 10 aryl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon group or 3-7 membered heterocyclic hydrocarbon group, wherein the aryl, heteroaryl, cyclic hydrocarbon group or heterocyclic hydrocarbon group is divided by two R 1S Replacement.

[0660] In some implementations, R1 is C6-C 10 aryl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon group or 3-7 membered heterocyclic hydrocarbon group, wherein the aryl, heteroaryl, cyclic hydrocarbon group or heterocyclic hydrocarbon group is determined by three R groups. 1S Replacement.

[0661] In some implementations, R1 is C6-C 10 Aryl.

[0662] In some embodiments, R1 is a C6 aryl group (e.g., phenyl). In some embodiments, R1 is a C8 aryl group. In some embodiments, R1 is a C... 10 Aryl.

[0663] In some implementations, R1 is optionally defined by one or more R 1S Replacement C6-C 10 Aryl.

[0664] In some implementations, R1 is controlled by one or more R... 1S Replacement C6-C 10 Aryl.

[0665] In some implementations, R1 is controlled by an R 1S Replacement C6-C 10 Aryl. In some embodiments, R1 is composed of two R... 1S Replacement C6-C 10 Aryl. In some embodiments, R1 is composed of three R... 1S Replacement C6-C 10 Aryl.

[0666] In some implementations, R1 is a 5-10 member heteroaryl group.

[0667] In some embodiments, R1 is a 5-membered heteroaryl group. In some embodiments, R1 is a 6-membered heteroaryl group. In some embodiments, R1 is a 7-membered heteroaryl group. In some embodiments, R1 is an 8-membered heteroaryl group. In some embodiments, R1 is a 9-membered heteroaryl group. In some embodiments, R1 is a 10-membered heteroaryl group.

[0668] In some implementations, R1 is optionally defined by one or more R 1S Substituted 5-10 heteroaryl groups.

[0669] In some implementations, R1 is controlled by one or more R... 1S Substituted 5-10 heteroaryl groups.

[0670] In some implementations, R1 is controlled by an R 1S The substituted 5-10 aryl group. In some embodiments, R1 is replaced by two R... 1S The substituted 5-10 aryl group. In some embodiments, R1 is replaced by three R... 1S Substituted 5-10 heteroaryl groups.

[0671] In some implementations, R1 is a C3-C7 cyclic hydrocarbon group.

[0672] 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.

[0673] In some implementations, R1 is optionally defined by one or more R 1S Substituted C3-C7 cyclic hydrocarbon groups.

[0674] In some implementations, R1 is controlled by one or more R... 1S Substituted C3-C7 cyclic hydrocarbon groups.

[0675] In some implementations, R1 is controlled by an R 1S Substituted C3-C7 cyclic hydrocarbon group. In some embodiments, R1 is replaced by two R... 1S Substituted C3-C7 cyclic hydrocarbon groups. In some embodiments, R1 is replaced by three R... 1S Substituted C3-C7 cyclic hydrocarbon groups.

[0676] In some implementations, R1 is a 3-7 membered heterocyclic hydrocarbon group.

[0677] In some embodiments, R1 is a 3-membered heterocyclic hydrocarbon group. In some embodiments, R1 is a 4-membered heterocyclic hydrocarbon group. In some embodiments, R1 is a 5-membered heterocyclic hydrocarbon group. In some embodiments, R1 is a 6-membered heterocyclic hydrocarbon group. In some embodiments, R1 is a 7-membered heterocyclic hydrocarbon group.

[0678] In some implementations, R1 is optionally defined by one or more R 1S Substituted 3-7 membered heterocyclic hydrocarbon groups.

[0679] In some implementations, R1 is controlled by one or more R... 1S Substituted 3-7 membered heterocyclic hydrocarbon groups.

[0680] In some implementations, R1 is controlled by an R 1S Substituted 3-7 membered heterocyclic hydrocarbon groups. In some embodiments, R1 is replaced by two R... 1S Substituted 3-7 membered heterocyclic hydrocarbon groups. In some embodiments, R1 is replaced by three R groups. 1S Substituted 3-7 membered heterocyclic hydrocarbon groups.

[0681] In some implementations, when R1 is a heterocyclic hydrocarbon group, R1 is bonded by a nitrogen atom.

[0682] In some implementations, R1 is -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group).

[0683] In some implementations, R1 is -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 Cyclic hydrocarbon group) or -O-(3-7 membered heterocyclic hydrocarbon group).

[0684] In some implementations, R1 is -O-(C6-C 10 Aryl).

[0685] In some embodiments, R1 is -O-(C6 aryl). In some embodiments, R1 is -O-(C8 aryl). In some embodiments, R1 is -O-(C6 aryl). 10 Aryl).

[0686] In some implementations, R1 is -O-(5-10 heteroaryl).

[0687] 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).

[0688] In some implementations, R1 is -O-(C3-C 10 (cyclic hydrocarbon group).

[0689] In some embodiments, R1 is -O-(C3 cyclic hydrocarbon group). In some embodiments, R1 is -O-(C4 cyclic hydrocarbon group). In some embodiments, R1 is -O-(C5 cyclic hydrocarbon group). In some embodiments, R1 is -O-(C6 cyclic hydrocarbon group). In some embodiments, R1 is -O-(C7 cyclic hydrocarbon group). In some embodiments, R1 is -O-(C8 cyclic hydrocarbon group). In some embodiments, R1 is -O-(C9 cyclic hydrocarbon group). In some embodiments, R1 is -O-(C... 10 (cyclic hydrocarbon group).

[0690] In some implementations, R1 is -O-(3-7 membered heterocyclic hydrocarbon group).

[0691] In some embodiments, R1 is -O- (a 3-membered heterocyclic hydrocarbon group). In some embodiments, R1 is -O- (a 4-membered heterocyclic hydrocarbon group). In some embodiments, R1 is -O- (a 5-membered heterocyclic hydrocarbon group). In some embodiments, R1 is -O- (a 6-membered heterocyclic hydrocarbon group). In some embodiments, R1 is -O- (a 7-membered heterocyclic hydrocarbon group).

[0692] In some implementations, R1 is -NH-(C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group).

[0693] In some implementations, R1 is -NH-(C6-C 10 Aryl).

[0694] In some embodiments, R1 is -NH-(C6 aryl). In some embodiments, R1 is -NH-(C8 aryl). In some embodiments, R1 is -NH-(C6 aryl). 10 Aryl).

[0695] In some implementations, R1 is -NH-(5-10 heteroaryl).

[0696] 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).

[0697] In some implementations, R1 is -NH-(C3-C 10 (cyclic hydrocarbon group).

[0698] In some embodiments, R1 is -NH- (C3 cyclic hydrocarbon group). In some embodiments, R1 is -NH- (C4 cyclic hydrocarbon group). In some embodiments, R1 is -NH- (C5 cyclic hydrocarbon group). In some embodiments, R1 is -NH- (C6 cyclic hydrocarbon group). In some embodiments, R1 is -NH- (C7 cyclic hydrocarbon group). In some embodiments, R1 is -NH- (C8 cyclic hydrocarbon group). In some embodiments, R1 is -NH- (C9 cyclic hydrocarbon group). In some embodiments, R1 is -NH- (C... 10 (cyclic hydrocarbon group).

[0699] In some implementations, R1 is -NH-(3-7 membered heterocyclic hydrocarbon group).

[0700] In some embodiments, R1 is -NH- (a 3-membered heterocyclic hydrocarbon group). In some embodiments, R1 is -NH- (a 4-membered heterocyclic hydrocarbon group). In some embodiments, R1 is -NH- (a 5-membered heterocyclic hydrocarbon group). In some embodiments, R1 is -NH- (a 6-membered heterocyclic hydrocarbon group). In some embodiments, R1 is -NH- (a 7-membered heterocyclic hydrocarbon group).

[0701] In some embodiments, R1 is methyl, isopropyl, ethyl, -CF3, -CHF2, CH2F, -CF2CH3, -CF(CH3)2, cyclopropyl, or fluorocyclopropyl.

[0702] In some embodiments, R1 is methyl, ethyl, -CF3, CHF2, or CH2F.

[0703] In some implementations, R1 is methyl or ethyl.

[0704] In some implementations, R1 is -CF3, CHF2, or CH2F.

[0705] In some implementations, each R 1S Independently, it is 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 alkoxy, C3-C7 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon.

[0706] In some implementations, each R 1S It can be 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 alkoxy, C3-C7 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon.

[0707] In some implementations, each R 1S It can be oxidized, halogenated, or -CN on its own.

[0708] In some implementations, each R 1S It is oxygenation on its own.

[0709] In some implementations, each R 1S It is a halogen on its own.

[0710] In some implementations, each R 1S It is independently F, Cl, Br, or I. In some implementations, each R 1S It is independently F, Cl, or Br. In some implementations, each R 1S It is either F or Cl on its own.

[0711] In some implementations, each R 1S Independently, it is F. In some implementations, each R1S Independently, it is Cl. In some implementations, each R 1S Independently, it is Br. In some implementations, each R 1S I is independent.

[0712] In some implementations, each R 1S Independently, it is -CN.

[0713] In some implementations, each R 1S Independently, it is -OH, -O-(CH2)2-OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl) or -SO2(C1-C6 alkyl).

[0714] In some implementations, each R 1S It can be -OH, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -S (C1-C6 alkyl) or -SO2 (C1-C6 alkyl).

[0715] In some implementations, each R 1s It is -OH on its own.

[0716] In some implementations, each R 1S It is independently an -O-(CH2)2-OC1-C6 alkyl group.

[0717] In some implementations, each R 1S It can be -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl) or -SO2(C1-C6 alkyl).

[0718] In some implementations, each R 1S It is independently -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0719] In some implementations, each R 1S It is -NH2 independently.

[0720] In some implementations, each R 1S Independently, it is -NH (C1-C6 alkyl).

[0721] In some implementations, each R 1S Independently, it is -NH (methyl). In some embodiments, each R 1S Independently, it is -NH(ethyl). In some embodiments, each R 1S Independently, it is -NH (propyl). In some embodiments, each R1S Independently, it is -NH (butyl). In some embodiments, each R 1S Independently, it is -NH(pentyl). In some embodiments, each R 1S Independently, it is -NH (hexyl).

[0722] In some implementations, each R 1S It is independently -N(C1-C6 alkyl)2.

[0723] In some implementations, each R 1S It is independently -S (C1-C6 alkyl) or -SO2 (C1-C6 alkyl).

[0724] In some implementations, each R 1S It is independently -S (C1-C6 alkyl).

[0725] In some implementations, each R 1S Independently, it is -S (methyl). In some embodiments, each R 1S Independently, it is -S(ethyl). In some embodiments, each R 1S Independently, it is -S (propyl). In some embodiments, each R 1S Independently, it is -S (butyl). In some implementations, each R 1S Independently, it is -S(heptyl). In some implementations, each R 1S Independently, it is -S (hexyl).

[0726] In some implementations, each R 1S It is independently -SO2 (C1-C6 alkyl).

[0727] In some implementations, each R 1S Independently, it is -SO2 (methyl). In some embodiments, each R 1S Independently, it is -SO2(ethyl). In some embodiments, each R 1S Independently, it is -SO2 (propyl). In some implementations, each R 1S Independently, it is -SO2 (butyl). In some implementations, each R 2S Independently, it is -SO2 (heptyl). In some implementations, each R 1S It is independently -SO2 (hexyl).

[0728] In some implementations, each R 1S It is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cyclic hydrocarbon or 3-7 membered heterocyclic hydrocarbon.

[0729] In some implementations, each R 1S It is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy.

[0730] In some implementations, each R 1S It is independently a C1-C6 alkyl group.

[0731] In some implementations, each R 1S Independently, it is methyl. In some embodiments, each R 1S It is ethyl independently. In some embodiments, each R 1S It is propyl, independently. In some embodiments, each R 1S It is butyl independently. In some implementations, each R 1S It is pentyl independently. In some embodiments, each R 1S It is independently a base. In some implementations, each R is... 1S Independently, it is isopropyl. In some embodiments, each R... 1S Independently, it is isobutyl. In some implementations, each R... 1S Independently, it is isopentyl. In some embodiments, each R... 1S Independently, it is a heterobase. In some implementations, each R... 1S It is independently sec-butyl. In some implementations, each R 1S Independently, it is sec-amyl. In some implementations, each R... 1S Independently, it is Zhongjiji. In some implementations, each R... 1S It is tert-butyl independently.

[0732] In some implementations, each R 1S It is independently a C2-C6 alkenyl group.

[0733] In some implementations, each R 1S Independently, it is a C2 alkenyl group. In some embodiments, each R 1S It is independently a C3 alkenyl group. In some embodiments, each R 1S It is independently a C4 alkenyl group. In some embodiments, each R 1S It is independently a C5 alkenyl group. In some embodiments, each R 1S It is independently a C6 alkenyl group.

[0734] In some implementations, each R 1S It is independently a C2-C6 ynyl group.

[0735] In some implementations, each R 1SIt is independently a C2 ynyl group. In some embodiments, each R 1S It is independently a C3 ynyl group. In some embodiments, each R 1S It is independently a C4 ynyl group. In some embodiments, each R 1S It is independently a C5 ynyl group. In some embodiments, each R 1S It is independently a C6 ynyl group.

[0736] In some implementations, each R 1S Independently, it is a C1-C6 alkoxy group.

[0737] In some implementations, each R 1S It is independently a methoxyl group. In some embodiments, each R... 1S It is independently ethoxylated. In some embodiments, each R 1S It is propoxy-based independently. In some embodiments, each R... 1S It is independently butoxyl. In some embodiments, each R 1S It is independently pentoxygenated. In some embodiments, each R 1S It is independently an hexoxy group.

[0738] In some implementations, each R 1S It is independently a C3-C7 cyclic hydrocarbon group or a 3-7 membered heterocyclic hydrocarbon group.

[0739] In some implementations, each R 1S It is independently a C3-C7 cyclic hydrocarbon group.

[0740] In some implementations, each R 1S Independently, it is cyclopropyl. In some embodiments, each R 1S Independently, it is cyclobutyl. In some embodiments, each R 1S Independently, it is cyclopentyl. In some embodiments, each R... 1S It is independently cyclohexyl. In some implementations, each R... 1S Independently, it is cycloheptanyl. In some embodiments, each R 1S It is cyclooctyl alone.

[0741] In some implementations, each R 1S It is independently a 3-7 membered heterocyclic hydrocarbon group.

[0742] In some implementations, each R 1S It is independently a 3-membered heterocyclic hydrocarbon group. In some embodiments, each R 1S It is independently a 4-membered heterocyclic hydrocarbon group. In some embodiments, each R 1SIt is independently a 5-membered heterocyclic hydrocarbon group. In some embodiments, each R 1S It is independently a 6-membered heterocyclic hydrocarbon group. In some embodiments, each R 1S It is independently a 7-membered heterocyclic hydrocarbon group.

[0743] 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 aryl), -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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group).

[0744] 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 aryl), -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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 2S replace.

[0745] In some implementations, R2 is a halogen or -CN.

[0746] In some implementations, R2 is a halogen.

[0747] 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.

[0748] In some embodiments, R2 is F. In some embodiments, R2 is Cl. In some embodiments, R2 is Br. In some embodiments, R2 is I.

[0749] In some implementations, R2 is -CN.

[0750] 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 aryl), -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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group).

[0751] 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 aryl), -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 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 2S replace.

[0752] In some implementations, R2 is -OH.

[0753] In some embodiments, R2 is -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -S (C1-C6 alkyl), or -S (C6-C6 alkyl). 10 Aryl).

[0754] In some embodiments, R2 is -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0755] In some implementations, R2 is -NH2.

[0756] In some embodiments, R2 is -NH (C1-C6 alkyl).

[0757] 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).

[0758] In some embodiments, R2 is --N(C1-C6 alkyl)2.

[0759] In some embodiments, R2 is -SH, -S (C1-C6 alkyl), -SO2 (C1-C6 alkyl), -S (C6-C 10 aryl) or -SO2(C6-C 10 Aryl).

[0760] In some implementations, R2 is -SH.

[0761] In some embodiments, R2 is -S (C1-C6 alkyl) or -S (C6-C6 alkyl) 10 Aryl).

[0762] In some embodiments, R2 is -S (C1-C6 alkyl).

[0763] 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).

[0764] In some implementations, R2 is -S(C6-C 10 Aryl).

[0765] In some embodiments, R2 is -S(C6 aryl). In some embodiments, R2 is -S(C8 aryl). In some embodiments, R2 is -S(C6 aryl). 10 Aryl).

[0766] In some embodiments, R2 is -SO2 (C1-C6 alkyl) or -SO2 (C6-C6 alkyl). 10 Aryl).

[0767] In some embodiments, R2 is -SO2 (C1-C6 alkyl).

[0768] 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).

[0769] In some implementations, R2 is -SO2(C6-C) 10 Aryl).

[0770] In some embodiments, R2 is -SO2(C6 aryl). In some embodiments, R2 is -SO2(C8 aryl). In some embodiments, R2 is -SO2(C6 aryl). 10 Aryl).

[0771] In some embodiments, R2 is a C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10(cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group).

[0772] In some embodiments, R2 is a C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon group, 3-7 membered heterocyclic hydrocarbon group, -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, alkenyl, aryl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 2S replace.

[0773] In some embodiments, R2 is a C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0774] In some embodiments, R2 is a C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl or alkenyl group is optionally surrounded by one or more R2 groups. 2S replace.

[0775] In some embodiments, R2 is a C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl or alkenyl group is influenced by one or more R2 groups. 2S replace.

[0776] In some embodiments, R2 is a C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl or alkenyl group is surrounded by an R 2S replace.

[0777] In some embodiments, R2 is a C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl or alkenyl group is divided by two R groups. 2S replace.

[0778] In some embodiments, R2 is a C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl or alkenyl group is surrounded by three R groups. 2S replace.

[0779] In some embodiments, R2 is a C1-C6 alkyl group.

[0780] 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.

[0781] In some implementations, R2 is optionally divided by one or more R 2S Substituted C1-C6 alkyl groups.

[0782] In some implementations, R2 is controlled by one or more R... 2S Substituted C1-C6 alkyl groups.

[0783] In some implementations, R2 is controlled by an R 2S Substituted C1-C6 alkyl groups. In some embodiments, R2 is composed of two R groups. 2S Substituted C1-C6 alkyl groups. In some embodiments, R2 is composed of three R groups. 2S Substituted C1-C6 alkyl groups.

[0784] In some implementations, R2 is a C2-C6 alkenyl group.

[0785] In some embodiments, R2 is C2-alkenyl. In some embodiments, R2 is C3-alkenyl. In some embodiments, R2 is C4-alkenyl. In some embodiments, R2 is C5-alkenyl. In some embodiments, R2 is C6-alkenyl.

[0786] In some implementations, R2 is optionally divided by one or more R 2S Substituted C2-C6 alkenyl groups.

[0787] In some implementations, R2 is controlled by one or more R... 2S Substituted C2-C6 alkenyl groups.

[0788] In some implementations, R2 is controlled by an R 2S Substituted C2-C6 alkenyl groups. In some embodiments, R2 is replaced by two R... 2S Substituted C2-C6 alkenyl groups. In some embodiments, R2 is replaced by three R groups. 2S Substituted C2-C6 alkenyl groups.

[0789] In some embodiments, R2 is a C1-C6 haloalkyl group.

[0790] In some embodiments, R2 is a halomethyl group. In some embodiments, R2 is a haloethyl group. In some embodiments, R2 is a halopropyl group. In some embodiments, R2 is a halobutyl group. In some embodiments, R2 is a halopentyl group. In some embodiments, R2 is a halohexyl group.

[0791] In some implementations, R2 is optionally divided by one or more R 2S Substituted C1-C6 haloalkyl groups.

[0792] In some implementations, R2 is controlled by one or more R... 2S Substituted C1-C6 haloalkyl groups.

[0793] In some implementations, R2 is controlled by an R 2S Substituted C1-C6 haloalkyl groups. In some embodiments, R2 is formed by two R groups. 2S Substituted C1-C6 haloalkyl groups. In some embodiments, R2 is composed of three R groups. 2S Substituted C1-C6 haloalkyl groups.

[0794] In some embodiments, R2 is a C1-C6 alkoxy group.

[0795] 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.

[0796] In some implementations, R2 is optionally divided by one or more R 2S Substituted C1-C6 alkoxy groups.

[0797] In some implementations, R2 is controlled by one or more R... 2S Substituted C1-C6 alkoxy groups.

[0798] In some implementations, R2 is controlled by an R 2S Substituted C1-C6 alkoxy groups. In some embodiments, R2 is replaced by two R groups. 2S Substituted C1-C6 alkoxy groups. In some embodiments, R2 is replaced by three R groups. 2S Substituted C1-C6 alkoxy groups.

[0799] In some implementations, R2 is C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon group or 3-7 membered heterocyclic hydrocarbon group.

[0800] In some implementations, R2 is C6-C 10 aryl, 5-10-membered heteroaryl, C3-C7 cyclic hydrocarbon, or 3-7-membered heterocyclic hydrocarbon, wherein the aryl, heteroaryl, cyclic hydrocarbon, and heterocyclic hydrocarbon are optionally surrounded by one or more R 2S replace.

[0801] In some implementations, R2 is C6-C 10 aryl, 5-10-membered heteroaryl, C3-C7 cyclic hydrocarbon or 3-7-membered heterocyclic hydrocarbon, wherein the aryl, heteroaryl, cyclic hydrocarbon and heterocyclic hydrocarbon are determined by one or more R 2S replace.

[0802] In some implementations, R2 is C6-C 10 aryl, 5-10-membered heteroaryl, C3-C7 cyclic hydrocarbon or 3-7-membered heterocyclic hydrocarbon, wherein the aryl, heteroaryl, cyclic hydrocarbon or heterocyclic hydrocarbon is determined by an R 2S replace.

[0803] In some implementations, R2 is C6-C 10 aryl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon group or 3-7 membered heterocyclic hydrocarbon group, wherein the aryl, heteroaryl, cyclic hydrocarbon group or heterocyclic hydrocarbon group is divided by two R 2s replace.

[0804] In some implementations, R2 is C6-C 10 aryl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon group or 3-7 membered heterocyclic hydrocarbon group, wherein the aryl, heteroaryl, cyclic hydrocarbon group or heterocyclic hydrocarbon group is determined by three R groups. 2S replace.

[0805] In some implementations, R2 is C6-C 10 Aryl.

[0806] In some embodiments, R2 is a C6 aryl group (e.g., phenyl). In some embodiments, R2 is a C8 aryl group. In some embodiments, R2 is a C... 10 Aryl.

[0807] In some implementations, R2 is optionally divided by one or more R 2S Replacement C6-C 10 Aryl.

[0808] In some implementations, R2 is controlled by one or more R... 2S Replacement C6-C 10 Aryl.

[0809] In some implementations, R2 is controlled by an R 2SReplacement C6-C 10 Aryl. In some embodiments, R2 is reacted with two R... 2S Replacement C6-C 10 Aryl. In some embodiments, R2 is composed of three R... 2S Replacement C6-C 10 Aryl.

[0810] In some implementations, R2 is a 5-10 member heteroaryl group.

[0811] In some embodiments, R2 is a 5-membered heteroaryl group. In some embodiments, R2 is a 6-membered heteroaryl group. In some embodiments, R2 is a 7-membered heteroaryl group. In some embodiments, R2 is an 8-membered heteroaryl group. In some embodiments, R2 is a 9-membered heteroaryl group. In some embodiments, R2 is a 10-membered heteroaryl group.

[0812] In some implementations, R2 is optionally divided by one or more R 2S Substituted 5-10 heteroaryl groups.

[0813] In some implementations, R2 is controlled by one or more R... 2S Substituted 5-10 heteroaryl groups.

[0814] In some implementations, R2 is controlled by an R 2S The substituted 5-10-membered heteroaryl group. In some embodiments, R2 is replaced by two R... 2S The substituted 5-10 aryl group. In some embodiments, R2 is replaced by three R... 2S Substituted 5-10 heteroaryl groups.

[0815] In some implementations, R2 is a C3-C7 cyclic hydrocarbon group.

[0816] 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.

[0817] In some implementations, R2 is optionally divided by one or more R 2S Substituted C3-C7 cyclic hydrocarbon groups.

[0818] In some implementations, R2 is controlled by one or more R... 2S Substituted C3-C7 cyclic hydrocarbon groups.

[0819] In some implementations, R2 is controlled by an R 2S Substituted C3-C7 cyclic hydrocarbon group. In some embodiments, R2 is replaced by two R... 2SSubstituted C3-C7 cyclic hydrocarbon groups. In some embodiments, R2 is replaced by three R... 2S Substituted C3-C7 cyclic hydrocarbon groups.

[0820] In some implementations, R2 is a 3-7 membered heterocyclic hydrocarbon group.

[0821] In some embodiments, R2 is a 3-membered heterocyclic hydrocarbon group. In some embodiments, R2 is a 4-membered heterocyclic hydrocarbon group. In some embodiments, R2 is a 5-membered heterocyclic hydrocarbon group. In some embodiments, R2 is a 6-membered heterocyclic hydrocarbon group. In some embodiments, R2 is a 7-membered heterocyclic hydrocarbon group.

[0822] In some implementations, R2 is optionally divided by one or more R 2S Substituted 3-7 membered heterocyclic hydrocarbon groups.

[0823] In some implementations, R2 is controlled by one or more R... 2S Substituted 3-7 membered heterocyclic hydrocarbon groups.

[0824] In some implementations, R2 is controlled by an R 2s Substituted 3-7 membered heterocyclic hydrocarbon groups. In some embodiments, R2 is replaced by two R... 2S Substituted 3-7 membered heterocyclic hydrocarbon groups. In some embodiments, R2 is replaced by three R... 2S Substituted 3-7 membered heterocyclic hydrocarbon groups.

[0825] In some implementations, R2 is -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 -O- (3-7 membered heterocyclic hydrocarbon group), -NH- (C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group).

[0826] In some implementations, R2 is -O-(C6-C 10 aryl), -O-(5-10 heteroaryl), -O-(C3-C 10 Cyclic hydrocarbon group) or -O-(3-7 membered heterocyclic hydrocarbon group).

[0827] In some implementations, R2 is -O-(C6-C 10 Aryl).

[0828] In some embodiments, R2 is -O-(C6 aryl). In some embodiments, R2 is -O-(C8 aryl). In some embodiments, R2 is -O-(C6 aryl). 10 Aryl).

[0829] In some implementations, R2 is -O-(5-10 heteroaryl).

[0830] 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).

[0831] In some implementations, R2 is -O-(C3-C 10 (cyclic hydrocarbon group).

[0832] In some embodiments, R2 is -O-(C3 cyclic hydrocarbon group). In some embodiments, R2 is -O-(C4 cyclic hydrocarbon group). In some embodiments, R2 is -O-(C5 cyclic hydrocarbon group). In some embodiments, R2 is -O-(C6 cyclic hydrocarbon group). In some embodiments, R2 is -O-(C7 cyclic hydrocarbon group). In some embodiments, R2 is -O-(C8 cyclic hydrocarbon group). In some embodiments, R2 is -O-(C9 cyclic hydrocarbon group). In some embodiments, R2 is -O-(C... 10 (cyclic hydrocarbon group).

[0833] In some implementations, R2 is -O-(3-7 membered heterocyclic hydrocarbon group).

[0834] In some embodiments, R2 is -O- (a 3-membered heterocyclic hydrocarbon group). In some embodiments, R2 is -O- (a 4-membered heterocyclic hydrocarbon group). In some embodiments, R2 is -O- (a 5-membered heterocyclic hydrocarbon group). In some embodiments, R2 is -O- (a 6-membered heterocyclic hydrocarbon group). In some embodiments, R2 is -O- (a 7-membered heterocyclic hydrocarbon group).

[0835] In some implementations, R2 is -NH-(C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group).

[0836] In some implementations, R2 is -NH-(C6-C 10 Aryl).

[0837] In some embodiments, R2 is -NH-(C6 aryl). In some embodiments, R2 is -NH-(C8 aryl). In some embodiments, R2 is -NH-(C6 aryl). 10 Aryl).

[0838] In some implementations, R2 is -NH-(5-10 heteroaryl).

[0839] 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).

[0840] In some implementations, R2 is -NH-(C3-C 10 (cyclic hydrocarbon group).

[0841] In some embodiments, R2 is -NH-(C3 cyclic hydrocarbon group). In some embodiments, R2 is -NH-(C4 cyclic hydrocarbon group). In some embodiments, R2 is -NH-(C5 cyclic hydrocarbon group). In some embodiments, R2 is -NH-(C6 cyclic hydrocarbon group). In some embodiments, R2 is -NH-(C7 cyclic hydrocarbon group). In some embodiments, R2 is -NH-(C8 cyclic hydrocarbon group). In some embodiments, R2 is -NH-(C9 cyclic hydrocarbon group). In some embodiments, R2 is -NH-(C... 10 (cyclic hydrocarbon group).

[0842] In some implementations, R2 is -NH-(3-7 membered heterocyclic hydrocarbon group).

[0843] In some embodiments, R2 is -NH- (a 3-membered heterocyclic hydrocarbon group). In some embodiments, R2 is -NH- (a 4-membered heterocyclic hydrocarbon group). In some embodiments, R2 is -NH- (a 5-membered heterocyclic hydrocarbon group). In some embodiments, R2 is -NH- (a 6-membered heterocyclic hydrocarbon group). In some embodiments, R2 is -NH- (a 7-membered heterocyclic hydrocarbon group).

[0844] In some implementations, R2 is

[0845] In some implementations, R2 is

[0846] In some implementations, R2 is

[0847] In some implementations, R2 is

[0848] In some implementations, R2 is

[0849] In some implementations, R2 is

[0850] In some implementations, R2 is -CN,

[0851] In some implementations, R2 is

[0852] In some implementations, R2 is

[0853] In some implementations, each R 2S Independently, it is an 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 alkoxy, C1-C6 haloalkyl, C3-C7 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon.

[0854] In some implementations, each R 2S It can be 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 alkoxy, C3-C7 cyclic hydrocarbon, or 3-7 membered heterocyclic hydrocarbon.

[0855] In some implementations, each R 2s It can be oxidized, halogenated, or -CN on its own.

[0856] In some implementations, each R 2S It is oxygenation on its own.

[0857] In some implementations, each R 2S It is a halogen on its own.

[0858] In some implementations, each R 2S It is independently F, Cl, Br, or I. In some implementations, each R 2S It is independently F, Cl, or Br. In some implementations, each R 2S It is either F or Cl on its own.

[0859] In some implementations, each R 2S Independently, it is F. In some implementations, each R2S Independently, it is Cl. In some implementations, each R 2S Independently, it is Br. In some implementations, each R 2S I is independent.

[0860] In some implementations, each R 2S Independently, it is -CN.

[0861] In some implementations, each R 2S It can be -OH, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -S (C1-C6 alkyl) or -SO2 (C1-C6 alkyl).

[0862] In some implementations, each R 2S It is -OH on its own.

[0863] In some implementations, each R 2S It can be -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl) or -SO2(C1-C6 alkyl).

[0864] In some implementations, each R 2S It is independently -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0865] In some implementations, each R 2S It is -NH2 independently.

[0866] In some implementations, each R 2S Independently, it is -NH (C1-C6 alkyl).

[0867] In some implementations, each R 2S Independently, it is -NH (methyl). In some embodiments, each R 2S Independently, it is -NH(ethyl). In some embodiments, each R 2S Independently, it is -NH (propyl). In some embodiments, each R 2S Independently, it is -NH (butyl). In some embodiments, each R 2S Independently, it is -NH(pentyl). In some embodiments, each R 2S Independently, it is -NH (hexyl).

[0868] In some implementations, each R 2S It is independently -N(C1-C6 alkyl)2.

[0869] In some implementations, each R2S It is independently -S (C1-C6 alkyl) or -SO2 (C1-C6 alkyl).

[0870] In some implementations, each R 2S It is independently -S (C1-C6 alkyl).

[0871] In some implementations, each R 2S Independently, it is -S (methyl). In some embodiments, each R 2S Independently, it is -S(ethyl). In some embodiments, each R 2S Independently, it is -S (propyl). In some embodiments, each R 2S Independently, it is -S (butyl). In some implementations, each R 2S Independently, it is -S(heptyl). In some implementations, each R 2S Independently, it is -S (hexyl).

[0872] In some implementations, each R 2S It is independently -SO2 (C1-C6 alkyl).

[0873] In some implementations, each R 2S Independently, it is -SO2 (methyl). In some embodiments, each R 2S Independently, it is -SO2(ethyl). In some embodiments, each R 2S Independently, it is -SO2 (propyl). In some implementations, each R 2S Independently, it is -SO2 (butyl). In some implementations, each R 2S Independently, it is -SO2 (heptyl). In some implementations, each R 2S It is independently -SO2 (hexyl).

[0874] In some implementations, each R 2S It is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C7 cyclic hydrocarbon or 3-7 membered heterocyclic hydrocarbon.

[0875] In some implementations, each R 2S It is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cyclic hydrocarbon or 3-7 membered heterocyclic hydrocarbon.

[0876] In some implementations, each R 2S It is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0877] In some implementations, each R 2S It is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy.

[0878] In some implementations, each R 2S It is independently a C1-C6 alkyl group.

[0879] In some implementations, each R 2S Independently, it is methyl. In some embodiments, each R 2S It is ethyl independently. In some embodiments, each R 2S It is propyl, independently. In some embodiments, each R 2S It is butyl independently. In some implementations, each R 2S It is pentyl independently. In some embodiments, each R 2S It is independently a base. In some implementations, each R is... 2S Independently, it is isopropyl. In some embodiments, each R... 2S Independently, it is isobutyl. In some implementations, each R... 2S Independently, it is isopentyl. In some embodiments, each R... 2S Independently, it is a heterobase. In some implementations, each R... 2S It is independently sec-butyl. In some implementations, each R 1S Independently, it is sec-amyl. In some implementations, each R... 2S Independently, it is Zhongjiji. In some implementations, each R 2S It is tert-butyl independently.

[0880] In some implementations, each R 2S It is independently a C2-C6 alkenyl group.

[0881] In some implementations, each R 2S Independently, it is a C2 alkenyl group. In some embodiments, each R 2S It is independently a C3 alkenyl group. In some embodiments, each R 2S Independently, it is a C4 alkenyl group. In some embodiments, each R 2S It is independently a C5 alkenyl group. In some embodiments, each R 2S It is independently a C6 alkenyl group.

[0882] In some implementations, each R 2S It is independently a C2-C6 ynyl group.

[0883] In some implementations, each R2S It is independently a C2 ynyl group. In some embodiments, each R 2S It is independently a C3 ynyl group. In some embodiments, each R 2S It is independently a C4 ynyl group. In some embodiments, each R 2S It is independently a C5 ynyl group. In some embodiments, each R 2S It is independently a C6 ynyl group.

[0884] In some implementations, each R 2S Independently, it is a C1-C6 alkoxy group.

[0885] In some implementations, each R 2S It is independently a methoxyl group. In some embodiments, each R... 2S It is independently ethoxylated. In some embodiments, each R 2S It is propoxy-based independently. In some embodiments, each R... 2S It is independently butoxyl. In some embodiments, each R 2S It is independently pentoxygenated. In some embodiments, each R 2S It is independently an hexoxy group.

[0886] In some implementations, each R 2S It is independently a C1-C6 haloalkyl group.

[0887] In some implementations, each R 2S It is independently a C1 haloalkyl group. In some embodiments, each R 2S It is independently a C2 haloalkyl group. In some embodiments, each R 2S It is independently a C3 haloalkyl group. In some embodiments, each R 2S It is independently a C4 haloalkyl group. In some embodiments, each R 2S It is independently a C5 haloalkyl group. In some embodiments, each R 2S It is independently a C6 haloalkyl group.

[0888] In some implementations, each R 2S It is independently a C3-C7 cyclic hydrocarbon group or a 3-7 membered heterocyclic hydrocarbon group.

[0889] In some implementations, each R 2S It is independently a C3-C7 cyclic hydrocarbon group.

[0890] In some implementations, each R 2S Independently, it is cyclopropyl. In some embodiments, each R 2S Independently, it is cyclobutyl. In some embodiments, each R2S Independently, it is cyclopentyl. In some embodiments, each R... 2S It is independently cyclohexyl. In some implementations, each R... 2S Independently, it is cycloheptanyl. In some embodiments, each R 2S It is cyclooctyl alone.

[0891] In some implementations, each R 2S It is independently a 3-7 membered heterocyclic hydrocarbon group.

[0892] In some implementations, each R 2S It is independently a 3-membered heterocyclic hydrocarbon group. In some embodiments, each R 2S It is independently a 4-membered heterocyclic hydrocarbon group. In some embodiments, each R 2S It is independently a 5-membered heterocyclic hydrocarbon group. In some embodiments, each R 2S It is independently a 6-membered heterocyclic hydrocarbon group. In some embodiments, each R 2S It is independently a 7-membered heterocyclic hydrocarbon group.

[0893] 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 Alkyl group.

[0894] In some embodiments, each R3 is independently a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0895] In some implementations, each R3 is independently a halogen.

[0896] 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.

[0897] 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.

[0898] In some implementations, each R3 is independently -CN.

[0899] In some implementations, each R3 is independently -OH.

[0900] In some embodiments, each R3 is independently -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0901] In some implementations, each R3 is independently -NH2.

[0902] In some embodiments, each R3 is independently -NH (C1-C6 alkyl).

[0903] 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).

[0904] In some embodiments, each R3 is independently -N(C1-C6 alkyl)2.

[0905] In some embodiments, each R3 is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 Alkyl group.

[0906] In some embodiments, each R3 is independently a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0907] In some implementations, each R3 is independently a C1-C6 alkyl group.

[0908] 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.

[0909] In some implementations, each R3 is independently a C2-C6 alkenyl group.

[0910] In some embodiments, each R3 is independently C2 alkenyl. In some embodiments, each R3 is independently C3 alkenyl. In some embodiments, each R3 is independently C4 alkenyl. In some embodiments, each R3 is independently C5 alkenyl. In some embodiments, each R3 is independently C6 alkenyl.

[0911] In some implementations, each R3 is independently a C2-C6 ynyl group.

[0912] In some embodiments, each R3 is independently a C2 ynyl group. In some embodiments, each R3 is independently a C3 ynyl group. In some embodiments, each R3 is independently a C4 ynyl group. In some embodiments, each R3 is independently a C5 ynyl group. In some embodiments, each R3 is independently a C6 ynyl group.

[0913] In some embodiments, each R3 is independently a C1-C6 haloalkyl or C1-C6 alkyl haloalkyl. 1-6 Alkyl group.

[0914] In some implementations, each R3 is independently a C1-C6 haloalkyl group.

[0915] In some embodiments, each R3 is independently a halomethyl group. In some embodiments, each R3 is independently a haloethyl group. In some embodiments, each R3 is independently a halopropyl group. In some embodiments, each R3 is independently a halobutyl group. In some embodiments, each R3 is independently a halopentyl group. In some embodiments, each R3 is independently a halohexyl group.

[0916] In some implementations, each R3 is independently C 1-6 Alkyl group.

[0917] 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.

[0918] In some implementations, R 4a It is 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 Alkoxy;

[0919] In some implementations, R 4aIt is a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0920] In some implementations, R 4a It is halogen.

[0921] In some implementations, R 4a It is F, Cl, Br, or I. In some implementations, R 4a It is F, Cl, or Br. In some implementations, R 4a It is either F or Cl.

[0922] In some implementations, R 4a It is F. In some implementations, R 4a It is Cl. In some implementations, R 4a It is Br. In some implementations, R 4a It's I.

[0923] In some implementations, R 4a Yes - CN.

[0924] In some implementations, R 4a It is -OH.

[0925] In some implementations, R 4a It is -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0926] In some implementations, R 4a It is -NH2.

[0927] In some implementations, R 4a It is -NH (C1-C6 alkyl).

[0928] In some implementations, R 4a It is -NH (methyl). In some embodiments, R 4a It is -NH(ethyl). In some embodiments, R 4a It is -NH (propyl). In some embodiments, R 4a It is -NH (butyl). In some implementations, R 4a It is -NH (pentyl). In some embodiments, R 4a It is -NH (hexyl).

[0929] In some implementations, R 4a It is -N(C1-C6 alkyl)2.

[0930] In some implementations, R 4aIt is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 Alkyl group.

[0931] In some implementations, R 4a It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl.

[0932] In some implementations, R 4a It is H.

[0933] In some implementations, R 4a It is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0934] In some implementations, R 4a It is a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0935] In some implementations, R 4a It is a C1-C6 alkyl group.

[0936] In some implementations, R 4a It is methyl. In some embodiments, R 4a It is ethyl. In some embodiments, R 4a It is propyl. In some embodiments, R 4a It is butyl. In some implementations, R 4a It is pentyl. In some implementations, R 4a It is self-based. In some implementations, R 4a It is isopropyl. In some embodiments, R 4a It is isobutyl. In some implementations, R 4a It is isopentyl. In some embodiments, R 4a It is an allohexyl group. In some implementations, R 4a It is sec-butyl. In some implementations, R 4a It is sec-amyl. In some implementations, R 4a It is Zhong Jiji. In some implementations, R 4a It is tert-butyl.

[0937] In some implementations, R 4a It is a C2-C6 alkenyl group.

[0938] In some implementations, R 4a It is C2-alkenyl. In some embodiments, R 4a It is a C3 alkenyl group. In some embodiments, R 4a It is a C4 alkenyl group. In some embodiments, R4a It is C5 alkenyl. In some embodiments, R 4a It is a C6 alkenyl group.

[0939] In some implementations, R 4a It is a C2-C6 acetylene group.

[0940] In some implementations, R 4a It is a C2 acetylene group. In some embodiments, R 4a It is a C3 acetylene group. In some embodiments, R 4a It is a C4 acetylene group. In some embodiments, R 4a It is a C5 acetylene group. In some embodiments, R 4a It is a C6 acetylene group.

[0941] In some implementations, R 4a It is a C1-C6 haloalkyl group.

[0942] In some implementations, R 4a It is a halomethyl group. In some embodiments, R 4a It is a haloethyl. In some embodiments, R 4a It is a halopropyl group. In some embodiments, R 4a It is a halogenated butyl. In some implementations, R 4a It is a halopentyl group. In some embodiments, R 4a It is a halogenated hexyl group.

[0943] In some implementations, R 4a It is C 1-6 Alkyl group.

[0944] In some implementations, R 4a It is a methoxy group. In some embodiments, R 4a It is ethoxylated. In some embodiments, R 4a It is propoxy. In some embodiments, R 4a It is butoxyl. In some embodiments, R 4a It is an pentoxygenated group. In some embodiments, R 4a It is hexyloxy group.

[0945] In some implementations, R 4b It is 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 Alkoxy;

[0946] In some implementations, R 4bIt is a halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0947] In some implementations, R 4b It is halogen.

[0948] In some implementations, R 4b It is F, Cl, Br, or I. In some implementations, R 4b It is F, Cl, or Br. In some implementations, R 4b It is either F or Cl.

[0949] In some implementations, R 4b It is F. In some implementations, R 4b It is Cl. In some implementations, R 4b It is Br. In some implementations, R 4b It's I.

[0950] In some implementations, R 4b Yes - CN.

[0951] In some implementations, R 4b It is -OH.

[0952] In some implementations, R 4b It is -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0953] In some implementations, R 4b It is -NH2.

[0954] In some implementations, R 4b It is -NH (C1-C6 alkyl).

[0955] In some implementations, R 4b It is -NH (methyl). In some embodiments, R 4b It is -NH(ethyl). In some embodiments, R 4b It is -NH (propyl). In some embodiments, R 4b It is -NH (butyl). In some implementations, R 4b It is -NH (pentyl). In some embodiments, R 4b It is -NH (hexyl).

[0956] In some implementations, R 4b It is -N(C1-C6 alkyl)2.

[0957] In some implementations, R 4bIt is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C 1-6 Alkyl group.

[0958] In some implementations, R 4b It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl.

[0959] In some implementations, R 4b It is H.

[0960] In some implementations, R 4b It is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0961] In some implementations, R 4b It is a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0962] In some implementations, R 4b It is a C1-C6 alkyl group.

[0963] In some implementations, R 4b It is methyl. In some embodiments, R 4b It is ethyl. In some embodiments, R 4b It is propyl. In some embodiments, R 4b It is butyl. In some implementations, R 4b It is pentyl. In some implementations, R 4b It is self-based. In some implementations, R 4b It is isopropyl. In some embodiments, R 4b It is isobutyl. In some implementations, R 4b It is isopentyl. In some embodiments, R 4b It is an allohexyl group. In some implementations, R 4b It is sec-butyl. In some implementations, R 4b It is sec-amyl. In some implementations, R 4b It is Zhong Jiji. In some implementations, R 4b It is tert-butyl.

[0964] In some implementations, R 4b It is a C2-C6 alkenyl group.

[0965] In some implementations, R 4b It is C2-alkenyl. In some embodiments, R 4b It is a C3 alkenyl group. In some embodiments, R 4b It is a C4 alkenyl group. In some embodiments, R4b It is C5 alkenyl. In some embodiments, R 4b It is a C6 alkenyl group.

[0966] In some implementations, R 4b It is a C2-C6 acetylene group.

[0967] In some implementations, R 4b It is a C2 acetylene group. In some embodiments, R 4b It is a C3 acetylene group. In some embodiments, R 4b It is a C4 acetylene group. In some embodiments, R 4b It is a C5 acetylene group. In some embodiments, R 4b It is a C6 acetylene group.

[0968] In some implementations, R 4b It is a C1-C6 haloalkyl group.

[0969] In some implementations, R 4b It is a halomethyl group. In some embodiments, R 4b It is a haloethyl. In some embodiments, R 4b It is a halopropyl group. In some embodiments, R 4b It is a halogenated butyl. In some implementations, R 4b It is a halopentyl group. In some embodiments, R 4b It is a halogenated hexyl group.

[0970] In some implementations, R 4b It is C 1-6 Alkyl group.

[0971] In some implementations, R 4b It is a methoxy group. In some embodiments, R 4b It is ethoxylated. In some embodiments, R 4b It is propoxy. In some embodiments, R 4b It is butoxyl. In some embodiments, R 4b It is an pentoxygenated group. In some embodiments, R 4b It is hexyloxy group.

[0972] In some implementations, n is 0, 1, 2, or 3. In some implementations, n is 0, 1, or 2. In some implementations, n is 0 or 1.

[0973] In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3.

[0974] In some implementations, m is 0, 1, 2, 3, 4, or 5. In some implementations, m is 0, 1, 2, 3, or 4. In some implementations, m is 0, 1, 2, or 3. In some implementations, m is 0, 1, or 2. In some implementations, m is 0 or 1.

[0975] In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4. In some implementations, m is 5.

[0976] In some implementations, p is 0, 1, 2, 3, or 4. In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 0, 1, or 2. In some implementations, p is 0 or 1.

[0977] In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4.

[0978] In some embodiments, the compound has formula (I-1):

[0979]

[0980] Or it may be a prodrug, solvate, or pharmaceutically acceptable salt, where q is 0, 1, 2, 3, 4, or 5.

[0981] In some embodiments, the compound has formula (I-1) or its prodrug, solvate or pharmaceutically acceptable salt.

[0982] In some embodiments, the compound has the formula (I-1a), (I-1b), or (I-1c):

[0983]

[0984] Or it may be a prodrug, solvate, or pharmaceutically acceptable salt, where q is 0, 1, 2, 3, 4, or 5.

[0985] In some embodiments, the compound has formula (I-1a) or its prodrug, solvate or pharmaceutically acceptable salt.

[0986] In some embodiments, the compound has formula (I-1b) or its prodrug, solvate or pharmaceutically acceptable salt.

[0987] In some embodiments, the compound has formula (I-1c) or its prodrug, solvate or pharmaceutically acceptable salt.

[0988] In some embodiments, the compound has formula (I-2):

[0989]

[0990] Or it may be a prodrug, solvate, or pharmaceutically acceptable salt, where q is 0, 1, 2, 3, 4, or 5.

[0991] In some embodiments, the compound has formula (I-2) or its prodrug, solvate or pharmaceutically acceptable salt.

[0992] In some embodiments, the compound has the formula (I-2a), (I-2b), or (I-2c):

[0993]

[0994] Or it may be a prodrug, solvate, or pharmaceutically acceptable salt, where q is 0, 1, 2, 3, 4, or 5.

[0995] In some embodiments, the compound has formula (I-2a) or its prodrug, solvate or pharmaceutically acceptable salt.

[0996] In some embodiments, the compound has formula (I-2b) or its prodrug, solvate or pharmaceutically acceptable salt.

[0997] In some embodiments, the compound has formula (I-2c) or its prodrug, solvate or pharmaceutically acceptable salt.

[0998] In some embodiments, the compound has formula (I-3):

[0999]

[1000] Or it may be a prodrug, solvate, or pharmaceutically acceptable salt, where q is 0, 1, 2, 3, 4, or 5.

[1001] In some embodiments, the compound has formula (I-3) or its prodrug, solvate or pharmaceutically acceptable salt.

[1002] In some embodiments, the compound has the formula (I-3a), (I-3b), or (I-3c):

[1003]

[1004] Or it may be a prodrug, solvate, or pharmaceutically acceptable salt, where q is 0, 1, 2, 3, 4, or 5.

[1005] In some embodiments, the compound has formula (I-3a) or its prodrug, solvate or pharmaceutically acceptable salt.

[1006] In some embodiments, the compound has formula (I-3b) or its prodrug, solvate or pharmaceutically acceptable salt.

[1007] In some embodiments, the compound has formula (I-3c) or its prodrug, solvate or pharmaceutically acceptable salt.

[1008] In some embodiments, the compound has formula (II-1):

[1009]

[1010] Or it may be a prodrug, solvate, or pharmaceutically acceptable salt, where q is 0, 1, 2, 3, 4, or 5.

[1011] In some embodiments, the compound has formula (II-1) or its prodrug, solvate or pharmaceutically acceptable salt.

[1012] In some embodiments, the compound has the formula (II-1a), (II-1b), or (II-1c):

[1013]

[1014]

[1015] Or it may be a prodrug, solvate, or pharmaceutically acceptable salt, where q is 0, 1, 2, 3, 4, or 5.

[1016] In some embodiments, the compound has formula (II-1a) or its prodrug, solvate or pharmaceutically acceptable salt.

[1017] In some embodiments, the compound has formula (II-1b) or its prodrug, solvate or pharmaceutically acceptable salt.

[1018] In some embodiments, the compound has formula (II-1c) or its prodrug, solvate or pharmaceutically acceptable salt.

[1019] In some embodiments, the compound has formula (III-1):

[1020]

[1021] Or it may be a prodrug, solvate, or pharmaceutically acceptable salt, where q is 0, 1, 2, 3, 4, or 5.

[1022] In some embodiments, the compound has formula (III-1) or its prodrug, solvate or pharmaceutically acceptable salt.

[1023] In some embodiments, the compound has the formula (III-1a), (III-1b), or (III-1c):

[1024]

[1025] Or it may be a prodrug, solvate, or pharmaceutically acceptable salt, where q is 0, 1, 2, 3, 4, or 5.

[1026] In some embodiments, the compound has formula (III-1a) or its prodrug, solvate or pharmaceutically acceptable salt.

[1027] In some embodiments, the compound has formula (III-1b) or its prodrug, solvate or pharmaceutically acceptable salt.

[1028] In some embodiments, the compound has formula (III-1c) or its prodrug, solvate or pharmaceutically acceptable salt.

[1029] 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.

[1030] 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.

[1031] 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.

[1032] 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.

[1033] 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.

[1034] 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.

[1035] It should be understood that for any compound of any formula described herein, X, Y, Z, R X1 R X2 R Y R Z Ar1, R1, R 1S R2, R 2s R3, R 4a R 4b , n, m or p can each be selected from the groups described herein (where applicable), and this document relates to X, Y, Z, R X1 R X2 R Y R Z Ar1, R1, R 1S R2, R 2S R3, R 4a R 4b Any group of descriptions of any of the following can be used in relation to X, Y, Z, R. X1 R X2 R Y R Z Ar1, R1, R 1S R2, R 2S R3, R4a R 4b Any combination of one or more of the remaining descriptions from n, m, or p (where applicable).

[1036] In some embodiments, the compound is selected from the compounds described in Table 1, their prodrugs, and pharmaceutically acceptable salts.

[1037] In some embodiments, the compound is selected from the compounds described in Table 1 and their pharmaceutically acceptable salts.

[1038] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 1 and their pharmaceutically acceptable salts.

[1039] In some embodiments, the compound is selected from the compounds described in Table 1.

[1040] In some embodiments, the compound is selected from the compounds described in Table 2, their prodrugs, and pharmaceutically acceptable salts.

[1041] In some embodiments, the compound is selected from the compounds described in Table 2 and their pharmaceutically acceptable salts.

[1042] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 2 and their pharmaceutically acceptable salts.

[1043] In some embodiments, the compound is selected from the compounds described in Table 2.

[1044] In some embodiments, the compound is selected from the compounds described in Table 3, their prodrugs, and pharmaceutically acceptable salts.

[1045] In some embodiments, the compound is selected from the compounds described in Table 3 and their pharmaceutically acceptable salts.

[1046] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 3 and their pharmaceutically acceptable salts.

[1047] In some embodiments, the compound is selected from the compounds described in Table 3.

[1048] In some embodiments, the compound is selected from the compounds described in Table 4, their prodrugs, and pharmaceutically acceptable salts.

[1049] In some embodiments, the compound is selected from the compounds described in Table 4 and their pharmaceutically acceptable salts.

[1050] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 4 and their pharmaceutically acceptable salts.

[1051] In some embodiments, the compound is selected from the compounds described in Table 4.

[1052] In some embodiments, the compound is selected from the compounds described in Table 5, their prodrugs, and pharmaceutically acceptable salts.

[1053] In some embodiments, the compound is selected from the compounds described in Table 5 and their pharmaceutically acceptable salts.

[1054] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 5 and their pharmaceutically acceptable salts.

[1055] In some embodiments, the compound is selected from the compounds described in Table 5.

[1056] Table 1

[1057]

[1058]

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065]

[1066]

[1067]

[1068]

[1069]

[1070]

[1071]

[1072]

[1073]

[1074]

[1075]

[1076]

[1077]

[1078]

[1079]

[1080]

[1081]

[1082]

[1083]

[1084]

[1085]

[1086]

[1087]

[1088]

[1089]

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096]

[1097]

[1098]

[1099]

[1100]

[1101]

[1102]

[1103]

[1104] Table 2

[1105]

[1106]

[1107]

[1108]

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116]

[1117]

[1118]

[1119]

[1120]

[1121] Table 3

[1122]

[1123]

[1124]

[1125]

[1126]

[1127]

[1128]

[1129]

[1130]

[1131]

[1132]

[1133]

[1134]

[1135]

[1136]

[1137]

[1138]

[1139]

[1140]

[1141]

[1142]

[1143] Table 4

[1144]

[1145]

[1146]

[1147]

[1148]

[1149]

[1150]

[1151]

[1152]

[1153]

[1154]

[1155]

[1156]

[1157] Table 5

[1158]

[1159]

[1160]

[1161]

[1162]

[1163]

[1164]

[1165]

[1166]

[1167]

[1168]

[1169]

[1170]

[1171]

[1172]

[1173]

[1174]

[1175]

[1176] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds described in Table 1.

[1177] In some respects, this disclosure provides compounds that are isotopic derivatives (e.g., isotopically labeled compounds) of any of the compounds disclosed herein.

[1178] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 1, as well as its prodrug and pharmaceutically acceptable salt.

[1179] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 1 and a pharmaceutically acceptable salt thereof.

[1180] In some embodiments, the compound is an isotopic derivative of any prodrug of the compounds described in Table 1 and a pharmaceutically acceptable salt thereof.

[1181] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 1.

[1182] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds described in Table 2.

[1183] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 2, as well as its prodrug and pharmaceutically acceptable salt.

[1184] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 2 and a pharmaceutically acceptable salt thereof.

[1185] In some embodiments, the compound is an isotopic derivative of any prodrug of the compounds described in Table 2 and a pharmaceutically acceptable salt thereof.

[1186] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 2.

[1187] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds described in Table 3.

[1188] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 3, as well as its prodrug and pharmaceutically acceptable salt.

[1189] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 3 and a pharmaceutically acceptable salt thereof.

[1190] In some embodiments, the compound is an isotopic derivative of any prodrug of the compounds described in Table 3 and a pharmaceutically acceptable salt thereof.

[1191] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 3.

[1192] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds described in Table 4.

[1193] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 4, as well as its prodrug and pharmaceutically acceptable salt.

[1194] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 4 and a pharmaceutically acceptable salt thereof.

[1195] In some embodiments, the compound is an isotopic derivative of any prodrug of the compounds described in Table 4 and a pharmaceutically acceptable salt thereof.

[1196] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 4.

[1197] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds described in Table 5.

[1198] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 5, as well as its prodrug and pharmaceutically acceptable salt.

[1199] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 5 and a pharmaceutically acceptable salt thereof.

[1200] In some embodiments, the compound is an isotopic derivative of any prodrug of the compounds described in Table 5 and a pharmaceutically acceptable salt thereof.

[1201] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 5.

[1202] In some embodiments, the compound is selected from compounds numbered 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, and pharmaceutically acceptable salts thereof.

[1203] In some embodiments, the compound is selected from compounds numbered 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.

[1204] In some embodiments, the compound is selected from compounds numbered 21, 59, 129, 144, 145, 154 and 175, and their pharmaceutically acceptable salts.

[1205] In some embodiments, the compound is selected from compounds numbered 21, 59, 129, 144, 145, 154 and 175.

[1206] In some embodiments, the compound is selected from compounds numbered 144, 154 and 175, and their pharmaceutically acceptable salts.

[1207] In some embodiments, the compound is selected from compounds numbered 144, 154 and 175.

[1208] In some embodiments, the compound is compound number 21 and its pharmaceutically acceptable salt. In some embodiments, the compound is compound number 21.

[1209] In some embodiments, the compound is compound number 59 and its pharmaceutically acceptable salt.

[1210] In some embodiments, the compound is compound number 129 and its pharmaceutically acceptable salt.

[1211] In some embodiments, the compound is compound number 144 and its pharmaceutically acceptable salt.

[1212] In some embodiments, the compound is compound number 145 and its pharmaceutically acceptable salt.

[1213] In some embodiments, the compound is compound number 154 and its pharmaceutically acceptable salt.

[1214] In some embodiments, the compound is compound number 175 and its pharmaceutically acceptable salt.

[1215] It should be understood that isotope derivatives can be prepared using any of a variety of techniques recognized in the art. For example, isotope derivatives can typically be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents and by performing the procedures disclosed in the schemes described herein and / or in the examples.

[1216] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[1217] In some embodiments, the isotope derivative is a deuterium-labeled compound of any of the various compounds disclosed herein.

[1218] As used herein, the term "isotope derivative" refers to a derivative of a compound in which one or more atoms are enriched or labeled with an isotope. For example, an isotope derivative of a compound of formula (I'), (I), (II), or (III) is isotopically enriched or labeled with one or more isotopes compared to the corresponding compound of formula (I'), (I), (II), or (III). In some embodiments, the isotope derivative is enriched or labeled with one or more atoms selected from... 2 H, 13 C 14 C 15 N、 18 O、 29 Si、 31 P and 34 S. In some embodiments, the isotope derivative is a deuterium-labeled compound (i.e., deuterium-labeled with respect to one or more atoms). 2 H enrichment). In some embodiments, the compound is 18 An F-labeled compound. In some embodiments, the compound is... 123 I-labeled compounds, 124 I-labeled compounds, 125 I-labeled compounds, 129 I-labeled compounds, 131 I-labeled compounds, 135 I-labeled compounds or any combination thereof. In some embodiments, the compound is... 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds,36 S-labeled compounds or any combination thereof.

[1219] It should be understood that any of a variety of techniques recognized in the art can be used to prepare 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and / or 36 S-labeled compounds. For example, by performing the procedures disclosed in the schemes described herein and / or in the examples, by using... 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S and / or 36 Deuterium-labeled compounds can usually be prepared by using S-labeled reagents instead of non-isotope-labeled reagents.

[1220] Containing the aforementioned 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and 36 One or more of the compounds of the present invention, or their pharmaceutically acceptable salts or solvates, containing the S atom 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 S) replacement may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements.

[1221] To avoid confusion, it should be understood that when a group is defined in this specification as “described herein”, the group includes the first and broadest definition and each and all of the specific definitions within that group.

[1222] Typically, various functional groups and substituents constituting compounds of formula (I'), (I), (II), or (III) are chosen such that the molecular weight of the compound does not exceed 1000 Daltons. More typically, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 Daltons. More conveniently, the molecular weight is less than 600, for example 550 Daltons or less.

[1223] Suitable pharmaceutically acceptable salts of the compounds disclosed herein are, for example, acid addition salts of the compounds of this disclosure that are sufficiently basic, such as acid addition salts formed with, for example, inorganic or organic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid). Furthermore, suitable pharmaceutically acceptable salts of the compounds of this disclosure that are sufficiently acidic are 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 provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tri-(2-hydroxyethyl)amine.

[1224] It should be understood that any compound of any kind disclosed herein and any pharmaceutically acceptable salt thereof includes stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compound.

[1225] As used in this article, "isomerism" refers to compounds with the same molecular formula but different atomic bonding sequences or spatial arrangements. Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are non-overlapping mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of enantiomers with opposite chirality is called a "racemic mixture."

[1226] As used in this article, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[1227] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having more than one chiral center may exist as individual diastereomers or as mixtures of diastereomers, referred to as "diastereomer mixtures." When a chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration indicates the spatial arrangement of substituents attached to the chiral center. Substituents connected to the chiral center under consideration were ordered according to the order rules of Cahn, Ingold, and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[1228] As used herein, the term "geometric isomer" refers to diastereomers that exist due to hindered rotation around a double bond or a cyclic hydrocarbon linker (e.g., 1,3-cyclobutyl). According to the Cahn-Ingold-Prelog rule, these configurations are distinguished by the prefixes cis and trans, or Z and E, indicating that the groups are located on the same or opposite sides of the double bond in the molecule.

[1229] It should be understood that the compounds of this disclosure may be described as different chiral or geometric isomers. It should also be understood that when 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 compound does not exclude any isomer. It should be understood that not all isomers may have the same level of activity.

[1230] It should be understood that the structures and other compounds discussed in this disclosure include all their transisomers. It should also be understood that not all transisomers possess the same level of activity.

[1231] The term "trans-isomer" as used in this article refers to a class of stereoisomers in which the atoms of the two isomers are arranged differently in space. The existence of trans-isomers is attributed to restricted rotation caused by the impeded rotation of the large group around the central bond. Such trans-isomers usually exist as mixtures, but due to recent advances in chromatographic techniques, mixtures of two trans-isomers can now be separated under certain conditions.

[1232] As used in this article, a "tautomer" is one of two or more structural isomers existing in equilibrium, and which readily transforms from one isomer to another. This transformation results in the migration of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer combinations in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert through tautomerization is called tautomerism. Of the various possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, simultaneous shifts of electrons and hydrogen atoms occur. Ring-chain tautomerism arises because the aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule to produce a cyclic (ring-like) form, as exhibited by glucose.

[1233] It should be understood that the compounds of this disclosure may be described as different tautomers. It should also be understood that when a compound has tautomer forms, all tautomer forms are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any tautomer form. It should be understood that some tautomers may have higher activity levels than others.

[1234] Compounds with the same molecular formula but different atomic bonding properties or sequences, or different spatial arrangements of atoms, are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, when it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetry center and described by the R- and S-ordering rules of Cahn and Prelog, or by rotating the molecular polarization plane and specifying them as dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as single enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[1235] The compounds of this disclosure may have one or more asymmetric centers; therefore, such compounds can be prepared as individual (R)- or (S)- stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include its single enantiomer and racemic or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolving the racemic form. Some compounds of this disclosure may have geometric isomer centers (E- and Z-isomers). It should be understood that this disclosure covers all optical diastereomers and geometric isomers and mixtures thereof with orexin-modifying activity.

[1236] This disclosure also includes compounds as defined herein that contain one or more isotope substitutions.

[1237] It should be understood that any compound of any kind described herein includes the compound itself, as well as, where applicable, their salts and their solvates. For example, salts can be formed between anion and a positively charged group (e.g., amino group) on the substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, hydrogen sulfate, aminosulfonate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[1238] 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 carboxyl group) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations such as tetramethylammonium or diethylamine ions. The substituted compounds disclosed herein also include those salts containing a quaternary nitrogen atom.

[1239] It should be understood that the compounds of this disclosure, such as salts of the compounds, may exist in hydrated or non-hydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[1240] As used herein, the term "solvent" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in their crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcohol. A hydrate is formed by the combination of one or more water molecules with a substance molecule, wherein the water retains its molecular state as H₂O.

[1241] As used herein, the term "analogue" refers to a compound that is structurally similar to another but has a slightly different composition (e.g., by substitution of an atom with an atom of a different element, or in the presence of a specific functional group, or by the substitution of one functional group by another). Therefore, an analogue is a compound that is functionally similar or equivalent in appearance but differs from the reference compound in structure or origin.

[1242] As used in this article, the term "derivative" refers to compounds that share a common core structure and are substituted by various groups as described herein.

[1243] As used herein, the term "bioisostere" refers to a compound resulting from the exchange of one atom or group of atoms with another substantially similar atom or group of atoms. The aim of bioisostere substitution is to create a new compound with biological properties similar to the parent compound. Bioisostere substitution can be based on physicochemical or topological principles. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazolium, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[1244] It should also be understood that certain compounds of any of the formulas disclosed herein may exist in both solvated and unsolvated forms, such as, for example, hydrated forms. Suitable pharmaceutically acceptable solvates are, for example, hydrates such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that this disclosure includes all such solvated forms having orexin-regulating activity.

[1245] It should also be understood that certain compounds of any of the formulas disclosed herein may exhibit polymorphism, and this disclosure includes all such forms or mixtures thereof possessing orexin-regulating activity. It is generally known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (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.

[1246] Compounds of any of the formulas disclosed herein may exist in many different tautomeric forms, and references to compounds of formula (I'), (I), (II), or (III) include all such forms. For the avoidance of confusion, where a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all other forms are still included by formula (I'), (I), (II), or (III). Examples of tautomeric forms include ketone-, enol-, and enolide- forms, such as in, for example, the following tautomeric pairs: ketone / enol (exemplified below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / acid nitro.

[1247]

[1248] Compounds containing any of the formulas disclosed herein, which contain amine functional groups, can also form N-oxides. Compounds of formula (I'), (I), (II), or (III) containing amine functional groups mentioned herein also include N-oxides. In the case where a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms in nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Jerry March, Advanced Organic Chemistry, 4th ed., Wiley Interscience, p. 1000. More specifically, N-oxides can be prepared by LWDeady's procedure (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example in an inert solvent such as dichloromethane.

[1249] Compounds of any of the formulas disclosed herein can be administered as prodrugs, which decompose in humans or animals to release the compounds of this disclosure. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of this disclosure. Prodrugs can be formed when the compounds of this disclosure contain suitable groups or substituents (to which modifying groups may be attached). Examples of prodrugs include derivatives of any of the formulas disclosed herein containing in vivo cleavable alkyl or acyl substituents at the ester or amide group.

[1250] Therefore, this disclosure includes compounds of any of the formulas disclosed herein as defined above, whether obtained by organic synthesis or obtained in humans or animals by cleavage of their prodrugs. Thus, this disclosure includes compounds of any of the formulas disclosed herein produced by organic synthesis, and compounds produced in humans or animals by the metabolism of prodrug compounds, i.e., compounds of any of the formulas disclosed herein can be synthetically produced or metabolically produced compounds.

[1251] A suitable pharmaceutically acceptable prodrug of any of the compounds disclosed herein is one that, based on reasonable medical judgment, is suitable for administration to humans or animals without undesirable pharmacological activity and without undue toxicity. Various forms of prodrugs have been described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309–396, eds. K. Widder et al. (Academic Press, 1985); b) Design of Pro-drugs, ed. H. Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, eds. Krogsgaard-Larsen and H. Bundgaard, Chapter 5, “Design and Application of Pro-drugs,” H. Bundgaard, pp. 113–191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1–38 (1992); e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Vol. 14; and h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[1252] Suitable pharmaceutically acceptable prodrugs of compounds having a hydroxyl group in any of the formulas disclosed herein are, for example, esters or ethers that are cleavable in vivo. Suitable pharmaceutically acceptable ester-forming groups of compounds containing a hydroxyl group in any of the formulas disclosed herein are, for example, pharmaceutically acceptable esters or ethers that are cleavable in vivo in a human or animal body to produce a parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups of the hydroxyl group include inorganic esters such as phosphate esters (including phosphoramide cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups of the hydroxyl group include C1-C1 esters. 10 Alkyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, C1-C 10 Alkoxycarbonyl groups include ethoxycarbonyl, N,N-(C1-C6 alkyl)2-carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Examples of cyclic substituents on the 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 neopentyloxymethyl.

[1253] Suitable pharmaceutically acceptable prodrugs of compounds having a carboxyl group of any of the formulas disclosed herein are, for example, amides that are cleavable in vivo, such as amides formed with amines such as ammonia, C1-4 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.

[1254] Suitable pharmaceutically acceptable prodrugs of compounds having an amino group of any of the formulas disclosed herein are, for example, amide derivatives that are cleavable in vivo. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, those with C1-C2 groups. 10 Alkyl groups include acetyl, benzoyl, phenylacetyl, and amides formed by substituted benzoyl and phenylacetyl groups. Examples of cyclic 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.

[1255] The in vivo effects of any compound of any formula disclosed herein may be exerted in part by one or more metabolites formed in a human or animal following administration of any compound of any formula disclosed herein. As described above, the in vivo effects of any compound of any formula disclosed herein may also be exerted through the metabolism of a prodrug.

[1256] As appropriate, this disclosure excludes any individual compound that does not have the biological activity defined herein.

[1257] Synthesis method

[1258] In some respects, this disclosure provides a method for preparing the compounds of this disclosure.

[1259] In some respects, this disclosure provides a method for preparing a compound, comprising one or more steps as described herein.

[1260] In some respects, this disclosure provides compounds that are obtainable, acquired, or directly obtained by methods used to prepare compounds as described herein.

[1261] In some respects, this disclosure provides intermediates as described herein, which are suitable for use in methods for preparing compounds as described herein.

[1262] The compounds of this disclosure can be prepared using any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying examples.

[1263] In the description of the synthetic methods described herein and any reference synthetic methods used to prepare the starting materials, it should be understood that all suggested reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration and post-treatment procedures, can be selected by those skilled in the art.

[1264] Those skilled in the field of organic synthesis will understand that the functional groups present on various parts of a molecule must be compatible with the reagents and reaction conditions used.

[1265] It should be understood that in the process of synthesizing the compounds disclosed herein using the methods defined herein, or in the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent them from reacting undesirably. A skilled chemist will understand when such protection is necessary, and how such protecting groups can be placed and subsequently removed. For examples of protecting groups, see one of the many general texts on the subject, such as Theodora Green's "Protective Groups in Organic Synthesis" (published by John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to a skilled chemist suitable for removing the protecting groups in question, choosing such a method to achieve the removal of the protecting groups with minimal interference to groups elsewhere in the molecule. Therefore, if the reactants include, for example, groups such as amino, carboxyl, or hydroxyl groups, it may be necessary to protect these groups in some of the reactions mentioned herein.

[1266] As examples, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups like acetyl groups, alkoxycarbonyl groups like methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl groups, arylmethoxycarbonyl groups like benzyloxycarbonyl groups, or aromatic acyl groups like benzoyl groups. The deprotection conditions for these protecting groups necessarily vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl, alkoxycarbonyl, or aromatic acyl groups can be removed by hydrolysis, for example, with a suitable base (such as an alkali metal hydroxide, such as lithium hydroxide or sodium hydroxide). Alternatively, acyl groups such as tert-butoxycarbonyl groups can be removed, for example, by treatment with a suitable acid (such as hydrochloric acid, sulfuric acid, or phosphoric acid or trifluoroacetic acid), and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed, for example, by hydrogenation with a catalyst (such as carbon-supported palladium) or by treatment with a Lewis acid such as tri(trifluoroacetic acid)boron. Suitable alternative protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with alkylamines (e.g., dimethylaminopropylamine) or with hydrazine.

[1267] Suitable protecting groups for the hydroxyl group are, for example, acyl groups, such as alkanoyl groups like acetyl, aromatic acyl groups like benzoyl, or arylmethyl groups like benzyl. The deprotection conditions for these protecting groups necessarily vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl or aromatic acyl groups can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide) or ammonia. Alternatively, arylmethyl groups such as benzyl can be removed by hydrogenation, for example, via a catalyst (e.g., palladium supported on carbon).

[1268] Suitable protecting groups for the carboxyl group are, for example, esterification groups, such as methyl or ethyl, which can be removed by hydrolysis, for example, with a base (such as sodium hydroxide), or, for example, tert-butyl, which can be removed by treatment with an acid (such as an organic acid such as trifluoroacetic acid), or, for example, benzyl, which can be removed by hydrogenation, for example, with a catalyst (such as carbon-supported palladium).

[1269] Once a compound of formula (I'), formula (I), formula (II), or formula (III) has been synthesized by any of the methods defined herein, the method may further include the following additional steps: (i) removing any protecting groups present; (ii) converting a compound of formula (I'), formula (I), formula (II), or formula (III) into another compound of 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.

[1270] Compounds of formula (I'), (I), (II), or (III) can be isolated and purified using techniques well known in the art.

[1271] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under its respective reaction conditions. Examples of suitable solvents include, but are not limited to, hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE), or dioxane; ethylene glycol ethers, Such as ethylene glycol monomethyl ether or monoethyl ether or ethylene glycol dimethyl ether (diethylene glycol dimethyl ether); ketones such as acetone, methyl isobutyl ketone (MIBK) or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate, or mixtures of said solvents or mixtures with water.

[1272] The reaction temperature is appropriately between about -100°C and 300°C, depending on the reaction steps and the conditions used.

[1273] Reaction times typically range from less than a minute to several days, depending on the reactivity of the various compounds and the reaction conditions. Suitable reaction times can be readily determined using methods known in the art, such as reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally range from 10 minutes to 48 hours.

[1274] Furthermore, other compounds of this disclosure can be readily prepared using the procedures described herein in conjunction with common techniques in the art. Those skilled in the art will readily understand that these compounds can be prepared using known modifications to the conditions and methods of the following preparation procedures.

[1275] As those skilled in the art of organic synthesis will understand, the compounds of this disclosure can be readily obtained by a variety of synthetic routes, some of which are illustrated by way of example in the accompanying examples. Those skilled in the art will readily recognize which reagents and reaction conditions to use and how to apply and modify them in any particular case (whenever necessary or useful) to obtain the compounds of this disclosure. Furthermore, some compounds of this disclosure can be readily synthesized by reacting other compounds of this disclosure under suitable conditions, for example, by applying standard synthetic methods such as reduction, oxidation, addition, or substitution reactions, to convert a particular functional group present in a compound of this disclosure or a suitable precursor molecule into another; these methods are well known to those skilled in the art. Likewise, those skilled in the art will apply (whenever necessary or useful) synthetic protecting (or protective) groups; suitable protecting groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in PGM Uts, TW Greene, “Greene’s Protective Groups in Organic Synthesis,” 4th edition (2006) (John Wiley & Sons).

[1276] The general route for preparing the compounds of this application is described in Scheme 1 herein.

[1277] According to the method shown in Scheme 1 below, compound I (which is a compound of formula (I'), (I), (II) and (III), where Z = NH) can be prepared from commercially available and known compound A, in which P1 is a protecting group and X represents various leaving groups known in the art. Examples of the protecting group P1 for amino groups include, but are not limited to, urethane-type protecting groups such as tert-butyl urethane. Examples of leaving groups X include halogens, particularly bromine or iodine, or sulfonates such as methyl sulfonate.

[1278] Option 1

[1279]

[1280] Compound C can be generated by reacting compound A with compound B in the presence of a base via a nucleophilic substitution reaction. Examples of bases include, but are not limited to, lithium amide. Alternatively, compound C can also be generated by converting it to the corresponding enamine, and then reacting said enamine with compound B. Examples of amines that can be used for enamine formation include, but are not limited to, pyrrolidine.

[1281] Compound D can be generated by reductive amination of compound C. Examples of amines 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. Furthermore, a metal catalyst can be added to the reaction system. Examples of catalysts to be used include, but are not limited to, iridium catalysts.

[1282] Compound F can be generated by sulfonating compound D with compound E in the presence of a base. Compound E may be commercially available or can be generated by known methods. Examples of bases to be used include, but are not limited to, organic bases such as tertiary alkylamines such as N,N-diisopropylethylamine.

[1283] Compound G can be prepared by subjecting compound F to a deprotection reaction to remove the protecting group P1. The specific deprotection reaction will depend on the choice of the protecting group. For example, when P1 is tert-butyl carbamate, deprotection can be achieved by treatment with an acid such as hydrochloric acid or trifluoroacetic acid.

[1284] Compound I can be prepared by condensing compound G and compound H. Examples of compound H include, but are not limited to, acyl halides such as acyl chlorides, alkyl chloroformates, carbamoyl chlorides, etc.; activated carboxylic acids such as acid anhydrides, activated esters, etc. Examples of activators of carboxylic acids include, but are not limited to, carbodiimide condensing agents, carbonate condensing agents such as 1,1-carbonyldiimidazole (CDI), benzotriazol-1-yloxy-tris(dimethylaminophosphonium) salt (BOP reagent), alkyl chloroformates; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureon hexafluorophosphate (HATU), etc. When using a condensing agent, additives such as 1-hydroxybenzotriazole (HOBt) or dimethylaminopyridine (DMAP) can be added to the reaction system.

[1285] Compound I obtained by the above methods can be separated and purified by known methods (e.g., solvent extraction, phase transfer, crystallization, chromatography, etc.).

[1286] When compound I contains optical isomers, stereoisomers, and rotatable isomers, these compounds are also included in compound I, and each can be obtained by synthetic or separation methods. For example, when an optical isomer is present in compound I, the optical isomer separated from said compound is also included in compound I.

[1287] Biological assay

[1288] Once compounds designed, selected, and / or optimized using the methods described above are generated, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds possess biological activity. For example, the molecules can be characterized by conventional assays, including, but not limited to, those described below, to determine whether they possess predicted activity, binding activity, and / or binding specificity.

[1289] Furthermore, high-throughput screening can be used to accelerate analyses using such assays. Therefore, the activity of molecules described herein can be rapidly screened using techniques known in the art. General methods 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 can be performed using one or more different assay techniques, including, but not limited to, those described below.

[1290] Various in vitro or in vivo biological assays can be applied to detect 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 variation assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[1291] Despite the loss of orexinocytes and reduction of orexin peptides in the cerebrospinal fluid within NT1, the orexin receptors on postsynaptic neurons remain intact, making them suitable targets for pharmacological intervention. Orexin peptides A and B (OXA and OXB) can be cleaved from a single precursor molecule (proorexinogen) produced only in the lateral hypothalamus. Both orexin peptides bind to OX2R with similar high affinity, but the orexin-1 receptor (OX1R) is preferentially bound to OXA. Postsynaptic activation of these G protein-coupled orexin receptors stimulates the release of monoaminergic and cholinergic neurotransmitters that promote wakefulness and inhibitory neurotransmitters that suppress REM sleep relaxation.

[1292] In some implementations, the biological assays are described in the embodiments herein.

[1293] The biological activity of the compounds of this disclosure can be determined in cells that stably express orexin type 2 or orexin type 1 receptors. The activity can be measured in cells to which the compounds of this disclosure have been administered (e.g., Chinese hamster ovary (CHO) cells expressing human orexin type 2 receptor (hOX2R) or human orexin type 1 receptor (hOX1R)). The agonist activity of the compounds of this disclosure can be determined by fluorescence values.

[1294] The arousal-promoting potency of the compounds of this disclosure can be evaluated in models such as the B6.Cg-Tg(HCRT-MJD)1Stak / J(Atax) mouse model of NT1 and wild-type (WT) colony mates. Following administration of the compounds of this disclosure (e.g., orally), rapid, non-invasive classification of sleep and arousal in the models (e.g., mouse models) can be monitored by unsupervised machine learning of physiologically relevant readouts such as body movement and respiratory rate.

[1295] Pharmaceutical Composition

[1296] In some aspects, this disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, this disclosure provides a pharmaceutical composition comprising at least one compound of the various types described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, this disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[1297] The term “composition” as used herein is intended to include products containing specified amounts of specified ingredients, and any products directly or indirectly produced from combinations of specified amounts of specified ingredients.

[1298] The compounds of this disclosure can be formulated for oral administration in forms such as tablets, capsules (each including sustained-release or time-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., patch) administration, all in forms well known to those skilled in the pharmaceutical art.

[1299] The formulations disclosed herein may be in the form of an aqueous solution comprising an aqueous medium. The aqueous medium component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from: solubilizers, chelating agents, preservatives, tensioning agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[1300] Any suitable solubilizer can be used. Examples of solubilizers include cyclodextrins, such as those selected from: hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated β-cyclodextrin, ethylated β-cyclodextrin, triacetyl-β-cyclodextrin, fully acetylated β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonium)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfonyl ether, branched-chain β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated γ-cyclodextrin and trimethyl-γ-cyclodextrin, and mixtures thereof.

[1301] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the following: ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate and tetrasodium edetate and mixtures thereof.

[1302] Any suitable preservative may be used. Examples of preservatives include those selected from the following: quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzyl chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide, and butylparaben and sorbic acid, and mixtures thereof.

[1303] The aqueous medium may also include a tensioning agent to adjust the tension (osmotic pressure). The tensioning agent may be selected from glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerol, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[1304] The aqueous medium may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from: cellulose derivatives, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropyl methylcellulose, and crosslinked acrylic polymers (carbomers), such as acrylic polymers crosslinked with polyolefin ethers or divinyl glycol (carbomers—such as carbomer 934, carbomer 934P, carbomer 971, carbomer 974 and carbomer 974P) and mixtures thereof.

[1305] To adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically an inorganic acid or a metal hydroxide base selected from 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 an acceptable target pH range. Therefore, it may not be necessary to use both an acid and a base simultaneously—depending on the formulation, adding either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[1306] The aqueous medium may also contain a buffer to stabilize the pH. When used, the buffer is selected from the following: phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts, including disodium tetraborate), citrate buffers (such as citric acid or its salts, including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[1307] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from: polyoxypropylene-polyoxyethylene block copolymers (poloxam), polyethoxylated ethers of castor oil, polyoxyethylene-modified sorbitol esters (polysorbates), oxyethylated octylphenol polymers (teroxam), polyoxyethylene 40 stearate, ethylene glycol esters of fatty acids, glyceryl esters of fatty acids, sucrose fatty acid esters and polyoxyethylene fatty acid esters, and mixtures thereof.

[1308] Oral compositions typically comprise an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be blended with excipients and used in tablet, lozenge, or capsule form. Oral compositions may also be prepared using a liquid carrier for use as a mouthwash, wherein the compound in the fluid carrier is administered orally and by rinsing and spitting or swallowing. Pharmaceutically compatible binders and / or excipients may be included as part of the composition. The tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginate, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; gliding agents such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[1309] According to another aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[1310] The compositions disclosed herein may be in forms suitable for use as follows: oral administration (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical administration (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as finely pulverized powders or liquid aerosols), administration by blowing (e.g., as finely pulverized powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[1311] The compositions of this disclosure can be obtained through conventional procedures using conventional pharmaceutical excipients, as is well known in the art. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[1312] An effective amount of the compound disclosed herein used in a therapy is sufficient to treat or prevent the orexin-related conditions mentioned herein, slow their progression, and / or alleviate symptoms associated with the conditions.

[1313] An effective amount of the compound disclosed herein for use in a therapy is sufficient to treat the orexin-related disorders mentioned herein, slow their progression, and / or alleviate symptoms associated with the disorders.

[1314] The dosage of compounds of formula (I'), (I), (II), or (III) used for therapeutic or preventative purposes will naturally vary according to well-known medical principles, the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration. ...

Claims

1. Compounds of formula (I”'): (I”’) Or its pharmaceutically acceptable salt, wherein: X is -C(R X1 )₃, -OR X2 or -N(R X2 )₂; Y is -CH2-; Z is -NH-; Each R X1 Independently, it can be 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 membered heterocyclic alkyl group. Or two Rs X1 Together with the atoms they are attached to, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon groups or heterocyclic hydrocarbon groups are optionally substituted with 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 groups. Or three Rs X1 Together with the atoms they are attached to, they form C4-C 10 Cycloalkyl group, wherein the cycloalkyl group is optionally substituted with 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 R X2 Independently, it is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic hydrocarbon group, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocyclic hydrocarbon group is optionally substituted with one or more halogens, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic hydrocarbon group. Or two Rs X2 Together with the atoms to which they are attached, they form 3-7 membered heterocyclic hydrocarbon groups, wherein the heterocyclic hydrocarbon groups are optionally 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. Ar1 is a phenyl group optionally 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, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, 5-10 heteroaryl, C3-C7 cycloalkyl, 3-7 heterocyclic alkyl, -NH-(C6-C 10 aryl), -NH-(5-10 heteroaryl), -NH-(C3-C 10 (-cycloalkyl group) or -NH- (3-7 membered heterocyclic alkyl group), wherein the alkyl, alkenyl, heteroaryl, cycloalkyl group and heterocyclic alkyl group are optionally separated by one or more R groups. 1S replace; Each R 1S It is independently a halogen, -CN, -OH, -O-(CH2)2-OC1-C6 alkyl, C1-C6 alkyl, or C1-C6 alkoxy; R2 is optionally divided by one or more R 2S Substituted phenyl; Each R 2S It is independently a halogen, -CN, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; Each R3 is independently a halogen, -CN, C1-C6 alkyl, or C 1-6 Alkoxy; R 4a It is H; R 4b It is H; and n is 1 or 2.

2. The compound according to claim 1, wherein Z is -NH- and R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 membered heteroaryl, C3-C7 cyclic hydrocarbon, 3-7 membered heterocyclic hydrocarbon, -NH-(C3-C 10 (cyclic hydrocarbon group) or -NH- (3-7 membered heterocyclic hydrocarbon group), wherein the alkyl, heteroaryl, cyclic hydrocarbon group and heterocyclic hydrocarbon group are optionally surrounded by one or more R groups. 1S Replace; and Each R 1S It is independently a halogen, -CN, -OH, or C1-C6 alkoxy group.

3. The compound according to any one of claims 1-2, wherein X is -C(R) X1 )3 or -N(R X2 )2.

4. The compound according to any one of claims 1-2, wherein X is -OR X2 .

5. The compound according to claim 1, wherein X is , -O (methyl) , , , , , , , , , , , , , , , , , , , , , , or .

6. The compound according to any one of claims 1-2, wherein each R X1 Independently, it is 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.

7. The compound according to any one of claims 1-2, wherein the two Rs X1 Together with the atoms to which they are attached, they form C3-C7 cyclic hydrocarbon groups or 3-7 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon groups or heterocyclic hydrocarbon groups are optionally substituted by 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.

8. The compound according to any one of claims 1-2, wherein each R X2 It is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl or C1-C6 haloalkyl.

9. The compound according to any one of claims 1-2, wherein the two Rs X2 Together with the atoms to which they are attached, they form 3-7 membered heterocyclic hydrocarbon groups, wherein the heterocyclic hydrocarbon groups are optionally 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. The compound according to claim 1, wherein R1 is a C1-C6 alkyl or a C1-C6 haloalkyl.

11. The compound according to claim 1, wherein R1 is methyl, isopropyl, ethyl, -CF3, -CHF2, CH2F, -CF2CH3, -CF(CH3)2, cyclopropyl, or fluorocyclopropyl.

12. The compound according to any one of claims 1-2, wherein each R 1S It is halogen.

13. The compound according to any one of claims 1-2, wherein each R 1S It is independently a C3-C7 cyclic hydrocarbon group or a 3-7 membered heterocyclic hydrocarbon group.

14. The compound according to any one of claims 1-2, wherein each R3 is independently a halogen or -CN.

15. The compound according to claim 1, wherein the compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and And its pharmaceutically acceptable salts.

16. The compound according to claim 1, wherein the compound is selected from: , , , , , and And its pharmaceutically acceptable salts.

17. A pharmaceutical composition comprising a compound according to any one of claims 1-15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

18. The pharmaceutical composition according to claim 17, wherein the compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , and .

19. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-16 in the preparation of a medicament for modulating orexin-2 receptor activity.

20. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-16 in the preparation of a medicament for treating or preventing a disease or disorder, wherein the disease or disorder is associated with an orexin-2 receptor.

21. The use according to claim 20, wherein the disease or disorder is narcolepsy, excessive sleep disorder, neurodegenerative disorder, neurological disorder, symptoms of rare genetic disorder, psychiatric disorder, mental health disorder, circadian rhythm disorder, metabolic syndrome, osteoporosis, heart failure, coma, or promoting anesthesia recovery.

22. The use according to claim 20, wherein the disease or disorder is narcolepsy, idiopathic hypersomnia, or sleep apnea.

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