Pharmaceutical compositions comprising phenylsulfonamides and their therapeutic applications

Abstract

To provide compounds and pharmaceutical compositions for treating, preventing, or ameliorating one or more symptoms of neurodegenerative diseases.SOLUTION: A compound for the treatment of one or more symptoms of a neurodegenerative condition in a subject, wherein the compound is selected from the group consisting of 4 - (N - (3 - (methylsulfonamido) phenyl) sulfamoyl) benzoic acid; 3 - (N - (2-methyl-5 - (trifluoromethyl) phenyl) sulfamoyl) benzoic acid; 3 - (N - (3, 5-dimethoxyphenyl) sulfamoyl) benzoic acid; 3 - ((2-methoxy-5-nitrophenyl) sulfonamido) - 4-methylbenzoic acid; or 2-fluoro-4 - (N - (3 - (methylsulfonamido) phenyl) sulfamoyl) benzoic acid, or an enantiomer, tautomer, Or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Application No. 62 / 615,869, filed January 10, 2018. The benefit of priority is claimed, the disclosure of which is incorporated herein by reference in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made in part with funds awarded by the National Institutes of Health, R43AG05518 and R44AG0 This invention was made with government support under Patent Application No. 55182. The government has certain rights in this invention.

[0003] As used herein, phenylsulfonamide, or its enantiomer, enantiomer mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers mixtures, or isotopic variants; or pharmaceutically acceptable salts, solvates thereof , hydrate, or prodrug; and a pharmaceutical composition comprising a pharmaceutically acceptable excipient, Also provided herein are compositions for treating one or more symptoms of a disorder, disease, or condition. Methods for their use to treat, prevent, or ameliorate diseases are provided. [Background technology]

[0004] Alzheimer's disease (AD), a chronic neurodegenerative disease, is the most common cause of dementia. Ru. Ballard et al.,Lancet.2011,377,1019-10 31;Kumar and Walter,Aging 2011,3,803-812 ;Masters et al.,Nat.Rev.Dis.Primers 201 5,1,15056;Frigerio and Strooper,Annu.Rev Neurosci.2016,39,57-79. AD is a condition that affects the brain and regulates memory and mental functions. It is caused by abnormal deposition of proteins in the brain that destroy cells in certain areas of the brain. Ru. Ballard et al.,Lancet.2011,377,1019-10 31;Masters et al.,Nat.Rev.Dis.Primers 2 015,1,15056. Accumulation of amyloid β-peptide (Aβ) drives its progression. Aβ peptides cause plaque-like deposits in the brain. These build up gradually and progressively as a result of an imbalance in their production and clearance. Only when neuronal loss progresses and reaches a certain threshold do clinical symptoms of AD appear. Because Aβ accumulation occurs gradually over time, it is difficult for patients to detect any clear signs of the disease. It may take 10 to 20 years before it begins to show obvious signs.

[0005] The most common early symptom of AD is difficulty remembering recent events. Symptoms may then include problems with speech, disorientation, mood swings, and behavioral problems. People with this disorder may forget important people in their lives and experience dramatic personality changes. It can even be experienced as a progressive loss of bodily functions and ultimately death. The speed of diagnosis can vary, but the average life expectancy after diagnosis is 3 to 9 years. al., Nat. Rev. Dis. Primers 2015,1,15056.

[0006] Current AD medications may improve some of the symptoms of the disease. Ibid. However, currently, There is no cure for AD. Therefore, there is a need to develop effective treatments to treat AD. There is an unmet need. Summary of the Invention

[0007] As used herein, compounds of formula I: [ka] or its enantiomer, mixture of enantiomers, mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or or their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; and Pharmaceutical compositions comprising excipients acceptable to (In the formula: X is -SO2- and Y is -NR X or X is -NR X - and Y is -SO2-; Each R 1 are independently (a) cyano, halo, or nitro; (b) C 1-6 Al Kill, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-1 4 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c)-C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O) SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a、-OC(O)OR 1a 、 -OC(O)NR 1b R 1c 、-OC(O)SR 1a 、-OC(=NR 1a )NR 1b R 1c 、-OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1c 、-O S(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2 NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)O R 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(O)SR 1d 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR 1a C(S)OR 1d 、-NR 1a C(S)NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S( O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1 c, -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S (O)2NR 1b R 1c and; R 2 , R 5 , R 6 , and R X are each independently (a) hydrogen, deuterium, cyano, b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkini Lu, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, Heteroa aryl, or heterocyclyl; or (c) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -O C(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)S R 1a , -OC(=NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R1a , -O S(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1 a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(=NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c ,- NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and; R 3 is (a) cyano, halo, or nitro; (b) C 1-6 Alkyl, C 2-6 a Lukenil, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C6-14 Aryl, C7 -15 aralkyl, heteroaryl, or heterocyclyl; or (c)—C(O) R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C( NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1 b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(=NR 1a )NR 1b R 1c , -OC(S )R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1 a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(=NR1d ) NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d ,- NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and; R 4 is hydrogen, deuterium, cyano, or fluoro; Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 a Lukil, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6- 14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl ; or R 1a and R 1c together with the C and N atoms to which they are attached form heterocyclic groups. Forming a cyclyl; or R 1b and R 1c together with the N atoms to which they are attached. to form a heterocyclyl; m is an integer of 0, 1, 2, 3, or 4; Each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, Heteroaryl and heterocyclyl may be one or more, in one embodiment 1, 2, 3 or or four substituents Q (each Q is independently selected from the group consisting of: (a) deuterium, cyano, halo, and nitro) ;(b)C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Shik Roalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heteroaryl cyclyl (each of which has one or more, in one embodiment 1, 2, 3, or 4, substituents) Substituent Q a and (c) -C(O)R a , -C(O) OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C( S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a ,- OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(=NR a ) NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b Rc , -OS (O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)N R b R c , -NR a C(O)SR d , -NR a C(=NR d )NR b R c , -NR a C( S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S (O)2NR b R c (Each R a , R b , R c , and R d are independently: (i) hydrogen or (ii) C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl (each of which may be one or more, in one embodiment, 1, 2, 3 , or four substituents Q a (iii) R b and R c together with the N atoms to which they are attached, represent one or more, in one embodiment, , 2, 3, or 4 substituents Q a forming an optionally substituted heterocyclyl) optionally substituted with (selected from the group consisting of Each Q a are independently: (a) deuterium, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C6 -14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR fR g 、-O C(O)SR e 、-OC(=NR e )NR f R g 、-OC(S)R e 、-OC(S)OR e 、-OC(S)NR f R g 、-OS(O)R e 、-OS(O)2R e 、-OS(O)N R f R g 、-OS(O)2NR f R g 、-NR f R g 、-NR e C(O)R h 、-NR e C(O)OR f 、-NR e C(O)NR f R g 、-NR e C(O)SR f 、-NR e C( =NR h )NR f R g 、-NR e C(S)R h 、-NR e C(S)OR f 、-NR e C( S)NR f R g 、-NR e S(O)R h 、-NR e S(O)2R h 、-NR e S(O)N R f R g 、-NR e S(O)2NR f R g 、-SR e 、-S(O)R e 、-S(O)2R e 、-S(O)NRf R g , and -S(O)NR f R g (Each R e , R f , R g , and BiR h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) )R f and R g together with the N atom to which they are attached form a heterocyclyl provided is a compound selected from the group consisting of:

[0008] Also provided herein is a method for detecting a disorder, disease, or condition in a subject, in one embodiment, a neurodegenerative disorder. 1. A method for treating a sexual disorder comprising administering to a subject a compound of formula I, or an enantiomer thereof, mixture of two or more diastereomers, tautomers, mixture of two or more tautomers or a pharmaceutically acceptable salt or solvent thereof. administering to a subject a therapeutically effective amount of a solute, hydrate, or prodrug thereof. Provided.

[0009] Further provided herein is a method of inhibiting amyloid beta production in a subject, comprising administering to a subject a compound of formula Compound I, or its enantiomers, mixtures of enantiomers, two or more diastereomeric Mixtures of tautomers, tautomers, mixtures of two or more tautomers, or isotopic barriers or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof to a subject.

[0010] Provided herein is a method for reducing amyloid beta levels in a subject, comprising administering a compound of Formula I or its enantiomer, mixture of enantiomers, two or more diastereomers mixtures, tautomers, mixtures of two or more tautomers, or isotopic variants; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. The method includes administering to a subject a therapeutically effective amount of

[0011] Provided herein is a method for inhibiting amyloid-beta production in a cell, comprising administering to a subject a compound of Formula I a substance, or its enantiomer, a mixture of enantiomers, or two or more diastereomers mixtures of tautomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. A method is provided, comprising contacting a cell with

[0012] Provided herein is a method for reducing amyloid-beta-induced signaling activity in a subject. Thus, a compound of formula I, or an enantiomer thereof, a mixture of enantiomers, or two or more Mixtures of diastereomers, tautomers, mixtures of two or more tautomers, or isomers or a pharmaceutically acceptable salt, solvate, hydrate, or protease thereof. Methods are provided that include administering to a subject a therapeutically effective amount of a drug.

[0013] Provided herein is a method of inhibiting the production of tau protein in a subject, comprising administering to a subject a compound of Formula I or its enantiomer, mixture of enantiomers, two or more diastereomers mixtures, tautomers, mixtures of two or more tautomers, or isotopic variants; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the method comprises administering to a subject a therapeutically effective amount of a tau protein. In another embodiment, the tau protein is hyperphosphorylated. It is oxidized tau protein.

[0014] Provided herein is a method of reducing tau protein levels in a subject, comprising administering to a subject a compound of formula I A compound, or its enantiomer, a mixture of enantiomers, two or more diastereomeric mixture of tautomers, tautomers, mixture of two or more tautomers, or isotopic variants or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof In one embodiment, a method is provided comprising administering to a subject a therapeutically effective amount of tautan. In another embodiment, the protein level is a phosphorylated tau protein level. Protein levels are hyperphosphorylated tau protein levels.

[0015] Provided herein is a method for inhibiting the production of tau protein in a cell, comprising administering to a patient a compound of Formula I or its enantiomer, mixture of enantiomers, two or more diastereomers mixtures, tautomers, mixtures of two or more tautomers, or isotopic variants; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, a method is provided comprising contacting a cell with an amount of tau protein. is a phosphorylated tau protein. In another embodiment, the tau protein is hyperphosphorylated It is tau protein.

[0016] Provided herein are methods for reducing tau protein-induced signaling activity in a subject. a compound of formula I, or an enantiomer thereof, a mixture of two or more enantiomers thereof a mixture of diastereomers, tautomers, a mixture of two or more tautomers, or or a pharmaceutically acceptable salt, solvate, hydrate, or protease thereof. The method includes administering to a subject a therapeutically effective amount of a prodrug. [Brief explanation of the drawings]

[0017] [Figure 1] 1 shows the effect of compounds A1-A4 on the levels of amyloid beta 40 (Aβ40) in neurons after 24 hours of treatment.

[0018] [Figure 2] 1 shows the effect of compounds A1-A3 on the levels of amyloid β42 (Aβ40) in neurons after 24 hours of treatment. DETAILED DESCRIPTION OF THE INVENTION

[0019] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0020] Generally, the nomenclature used herein and the nomenclature used in organic chemistry, medicinal chemistry, biochemistry, and the like described herein Laboratory procedures in biology, biology, and pharmacology are well known and commonly used in the art. Unless otherwise defined, all techniques used herein are Technical and scientific terms are generally understood by one of ordinary skill in the art to which this disclosure belongs. has the same meaning as that given in the preceding sentence.

[0021] The term "subject" refers to a primate (e.g., a human), a cow, a pig, a sheep, a goat, a horse, a dog, The term " refers to an animal, including but not limited to a cat, rabbit, rat, or mouse. "Subject" and "patient" are used herein to refer to a mammalian subject, e.g., a human subject. are used interchangeably herein. In one embodiment, the subject is a human.

[0022] The terms "treat," "treating," and "treatment" refer to a disorder, disease, or condition, or or alleviating or abolishing one or more symptoms associated with a disorder, disease, or condition; or to alleviate or eradicate the cause(s) of the disorder, disease, or condition itself. It means to include.

[0023] The terms "prevent," "preventing," and "prevention" refer to the prevention of a disorder, disease, or condition, and / or delay and / or prevent the onset of its associated symptoms; to prevent a subject from acquiring a disorder, disease, or condition; or to prevent a subject from acquiring a disorder, disease, or condition This is meant to include methods to reduce the risk of such conditions.

[0024] The terms "alleviate" and "alleviating" refer to the alleviation of one or more symptoms of a disorder, disease, or condition. The term also refers to the alleviation or relief of a condition (e.g., pain) associated with an active ingredient. Sometimes, the benefit a subject derives from a prophylactic or therapeutic agent is reduced. The intended effects will not result in a cure of the disorder, disease or condition.

[0025] The term "contacting" or "contact" refers to the physiological and physiological effects that result from such contact. It refers to combining a therapeutic agent and a cell or tissue such that a chemical effect occurs. Contacting can occur in vitro, ex vivo, or in vivo. In embodiments, the therapeutic agent is contacted with cells in cell culture (in vitro) to induce cell In another embodiment, the effect of the therapeutic agent on the cell or tissue is determined. Contacting includes administering a therapeutic agent to a subject having the cell or tissue to be contacted. .

[0026] In certain embodiments, the compounds described herein reduce amyloid beta activity (e.g., In some embodiments, the compounds provided herein In some embodiments, the compounds described herein reduce amyloid beta activity by at least about 10%. The compounds provided herein reduce amyloid-beta activity by at least about 20%. In some embodiments, the compounds provided herein inhibit amyloid beta activity by at least about 30%. In some embodiments, the compounds provided herein reduce amyloid beta levels by %. In some embodiments, the activity of the compounds provided herein is reduced by at least about 40%. The compound reduces amyloid beta activity by at least about 50%. The compounds provided herein reduce amyloid-beta activity by at least about 60%. In some embodiments, the compounds provided herein inhibit at least one amyloid-beta activity. In some embodiments, the compounds provided herein also reduce amino In some embodiments, the compounds provided herein reduce β-peptide activity by at least about 80%. The compounds provided reduce amyloid-beta activity by at least about 90%. In one embodiment, the compounds provided herein reduce amyloid beta activity by at least about 95%. In certain embodiments, the compounds described herein inhibit at least one amyloid-beta activity. The amount of oxidative stress may also be reduced (e.g., partially reduced) by about 15% to about 65%. In this regard, the compounds described herein reduce amyloid beta activity by at least about 30% to about 65%. may be reduced (e.g., partially reduced).

[0027] In certain embodiments, the reduction of amyloid beta activity is achieved by methods known to those skilled in the art. In certain embodiments, the reduction in amyloid beta activity is assessed by administering a compound described herein. This is relative to amyloid-beta activity in the presence of a stimulus that does not involve either

[0028] A non-limiting example of an amyloid beta activity is amyloid beta induction or mediated signaling. Thus, in certain embodiments, the compounds provided herein inhibit amyloid-β-induced signaling. Reduce (e.g., partially reduce) amyloid-β-induced signaling Other non-limiting examples include glucose transporters, NMDARs, AMPARs, and acetonitriles. Interactions with (including blocking) receptors, including but not limited to cholinergic receptors, inflammation Activation of pathogenic signaling pathways and GSK-3, CDK5, PKC, PKA and E The activity is activation of one or more kinases, including but not limited to rk1 / 2. Blockade of ion channels, disruption of calcium homeostasis, mitochondrial oxidative stress, and energy These may include disorders of energy metabolism, abnormal glucose regulation and / or neuronal cell death.

[0029] In certain embodiments, the compounds described herein reduce tau protein activity ( In some embodiments, the compounds provided herein reduces tau protein activity by at least about 10%. The compounds provided herein reduce tau protein activity by at least about 20%. In some embodiments, the compounds provided herein inhibit at least one of the following: tau protein activity; In some embodiments, the compounds provided herein also reduce tau expression by about 30%. In some embodiments, the protein activity is reduced by at least about 40%. The compounds provided reduce tau protein activity by at least about 50%. In embodiments, the compounds provided herein inhibit tau protein activity by at least about 60 In some embodiments, the compounds provided herein reduce tau protein by %. In some embodiments, the method of claim 1 further comprises reducing the activity of the enzyme provided herein by at least about 70%. The compound reduces tau protein activity by at least about 80%. In this regard, the compounds provided herein reduce tau protein activity by at least about 90%. In some embodiments, the compounds provided herein inhibit tau protein activity. In certain embodiments, the compounds described herein reduce tau expression by at least about 95%. Protein can be reduced by at least about 15% to about 65% (e.g., can be partially reduced). In certain embodiments, the compounds described herein inhibit tau protein by at least about It may be reduced (eg, partially reduced) by 30% to about 65%.

[0030] In certain embodiments, the reduction of tau protein activity is achieved by methods known to those skilled in the art. In certain embodiments, the reduction in tau protein activity is assessed by administering a compound described herein. The results are for tau protein activity without any of the compounds.

[0031] Non-limiting examples of tau protein activity include tau protein-induced or mediated signal transduction. Thus, in certain embodiments, the compounds provided herein inhibit tau protein induction. Reduce (e.g., partially reduce) tau protein activity. Non-limiting examples include interacting with tubulin to stabilize microtubules, helical and and / or the formation of straight filaments, activation of inflammatory signaling pathways, and These include impaired insulin signaling.

[0032] The term "therapeutically effective amount" or "effective amount" refers to an amount that, when administered, is effective to treat the disorder, disease, or condition being treated. a disease or condition sufficient to prevent or alleviate to some extent one or more of the symptoms of the condition The term "therapeutically effective amount" or "effective amount" also refers to a therapeutically effective amount of a compound. a biological molecule (e.g., a protein) that is sought by a researcher, veterinarian, physician, or clinician. proteins, enzymes, RNA, or DNA), cells, tissues, systems, animals, or humans Refers to a compound in an amount sufficient to elicit a biological or medical response.

[0033] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable" and " A "physiologically acceptable carrier" or "physiologically acceptable excipient" is a pharmaceutically acceptable material, composition, or composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulant In one embodiment, each component is selected from ingredients that are compatible with the other components of the pharmaceutical formulation and do not cause excessive toxicity. without irritation, allergic reaction, immunogenicity, or other problems or complications. contact with tissues or organs of a subject (e.g., human or animal) at a reasonable benefit / risk ratio. "Pharmaceutically acceptable" means suitable for use in a pharmaceutical composition. on: The Science and Practice of Pharmacy ,22nd ed.;Allen Ed.: Philadelphia,PA,201 2;Handbook of Pharmaceutical Excipients, 8th ed.;Sheskey et al.,Eds.;The Pharmac eutical Press: 2017;Handbook of Pharmace utical Additives,3rd ed.;Ash and Ash Eds .;Gower Publishing Company: 2007;Pharmac eutical Preformulation and Formulation, 2nd ed.;Gibson Ed.;CRC Press LLC: Boca R See aton, FL, 2009.

[0034] The terms "about" or "approximately" refer to an acceptable error for a particular value as determined by one of ordinary skill in the art. means that the value is measured or determined in part. In embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to a given value or range. 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% of , 1%, 0.5%, or 0.05%.

[0035] The terms "active ingredient" and "active substance" refer to a substance that treats one or more symptoms of a disorder, disease, or condition. alone or in combination with one or more pharmaceutically acceptable excipients to treat, prevent, or ameliorate As used herein, "active component" refers to a compound administered to a subject in combination with The "molecule" and "active agent" may be an optically active isomer of a compound described herein.

[0036] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a drug or a compound that is used to treat one or more disorders, diseases, or conditions. A compound or pharmaceutical composition thereof administered to a subject to treat, prevent, or ameliorate the above symptoms. Refers to a composition.

[0037] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, , optionally substituted with one or more substituents Q as described herein. For example, , C 1-6 Alkyl is a linear saturated monovalent hydrocarbon group of 1 to 6 carbon atoms or 3 to 6 In certain embodiments, alkyl refers to a branched saturated monovalent hydrocarbon group of 1 to 10 carbon atoms. 20 pieces (C 1-20 ), 1~15 pieces (C 1-15 ), 1~10 pieces (C 1-10 ), or 1 to 6 (C 1-6 ) a linear saturated monovalent hydrocarbon group having 3 to 20 carbon atoms, pieces(C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 ~6 pieces (C 3-6 ) is a branched saturated monovalent hydrocarbon group of carbon atoms. In this case, linear C 1-6 and branched C 3-6 Alkyl groups are also called "lower alkyls." Examples of alkyl groups include methyl, ethyl, propyl (including all isomeric forms), n-Propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isopropyl isobutyl, sec-butyl, t-butyl, pentyl (including all isomeric forms), and Examples include, but are not limited to, hexyl and hexyl (including all isomeric forms).

[0038] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more In one embodiment, 1, 2, 3, 4, or 5, and in another embodiment, 1 carbon-carbon Alkenyl refers to one or more alkyl groups as described herein that contain a double bond(s). The term "alkenyl" refers to any group of alkyl groups, as understood by those skilled in the art. , in the "cis" or "trans" configuration or mixtures thereof, or alternatively, in the "Z " or "E" configuration or mixtures thereof. For example, C 2-6 a Alkenyl is a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or 3 to 6 carbon atoms. In certain embodiments, alkenyl refers to a branched, unsaturated monovalent hydrocarbon group having 2 to 20 carbon atoms. pieces(C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 ~6 pieces (C 2-6 ) straight-chain monovalent hydrocarbon radicals of carbon atoms, or 3 to 20 (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3- 6) A branched monovalent hydrocarbon group of carbon atoms. Examples of alkenyl groups include ethenyl, protonyl, and the like. These include pen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl. This includes, but is not limited to:

[0039] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more In one embodiment, 1, 2, 3, 4, or 5, and in another embodiment, 1 carbon-carbon Alkynyl refers to one or more groups as described herein that contain a triple bond(s). Optionally substituted with the above substituent Q. For example, C 2-6 Alkynyl is 2 to 6 carbon atoms A straight-chain unsaturated monovalent hydrocarbon group of 100 atoms or a branched unsaturated monovalent hydrocarbon group of 4 to 6 carbon atoms In certain embodiments, alkynyl refers to a group having 2 to 20 carbon atoms (C 2-20 ), 2 to 15 pieces(C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms A linear monovalent hydrocarbon group having 4 to 20 carbon atoms (C 4-20 ), 4~15 pieces (C 4-15 ), 4~10 pieces (C 4-10 ), or 4 to 6 (C 4-6 ) branched monovalent carbon atoms Examples of alkynyl groups include ethynyl (-C≡CH), propynyl (all All isomeric forms, e.g., 1-propynyl (-C≡CCH3) and propargyl (-C H≡C≡CH), butynyl (including all isomeric forms, e.g., 1-butyne-1- yl and 2-butyn-1-yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl 1-Hexyn-1-yl (including all isomeric forms, e.g., 1-hexyn-1-yl) Not limited to:

[0040] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon radical, any one of which is defined herein. and optionally substituted with the above substituent Q. In one embodiment, cycloalkyl is , saturated or unsaturated but non-aromatic, and / or bridged or non-bridged, and / or In certain embodiments, the cycloalkyl is a fused bicyclic group having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 7 (C 3-7 In one embodiment, the cycloalkyl is monocyclic. In yet another embodiment, the cycloalkyl is bicyclic. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl ... butyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl , cycloheptyl, cycloheptenyl, bicyclo[2.1.1]hexyl, bicyclo[2 .2.1]heptyl, decalinyl, and adamantyl .

[0041] The term "aryl" refers to a monovalent monocyclic aromatic carbonyl group containing at least one aromatic carbocyclic ring. It refers to a hydrogen radical and / or a monovalent polycyclic aromatic hydrocarbon radical. In certain embodiments, aryl 6 to 20 pieces (C 6-20 ), 6~15 pieces (C 6-15 ), or 6 to 10 (C 6- 10 ) ring carbon atoms. Examples of aryl groups include phenyl, naphthyl, fluorenyl, , azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl Aryl also includes, but is not limited to, bicyclic or tricyclic carbocyclic rings. wherein one of the rings is aromatic and the other rings can be saturated, partially unsaturated, or aromatic. , for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl ( In one embodiment, the aryl is monocyclic. In another embodiment, In yet another embodiment, the aryl is polycyclic. In yet another embodiment, the aryl is bicyclic. In another embodiment, the aryl is tricyclic. In certain embodiments, the aryl is: Optionally substituted with one or more substituents Q as described herein.

[0042] The term "aralkyl" or "arylalkyl" refers to an alkyl group substituted with one or more aryl groups. In certain embodiments, aralkyl refers to a monovalent alkyl group having 7 to 30 carbon atoms (C 7-30 ), 7~20 pieces (C 7-20 ), or 7 to 16 (C 7-16 ) carbon atoms. Examples of aralkyl groups include benzyl, 2-phenylethyl, and 3-phenylpropyl. In certain embodiments, aralkyl includes, but is not limited to, any of the groups described herein. and optionally substituted with one or more substituents Q,

[0043] The term "heteroaryl" refers to a monovalent monocyclic aromatic group containing at least one aromatic ring. or a monovalent polycyclic aromatic group in which at least one aromatic ring is selected from O, S, and N. It refers to a ring containing one or more heteroatoms, each independently selected. The heteroaryl is attached to the rest of the molecule through an aromatic ring. provided that the total number of heteroatoms in the ring is four or less and each ring contains at least one carbon atom. In particular, one or two O atoms, one or two S atoms, and / or one to four In certain embodiments, heteroaryl may contain 5 to 20, 5 to 10, or 10 N atoms. In one embodiment, heteroaryl has 5, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include furanyl, imidazolyl, isothiazolyl, Isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl yl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, thiazolyl Examples include, but are not limited to, tolazolyl, triazinyl, and triazolyl. In embodiments, the heteroaryl is bicyclic. Examples of bicyclic heteroaryl groups include benzophenone, ... Benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiazole Asiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolizinyl hydroxyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isobenzoyl isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl , pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalyl quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. In yet another embodiment, the heteroaryl is tricyclic. Examples of aryl groups include acridinyl, benzindolyl, carbazolyl, dibenzofuran, and the like. Ranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, These include phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl is any of the groups described herein. is optionally substituted with one or more substituents Q.

[0044] The term "heterocyclyl" or "heterocyclic" refers to a heterocyclic ring containing at least one non-aromatic ring. a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system in which one or more of the non-aromatic ring atoms is heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms. In certain embodiments, a heterocyclyl or heterocyclic group refers to a group having 3 having up to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms The heterocyclyl is attached to the rest of the molecule via a non-aromatic ring. In this embodiment, heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, The nitrogen or sulfur atoms may be optionally oxidized, and the nitrogen or sulfur atoms may be optionally bonded or bridged. atom may be optionally quaternized, some rings may be partially or fully saturated, or Heterocyclyl refers to a group consisting of a heteroatom and a carbon atom, which may be aromatic. may be attached to the structure, which results in a stable compound. Examples of heterocyclic groups include azepinyl, benzodioxanyl, benzodioxolyl, benzophenone, Benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrofuranyl tetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chloro Mannyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzyl Benzisothiazinil, dihydrobenzisoxazinil, dihydrofuryl, dihydroisoxazinil Andryl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyri dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl Furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetramethyl hydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, Isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroxybenzoates doloindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl , oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, Lazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetra Hydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl These include thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, heterocyclyl includes, but is not limited to, any of the groups described herein. and optionally substituted with one or more substituents Q,

[0045] The terms "halogen," "halide," or "halo" refer to fluorine, chlorine, bromine, and / or It refers to iodine.

[0046] The term "optionally substituted" refers to alkyl, alkenyl, alkynyl, cycloalkyl, Groups or substituents such as aryl, aralkyl, heteroaryl, or heterocyclyl groups is one or more, 1, 2, 3, or 4 substituents Q, each of which independently represents For example, (a) deuterium (-D), cyano (-CN), halo, and nitro (-NO2); b) C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloa Lukil, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl aryl (each of which may further comprise one or more, in one embodiment one, two, three, or four one substituent Q a and (c) -C(O)R a , -C(O) OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C( S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a ,- OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(=NR a ) NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OS (O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR aC(O)N R b R c , -NR a C(O)SR d , -NR a C(=NR d )NR b R c , -NR a C( S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S (O)2NR b R c (Each R a , R b , R c , and R d are independently: (i) hydrogen or (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl (each of which may be one or more, in one embodiment, one, two, Three or four substituents Q a (iii) R b and R c together with the N atoms to which they are attached, represent one or more, in one embodiment , 1, 2, 3, or 4 substituents Q a forming an optionally substituted heterocyclyl with It is intended to mean that the group may be optionally substituted with a group selected from the group consisting of As used herein, all groups that may be optionally substituted are referred to as "groups" unless otherwise specified. It has been arbitrarily replaced."

[0047] In one embodiment, each Q a are independently (a) deuterium, cyano, halo, and nitro ;(b)C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Shik Roalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heteroaryl Cyclyl; and (c)-C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e ,- C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O) NR f R g , -OC(O)SR e , -OC(=NR e )NR f R g , -OC(S)R e , -OC(S)OR e 、-OC(S)NR f R g 、-OS(O)R e 、-OS(O)2R e 、-OS(O)NR f R g 、-OS(O)2NR f R g 、-NR f R g 、-NR e C(O )R h 、-NR e C(O)OR f 、-NR e C(O)NR f R g 、-NR e C(O)SR f 、-NR e C(=NR h )NR f R g 、-NR e C(S)R h 、-NR e C(S)OR f 、-NR e C(S)NR f R g 、-NR e S(O)R h 、-NR e S(O)2R h 、- NR e S(O)NR f R g 、-NR e S(O)2NR f R g 、-SR e 、-S(O)R e 、-S(O)2R e 、-S(O)NR f R g 、and -S(O)2NR f R[[ID=]} g [[ID=}}](each R e 、R f 、R g 、and Rh are independently (i) hydrogen or deuterium; (ii) C 1-6 a Lukil, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6- 14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl or (iii) R f and R g together with the N atom to which they are attached to form hetero forming a cyclocyclyl).

[0048] In certain embodiments, "optically active" and "enantiomerically active" refer to compounds that are about 50% or more. or more, about 70% or more, about 80% or more, about 90% or more, about 91% or more, about 92% or more, about 9 3% or more, approximately 94% or more, approximately 95% or more, approximately 96% or more, approximately 97% or more, approximately 98% or more, having an enantiomeric excess of about 99% or more, about 99.5%, or about 99.8% or more In certain embodiments, an optically active compound refers to a collection of molecules. About 95% or more of one enantiomer and about 5% or less of the other, based on the total weight of the mixture Contains both enantiomers.

[0049] In describing an optically active compound, the absolute configuration of the compound about its chiral center(s). The prefixes R and S are used to denote the optical rotation of the compound, i.e. That is, it is used to describe the direction in which the plane of polarized light is rotated by an optically active compound. -) indicates that the compound is levorotatory, i.e., that the compound rotates the plane of polarized light left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e. This indicates that the compound rotates the plane of polarized light to the right or clockwise. The signs of rotation (+) and (-) have no relation to the absolute configurations of the compounds, R and S. .

[0050] The term "isotopically enriched" refers to an isotopically enriched compound in which one or more of the atoms that make up such a compound are unnaturally enriched. In certain embodiments, an isotopically enriched compound refers to a compound containing a proportion of hydrogen isotopes. ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen -14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O ), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), Fluorine-1 7( 17 F), fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32( 32 P) , Phosphorus-33( 33 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S), chlorine-35( 35 Cl), salt Element-36( 36 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81 (81 Br), iodine-123( 123 I), iodine-125( 125 I), Iodine-1 27( 127 I), iodine-129( 129 I), and iodine-131( 131 I) Contains unnatural proportions of one or more isotopes, including, but not limited to, certain embodiments. In certain embodiments, the isotopically enriched compound is in a stable form, i.e., is non-radioactive. The isotopically enriched compound is hydrogen ( 1 H), deuterium ( 2 H), carbon-12( 12 C), carbon -13( 13 C), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-16( 16 O ), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), phosphorus-3 1( 31 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), Sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-37( 37 Cl), Bromine-79 ( 79 Br), Bromine-81( 81 Br), and iodine-127( 127 I) is included, but this In certain embodiments, the compound contains unnatural proportions of one or more isotopes, including but not limited to: The isotopically enriched compound is in an unstable form, i.e., radioactive. The tritium ( 3 H), carbon-11( 11 C), carbon-14( 14 C). Nitrogen-13( 13 N), oxygen-14( 14 O), oxygen-15( 15 O), fluorine-18( 18 F), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-35( 35 S), chlorine -36( 36 Cl), iodine-123( 123 I), iodine-125( 125 I), Yo Element-129( 129 I), and iodine-131( 131 I) including but not limited to In the compounds provided herein, Where practicable according to the judgment of one skilled in the art, any hydrogen may be, for example, 2 H or any The carbon atom may be, for example, 13 C, or any nitrogen can be, for example, 15 N, Or any oxygen, e.g. 18 It is understood that the number of ions may be O.

[0051] The term "isotopically enriched" refers to the enrichment of a more common isotope of an element (e.g., protium or hydrogen). Element-1 1 H) instead of a less common isotope of that element (e.g., deuterium or hydrogen) As used herein, the term "incorporation" refers to the proportion of D) of element-2 incorporated at a given position in a molecule. In this case, atoms at specific positions in a molecule are designated as specific, less common isotopes. If the isotope is present in a region, the abundance of that isotope at that location is substantially greater than its natural abundance. is understood.

[0052] The term "isotopic enrichment factor" refers to the ratio between the isotopic abundance in an isotopically enriched compound and the specific isotope It refers to the ratio between the natural abundance of

[0053] The term "hydrogen" or the symbol "H" refers to protium ( 1 H), deuterium ( 2 H or D), and and tritium ( 3 The composition of naturally occurring hydrogen isotopes, including H, at their natural abundance Protium is the most common hydrogen isotope with a natural abundance of over 99.98%. Deuterium is a less common hydrogen isomer with a natural abundance of about 0.0156%. It is a positional body.

[0054] The term "deuterium enriched" refers to a molecule in which deuterium has been incorporated in place of hydrogen at a given position in the molecule. For example, a 1% deuterium enrichment at a given position is equivalent to a 1% deuterium enrichment at a given position. This means that 1% of the molecules contain deuterium at a particular position. The naturally occurring distribution of deuterium is The average concentration is approximately 0.0156%, which is comparable to the concentration of the compound synthesized using non-enriched starting materials. The deuterium enrichment at any location is about 0.0156% on average. In this case, when a particular position in an isotopically enriched compound is designated as having deuterium, The abundance of deuterium at that position in that compound is its natural abundance (0.0156%) It is understood that the amount of oxygen in the atmosphere is substantially greater than the amount of oxygen in the atmosphere.

[0055] The term "carbon" or the symbol "C" refers to carbon-12 ( 12 C) and carbon-13 ( 13 C) Carbon-12 refers to the composition of naturally occurring carbon isotopes at their natural abundance, including: It is the most common carbon isotope with a natural abundance of over 98.89%. , a less common carbon isotope with a natural abundance of about 1.11%.

[0056] The terms "carbon-13 enriched" or " 13 "C enrichment" refers to the substitution of carbon at a given position in the molecule. For example, 10% of carbon-13 at a given position is 3 Enrichment means that 10% of the molecules in a given sample contain carbon-13 at a particular position This means that the natural distribution of carbon-13 averages about 1.11%. The carbon-13 enrichment at any position in compounds synthesized using the activating agent averages about As used herein, a specific position in an isotopically enriched compound is When specified as having carbon-13, the carbon- It is understood that the abundance of 13 is substantially greater than its natural abundance (1.11%).

[0057] The terms "substantially pure" and "substantially homogeneous" refer to the presence or absence of a substance that is substantially homogeneous, as determined by thin layer chromatography (TLC), Gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (G C), nuclear magnetic resonance (NMR), and mass spectrometry (MS), readily detectable as determined by standard analytical methods used by those skilled in the art be sufficiently homogeneous to appear free of significant impurities; or However, the physical, chemical, biological, and / or pharmacological properties of the substance, such as enzymatic activity and It means that the biological activity is sufficiently pure so as not to be detectably altered. In embodiments, "substantially pure" or "substantially homogeneous" refers to a molecule that is at least about 50 times pure. %, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 98% by weight, at least about 99% by weight, or at least At least about 99.5% by weight is a single enantiomer, as determined by standard analytical methods. A molecule that is a single compound containing a thiomer, a racemic mixture, or a mixture of enantiomers As used herein, an atom at a particular position in an isotopically enriched molecule refers to a set of , if specified as a particular less common isotope, the specified Molecules containing non-isotopes are impurities with respect to the isotopically enriched compound. For deuterated compounds with atoms at specific positions designated as Compounds containing rhodium are impurities.

[0058] The term "solvate" refers to a solute, e.g., a compound, which is present in a stoichiometric or non-stoichiometric amount. A compound formed by one or more molecules of a compound provided herein and one or more molecules of a solvent. Suitable solvents include water, methanol, ethanol, n-propyl Examples of suitable alcohols include, but are not limited to, propanol, isopropanol, and acetic acid. In one embodiment, the solvent is pharmaceutically acceptable. In another embodiment, the complex or aggregate is in a non-crystalline form. When water is used, the solvate is a hydrate. Examples of hydrates include hemihydrate, monohydrate, dihydrate, These include, but are not limited to, the monohydrate, trihydrate, tetrahydrate and pentahydrate.

[0059] The phrase "its enantiomer, mixture of enantiomers, two or more diastereomers" mixtures, tautomers, mixtures of two or more tautomers, or isotopic variants; or or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof" is intended to be used in conjunction with the phrase "(i) any enantiomer, mixture of enantiomers, or combination of two of the compounds referred to therein" A mixture of the above diastereomers, tautomers, a mixture of two or more tautomers, or or (ii) a pharmaceutically acceptable derivative of any of the compounds referred to therein. a salt, solvate, hydrate, or prodrug thereof, or (iii) any of the compounds referred to therein; Enantiomers of a compound, mixtures of enantiomers, or mixtures of two or more diastereomers tautomers, mixtures of two or more tautomers, or isotopic variants "Acceptable salt, solvate, hydrate, or prodrug" has the same meaning as "acceptable salt, solvate, hydrate, or prodrug."

[0060] Pharmaceutical Compositions In one embodiment, provided herein is a compound of formula I: [ka] or its enantiomer, mixture of enantiomers, mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or or their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; and Pharmaceutical compositions comprising excipients acceptable to (In the formula: X is -SO2- and Y is -NR X or X is -NR X - and Y is -SO2-; Each R 1 are independently (a) cyano, halo, or nitro; (b) C 1-6 Al Kill, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-1 4 Aryl, C 7-15aralkyl, heteroaryl, or heterocyclyl; or (c)-C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O) SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(=NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -O S(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)O R 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(=NR 1d )NR 1b R 1c , -NR1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S( O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1 c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S (O)2NR 1b R 1c and; R 2 , R 5 , R 6 , and R X are each independently (a) hydrogen, deuterium, cyano, b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkini Lu, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, Heteroa aryl, or heterocyclyl; or (c) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1bR 1c 、-OR 1a 、-O C(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(O)S R 1a 、-OC(=NR 1a )NR 1b R 1c 、-OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-O S(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1 a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、 -NR 1a C(O)SR 1d 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR 1a C(S)OR 1d 、-NR 1a C(S)NR 1b R 1c 、- NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c, -NR 1a S(O)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and; R 3 is (a) cyano, halo, or nitro; (b) C 1-6 Alkyl, C 2-6 a Lukenil, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C7 -15 aralkyl, heteroaryl, or heterocyclyl; or (c)—C(O) R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C( NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1 b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(=NR 1a )NR 1b R 1c , -OC(S )R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1 a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(=NR 1d ) NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d ,- NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and; R 4 is hydrogen, deuterium, cyano, or fluoro; Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C1-6 a Lukil, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6- 14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl ; or R 1a and R 1c together with the C and N atoms to which they are attached form hetero or R 1b and R 1c together with the N atom to which they are attached to form a heterocyclyl; m is an integer of 0, 1, 2, 3, or 4; Each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, Heteroaryl and heterocyclyl may be one or more, in one embodiment 1, 2, 3 or or four substituents Q (each Q is independently selected from the group consisting of: (a) deuterium, cyano, halo, and nitro) ;(b)C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Shik Roalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heteroaryl cyclyl (each of which has one or more, in one embodiment 1, 2, 3, or 4, substituents) Substituent Q a and (c) -C(O)R a , -C(O) OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C( S)Ra 、-C(S)OR a 、-C(S)NR b R c 、-OR a 、-OC(O)R a 、- OC(O)OR a 、-OC(O)NR b R c 、-OC(O)SR a 、-OC(=NR a ) NR b R c 、-OC(S)R a 、-OC(S)OR a 、-OC(S)NR b R c 、-OS (O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)N R b R c 、-NR a C(O)SR d 、-NR a C(=NR d )NR b R c 、-NR a C( S)R d 、-NR a C(S)OR d 、-NR a C(S)NR b R c 、-NR a S(O)R d 、-NR a S(O)2R d 、-NR a S(O)NR bR c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S (O)2NR b R c (Each R a , R b , R c , and R d are independently: (i) hydrogen or (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl (each of which may be one or more, in one embodiment, 1, 2, 3 , or four substituents Q a (iii) R b and R c together with the N atoms to which they are attached, represent one or more, in one embodiment, , 2, 3, or 4 substituents Q a forming an optionally substituted heterocyclyl) optionally substituted with (selected from the group consisting of Each Q a are independently: (a) deuterium, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C6 -14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and に(c)-C(O)R e 、-C(O)OR e 、-C(O)NR f R g 、-C(O)SR e 、-C(NR e )NR f R g 、-C(S)R e 、-C(S)OR e 、-C(S)NR f R g 、-OR e 、-OC(O)R e 、-OC(O)OR e 、-OC(O)NR f R g 、-O C(O)SR e 、-OC(=NR e )NR f R g 、-OC(S)R e 、-OC(S)OR e 、-OC(S)NR f R g 、-OS(O)R e 、-OS(O)2R e 、-OS(O)N R f R g 、-OS(O)2NR f R g 、-NR f R g 、-NR e C(O)R h 、-NR e C(O)OR f 、-NR e C(O)NR f R g 、-NR e C(O)SR f 、-NR e C( =NR h )NR f R g 、-NR e C(S)R h 、-NR e C(S)ORf , -NR e C( S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)N R f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R g (Each R e , R f , R g , and BiR h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) )R f and R g together with the N atom to which they are attached form a heterocyclyl provided is a compound selected from the group consisting of:

[0061] In one embodiment, the compounds provided herein have the structure of Formula II: [ka] or its enantiomer, mixture of enantiomers, mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or are pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, and m are each defined herein. (It is a)

[0062] In another embodiment, the compounds provided herein have the structure of Formula III: [ka] or its enantiomer, mixture of enantiomers, mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or are pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, and m are each defined herein. (It is a)

[0063] In yet another embodiment, the compounds provided herein have the structure of formula IV: [ka] or its enantiomer, mixture of enantiomers, mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or are pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof (R 1 , R 2 , R3 , R 4 , R 5 , R 6 , X, and Y are each as defined herein. (There is a certain

[0064] In yet another embodiment, the compounds provided herein have the structure of Formula V: [ka] or its enantiomer, mixture of enantiomers, mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or are pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R X , and m are each as defined herein. (which is

[0065] In yet another embodiment, the compounds provided herein have the structure of Formula VI: [ka] or its enantiomer, mixture of enantiomers, mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or are pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R X , and m are each as defined herein. (which is

[0066] In yet another embodiment, the compounds provided herein have the structure of Formula VII: [ka] or its enantiomer, mixture of enantiomers, mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or are pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R X , and m are each as defined herein. (which is

[0067] In yet another embodiment, the compounds provided herein have the structure of Formula VIII: [ka] or its enantiomer, mixture of enantiomers, mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or are pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R X are each as defined herein. (It has).

[0068] In yet another embodiment, the compounds provided herein have the structure of formula IX: [ka] or its enantiomer, mixture of enantiomers, mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or are pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R X , and m are each as defined herein. (which is

[0069] In yet another embodiment, the compounds provided herein have the structure of Formula X: [ka] or its enantiomer, mixture of enantiomers, mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or are pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R X , and m are each as defined herein. (which is

[0070] In yet another embodiment, the compounds provided herein have the structure of formula XI: [ka] or its enantiomer, mixture of enantiomers, mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or are pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R X , and m are each as defined herein. (which is

[0071] In yet another embodiment, the compounds provided herein have the structure of Formula XII: [ka] or its enantiomer, mixture of enantiomers, mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or are pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R X are each as defined herein. (It has).

[0072] In one embodiment, in any one of Formulas I-XII: Each R 1 are independently (a) cyano, halo, or nitro; (b) C 1-6 Al Kill, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-1 4 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(O) SR 1a 、-C(NR 1a )NR 1b R 1c 、-C(S)R 1a 、-C(S)OR 1a 、 -C(S)NR 1b R 1c 、C 1-6 アルコキシ、-OC(O)R 1a 、-OC(O)O R 1a 、-OC(O)NR 1b R 1c 、-OC(O)SR 1a 、-OC(=NR 1a )N R 1b R 1c 、-OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1 c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS (O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C (O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(O)SR 1d 、- NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR1a C( S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c ,if KUHA-S(O)2NR 1b R 1c and; R 2 , R 5 , R 6 , and R X are each independently (a) hydrogen, deuterium, cyano, b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkini Lu, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, Heteroa aryl, or heterocyclyl; or (c) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -O C(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(O)S R 1a 、-OC(=NR 1a )NR 1b R 1c 、-OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-O S(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1 a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、 -NR 1a C(O)SR 1d 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR 1a C(S)OR 1d 、-NR 1a C(S)NR 1b R 1c 、- NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and; R 3 is (a) cyano, halo, or nitro; (b) C 1-6 Alkyl, C 2-6 a Lukenil, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C7 -15 aralkyl, heteroaryl, or heterocyclyl; or (c)—C(O) -C 1-6 Alkyl, -C(O)OR 1a , -C(O)NHR 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S )NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC( O)NR 1b R 1c , -OC(O)SR 1a , -OC(=NR 1a )NR 1b R 1c ,- OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O) R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(=N R 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d ,- NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -S (O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2 NR 1b R 1c and; R 4 is hydrogen, deuterium, cyano, or fluoro; m is an integer of 0, 1, 2, 3, or 4; R 1a , R 1b , R 1c , and R 1d are each as defined herein. can be; Each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, Heteroaryl and heterocyclyl may independently and optionally be one or more of the following: is substituted with 1, 2, 3, or 4 substituents Q.

[0073] In another embodiment, in any one of Formulas I-XII: R X is (a) hydrogen or deuterium; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Ara alkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a ,- C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a ) NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(=NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O )2R1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O) NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(=NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)N R 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S (O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -S(O)R 1a , -S (O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c Yes the law of nature; Each R 1 are independently (a) cyano, halo, or nitro; (b) C 1-6 Al Kill, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C6-1 4 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c)-C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O) SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , C 1-6 Alkoxy, -OC(O)R 1a , -OC(O)O R 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(=NR 1a )N R 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1 c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS (O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C (O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d ,- NR 1aC(=NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C( S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c ,if KUHA-S(O)2NR 1b R 1c and; R 2 and R 4 are hydrogen; R 3 is (a) cyano, halo, or nitro; (b) C 1-6 Alkyl, C 2-6 a Lukenil, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C7 -15 aralkyl, heteroaryl, or heterocyclyl; or (c)—C(O) -C 1-6 Alkyl, -C(O)OR 1a , -C(O)NHR 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC( O)NR 1b R 1c 、-OC(O)SR 1a 、-OC(=NR 1a )NR 1b R 1c 、- OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1c 、-OS(O) R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、 -NR 1a C(O)NR 1b R 1c 、-NR 1a C(O)SR 1d 、-NR 1a C(=N R 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR 1a C(S)OR 1d 、- NR 1a C(S)NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R1c , -NR 1a S(O)NR 1b R 1c , -S (O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2 NR 1b R 1c and; R 5 and R 6 are each independently (a) hydrogen, deuterium, cyano, halo, or nitro Toro;(b)C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or is heterocyclyl; or (c) -C(O)R 1a , -C(O)OR 1a , -C(O)N R 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1 a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC (=NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC( S)NR1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1 b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1 d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C( O)SR 1d , -NR 1a C(=NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O )R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1 a S(O)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and; m is an integer of 0, 1, 2, 3, or 4; R 1a , R1b , R 1c , and R 1d are each as defined herein. can be; Each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, Heteroaryl and heterocyclyl may independently and optionally be one or more of the following: is substituted with 1, 2, 3, or 4 substituents Q.

[0074] In yet another embodiment, in any one of Formulas I-XII: R X is (a) hydrogen or deuterium; (b) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Ara alkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a ,- C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a ) NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(=NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O )2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O) NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(=NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)N R 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S (O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -S(O)R 1a , -S (O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c Yes the law of nature; Each R 1 are independently (a) cyano, halo, or nitro; (b) C1-6 Al Kill, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-1 4 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c)-C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O) SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , C 1-6 Alkoxy, -OC(O)R 1a , -OC(O)O R 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(=NR 1a )N R 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1 c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS (O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C (O)OR 1d , -NR 1a C(O)NR1b R 1c , -NR 1a C(O)SR 1d ,- NR 1a C(=NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C( S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c ,if KUHA-S(O)2NR 1b R 1c and; R 2 and R 4 are hydrogen; R 3 is nitro, C 1-6 Alkyl, -OR 1a , or -NR 1a S(O)2R 1d and; R 5 is hydrogen or -OR 1a and; R 6 is hydrogen, C 1-6 Alkyl, or -OR 1a and; m is an integer of 0, 1, 2, or 3; R 1a , R 1b , R 1c, and R 1d are each as defined herein. can be; Each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, Heteroaryl and heterocyclyl may independently and optionally be one or more of the following: is substituted with 1, 2, 3, or 4 substituents Q.

[0075] In yet another embodiment, in any one of Formulas I-XII: R X is hydrogen; Each R 1 are independently halo or C 1-6 is alkyl; R 2 and R 4 are hydrogen; R 3 is nitro, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 Alkyls It is sulfonamide; R 5 is hydrogen or C 1-6 is alkoxy; R 6 is hydrogen, C 1-6 Alkyl, or C 1-6 is alkoxy; m is an integer of 0, 1, or 2; Each of alkyl, alkoxy, and C 1-6 The alkyl sulfonamide is independently and Optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Q There are.

[0076] In yet another embodiment, in any one of Formulas I-XII: R X is hydrogen; Each R 1 independently, C 1-6 is alkyl; R 2 and R 4 are hydrogen; R 3 is nitro, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 Alkyls It is sulfonamide; R 5 is hydrogen or C 1-6 is alkoxy; R 6 is hydrogen, C 1-6 Alkyl, or C 1-6 is alkoxy; m is an integer of 0, 1, or 2; Each of alkyl, alkoxy, and C 1-6 The alkyl sulfonamide is independently and Optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Q There are.

[0077] In yet another embodiment, in any one of Formulas I-XII: R X is hydrogen; R 1 is methyl or fluoro; R 2 and R 4 are hydrogen; R 3 is nitro, trifluoromethyl, methoxy, or methylsulfonamide ; R 5 is hydrogen or methoxy; R 6 is hydrogen, methyl, or methoxy; m is an integer of 0 or 1.

[0078] In yet another embodiment, in any one of Formulas I-XII: R X is hydrogen; R 1is methyl; R 2 and R 4 are hydrogen; R 3 is nitro, trifluoromethyl, methoxy, or methylsulfonamide ; R 5 is hydrogen or methoxy; R 6 is hydrogen, methyl, or methoxy; m is an integer of 0 or 1.

[0079] In one embodiment, the compounds provided herein are 4-((4'-((4-(2,4- Dichlorophenyl)-1-ethyl-1H-imidazol-2-yl)methyl)-[1,1 '-biphenyl]-4-yl)oxy)-3-((3-(trifluoromethyl)phenyl )sulfonamido)benzoic acid and 3-(N-(5-(4-(4-cyanophenyl)piperidine) It is also not benzoic acid (1-carbonyl)-2-methylphenyl)sulfamoyl).

[0080] The group R in the formulae described herein, including formulae I to XII 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R X , X, Y, and m are further defined in the embodiments described herein. All combinations of the embodiments provided herein for such groups are within the scope of the present disclosure. is within the range.

[0081] In certain embodiments, R 1 is cyano. In certain embodiments, R 1 Is halo In certain embodiments, R 1is fluoro, chloro, or bromo. In terms of form, R 1 is nitro. In certain embodiments, R 1 is one or more substituents Q Optionally substituted C 1-6 In certain embodiments, R 1 is one or more positions methyl optionally substituted with a substituent Q. In certain embodiments, R 1 is one or more substitutions C optionally substituted with a group Q 2-6 In certain embodiments, R 1 is one C optionally substituted with the above substituent Q 2-6 In certain embodiments, R is alkynyl. 1 is C optionally substituted with one or more substituents Q 3-10 It is cycloalkyl. In embodiments, R 1 is C optionally substituted with one or more substituents Q 6-14 Aryl In certain embodiments, R 1 is C optionally substituted with one or more substituents Q 7-15 a In certain embodiments, R 1 is optionally substituted with one or more substituents Q benzyl. In certain embodiments, R 1 is optionally substituted with one or more substituents Q In certain embodiments, R is heteroaryl. 1 is optionally substituted with one or more substituents Q It is a heterocyclyl.

[0082] In certain embodiments, R 1 is -C(O)R 1a (R 1a is defined herein In certain embodiments, R 1 is -C(O)OR1a (R 1a teeth , as defined herein). In certain embodiments, R 1 -C (O)NR 1b R 1c (R 1b and R 1c are each as defined herein In certain embodiments, R 1 is -C(O)SR 1a (R 1a This specification In certain embodiments, R 1 is -C(NR 1 a )NR 1b R 1c (R 1a , R 1b , and R 1c are each defined herein. In certain embodiments, R 1 is -C(S)R 1a (R 1a teeth, As defined herein. In certain embodiments, R 1 is -C( S)OR 1a (R 1a is as defined herein. In terms of form, R 1 is -C(S)NR 1b R 1c (R 1b and R 1c are the same as those in this specification. In certain embodiments, R 1 -OR 1a (R 1a is as defined herein. In certain embodiments, R 1 teeth , -OR 1a (R1a is C optionally substituted with one or more substituents Q 1-6 Al Kill, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 7-1 5 aralkyl, heteroaryl, or heterocyclyl). So, R 1 is C optionally substituted with one or more substituents Q 1-6 It is alkoxy. In an embodiment of the present invention, R 1 is -OC(O)R 1a (R 1a is as defined herein In certain embodiments, R 1 is -OC(O)OR 1a (R 1a teeth, As defined herein. In certain embodiments, R 1 -OC (O)NR 1b R 1c (R 1b and R 1c are each as defined herein In certain embodiments, R 1 is -OC(O)SR 1a (R 1a is Honmei In certain embodiments, R 1 is -OC(= NR 1a )NR 1b R 1c (R 1a , R 1b , and R 1c are each defined herein. In certain embodiments, R 1 is -OC(S)R 1a (R 1ais as defined herein. In certain embodiments, R 1 teeth , -OC(S)OR 1a (R 1a is as defined herein). In certain embodiments, R 1 is -OC(S)NR 1b R 1c (R 1b and R 1c Each and as defined herein. In certain embodiments, R 1 teeth,- OS(O)R 1a (R 1a is as defined herein). In embodiments, R 1 is -OS(O)2R 1a (R 1a is as defined herein In certain embodiments, R 1 is -OS(O)NR 1b R 1c (R 1 b and R 1c and (wherein each is as defined herein). In terms of form, R 1 is -OS(O)2NR 1b R 1c (R 1b and R 1c are respectively In certain embodiments, R 1 is -NR 1b R 1c (R 1b and R 1c and In certain embodiments, R 1 is -NR 1a C(O)R 1d (R 1a and R1d Each and as defined herein. In certain embodiments, R 1 teeth,- NR 1a C(O)OR 1d (R 1a and R 1d are each defined herein. In certain embodiments, R 1 is -NR 1a C(O)NR 1b R 1c (R 1a , R 1b , and R 1c are each as defined herein) In certain embodiments, R 1 is -NR 1a C(O)SR 1d (R 1a and R 1d teeth each as defined herein). In certain embodiments, R 1 is -NR 1a C(=NR 1d )NR 1b R 1c (R 1a , R 1b , R 1c , and R 1d and each are as defined herein. In certain embodiments, R 1 is -NR 1a C(S)R 1d (R 1a and R 1d are each defined herein. In certain embodiments, R 1 is -NR 1a C(S)OR 1d (R 1a and R 1d are each as defined herein. In an embodiment of the present invention, R 1 is -NR 1a C(S)NR 1b R 1c (R 1a , R 1b , and R 1c and each are as defined herein. In certain embodiments, , R 1 is -NR 1a S(O)R 1d (R 1a and R 1d are each defined herein. In certain embodiments, R 1 is -NR 1a S(O)2R 1d (R 1a and R 1d are each as defined herein). In certain embodiments, R 1 is -NR 1a S(O)NR 1b R 1c (R 1a , R 1b , and BiR 1c and each are as defined herein. So, R 1 is -NR 1a S(O)NR 1b R 1c (R 1a , R 1b , and R 1c Haso and , each as defined herein. In certain embodiments, R 1 teeth , -S(O)R 1a (R 1a is as defined herein. In an embodiment of the present invention, R 1 is -S(O)2R 1a (R 1a is as defined herein In certain embodiments, R 1 is -S(O)NR 1b R 1c (R 1b and R 1c and each are as defined herein. In this state, R 1 is -S(O)NR 1b R 1c (R 1b and R 1c are the same as those in this specification. (as defined in

[0083] In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is deuterium In certain embodiments, R 2 is cyano. In certain embodiments, R 2 Ha, Hello In certain embodiments, R 2 is fluoro, chloro, or bromo. In the embodiment, R 2 is chloro. In certain embodiments, R 2 is nitro. In an embodiment of the present invention, R 2 is C optionally substituted with one or more substituents Q 1-6 Alkyl In certain embodiments, R 2 is methyl optionally substituted with one or more substituents Q In certain embodiments, R 2 is C optionally substituted with one or more substituents Q 2-6 Arke In certain embodiments, R 2 is a C2 optionally substituted with one or more substituents Q -6 In certain embodiments, R is alkynyl. 2 is optionally substituted with one or more substituents Q C3-10 In certain embodiments, R 2 is one or more substitutions C optionally substituted with a group Q 6-14 In certain embodiments, R 2 is one C optionally substituted with the above substituent Q 7-15 In certain embodiments, R 2 is heteroaryl optionally substituted with one or more substituents Q. So, R 2 is heterocyclyl optionally substituted with one or more substituents Q.

[0084] In certain embodiments, R 2 is -C(O)R 1a (R 1a is defined herein In certain embodiments, R 2 is -C(O)OR 1a (R 1a teeth , as defined herein). In certain embodiments, R 2 -C (O)NR 1b R 1c (R 1b and R 1c are each as defined herein In certain embodiments, R 2 is -C(O)SR 1a (R 1a This specification In certain embodiments, R 2 is -C(NR 1 a )NR 1b R 1c (R 1a , R 1b , and R 1c are each defined herein. In certain embodiments, R2 is -C(S)R 1a (R 1a teeth, As defined herein. In certain embodiments, R 2 is -C( S)OR 1a (R 1a is as defined herein. In terms of form, R 2 is -C(S)NR 1b R 1c (R 1b and R 1c are the same as those in this specification. In certain embodiments, R 2 -OR 1a (R 1a is as defined herein. In certain embodiments, R 2 teeth , C optionally substituted with one or more substituents Q 1-6 In certain embodiments, is R 2 is methoxy optionally substituted with one or more substituents Q. In certain embodiments, is R 2 is -OC(O)R 1a (R 1a are as defined herein) In certain embodiments, R 2 is -OC(O)OR 1a (R 1a is defined herein as In certain embodiments, R 2 is -OC(O)NR 1 b R 1c (R 1b and R 1c are each as defined herein) In certain embodiments, R 2 is -OC(O)SR 1a (R1a is defined herein In certain embodiments, R 2 is -OC(=NR 1a )N R 1b R 1c (R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, R 2 is -OC(S)R 1a (R 1a is Honmei In certain embodiments, R 2 is -OC(S ) OR 1a (R 1a is as defined herein. In this state, R 2 is -OC(S)NR 1b R 1c (R 1b and R 1c are the same as those in this specification. In certain embodiments, R 2 is -OS(O)R 1a (R 1a is as defined herein). In certain embodiments , R 2 is -OS(O)2R 1a (R 1a are as defined herein) In certain embodiments, R 2 is -OS(O)NR 1b R 1c (R 1b and R 1c and each are as defined herein. In certain embodiments, R 2 is -OS(O)2NR 1b R 1c (R1b and R 1c are each defined herein. In certain embodiments, R 2 is -NR 1b R 1c (R 1 b and R 1c and (wherein each is as defined herein). In terms of form, R 2 is -NR 1a C(O)R 1d (R 1a and R 1d are the same as those in this specification. In certain embodiments, R 2 is -NR 1a C( O)OR 1d (R 1a and R 1d are each as defined herein) In certain embodiments, R 2 is -NR 1a C(O)NR 1b R 1c (R 1a , R 1b , and R 1c are each as defined herein. In embodiments, R 2 is -NR 1a C(O)SR 1d (R 1a and R 1d are the books respectively. (as defined herein). In certain embodiments, R 2 is -NR 1 a C(=NR 1d )NR 1b R 1c (R 1a , R 1b , R 1c , and R 1d are respectively, As defined herein. In certain embodiments, R 2 is -NR 1a C(S)R 1d (R 1a and R 1d are each as defined herein. In certain embodiments, R 2 is -NR 1a C(S)OR 1d (R 1a and R 1d and each are as defined herein. In certain embodiments, is R 2 is -NR 1a C(S)NR 1b R 1c (R 1a , R 1b , and R 1c Each and as defined herein. In certain embodiments, R 2 teeth,- NR 1a S(O)R 1d (R 1a and R 1d are each as defined herein. In certain embodiments, R 2 is -NR 1a S(O)2R 1d (R 1a and R 1d and each are as defined herein. In this state, R 2 is -NR 1a S(O)NR 1b R 1c (R 1a , R 1b , and R 1c Haso and , each as defined herein. In certain embodiments, R 2 teeth , -NR 1aS(O)NR 1b R 1c (R 1a , R 1b , and R 1c are respectively In certain embodiments, R 2 is -S(O) R 1a (R 1a is as defined herein. In certain embodiments, is R 2 is -S(O)2R 1a (R 1a are as defined herein) In certain embodiments, R 2 is -S(O)NR 1b R 1c (R 1b and R 1c teeth each as defined herein). In certain embodiments, R 2 is -S(O)NR 1b R 1c (R 1b and R 1c are each defined herein. (As stated above).

[0085] In certain embodiments, R 3 is cyano. In certain embodiments, R 3 Is halo In certain embodiments, R 3 is fluoro, chloro, or bromo. In terms of form, R 3 is chloro. In certain embodiments, R 3 is nitro. In embodiments, R 3 is C optionally substituted with one or more substituents Q 1-6 is alkyl In certain embodiments, R 3 is methyl optionally substituted with one or more substituents Q. In certain embodiments, R 3 is monofluoromethyl, difluoromethyl, or trifluoromethyl. In certain embodiments, R 3 is trifluoromethyl. In the embodiment, R 3 is C optionally substituted with one or more substituents Q 2-6 Alkenyl In certain embodiments, R 3 is C optionally substituted with one or more substituents Q 2-6 Archi In certain embodiments, R 3 is a C3 optionally substituted with one or more substituents Q -10 In certain embodiments, R 3 is optionally one or more substituents Q C replaced by 6-14 In certain embodiments, R 3 is one or more substitutions C optionally substituted with a group Q 7-15 In certain embodiments, R 3 is 1 In certain embodiments, R is heteroaryl optionally substituted with one or more substituents Q. 3 is heterocyclyl optionally substituted with one or more substituents Q.

[0086] In certain embodiments, R 3 is -C(O)R 1a (R 1a is defined herein In certain embodiments, R 3 is -C(O)R 1a (R 1a teeth, C, each optionally substituted with one or more substituents Q 1-6 Alkyl, C 2-6 Alkenyl , C 2-6 Alkynyl, C 3-10Cycloalkyl, C 6-14 Aryl, C 7-15 a In certain embodiments, R 3 is -C( O)OR 1a (R 1a is as defined herein. In terms of form, R 3 is -C(O)NR 1b R 1c (R 1b and R 1c are the same as those in this specification. In certain embodiments, R 3 is -C(O)NR 1b R 1c (R 1b and R 1c are each independently (i) hydrogen; or (ii) C optionally substituted with one or more substituents Q 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aral In certain embodiments, R 3 is -C(O)SR 1a (R 1a is as defined herein) In certain embodiments, R 3 is -C(NR 1a )NR 1b R 1c (R 1a , R 1b , and R 1c and each are as defined herein. In this state, R 3 is -C(S)R 1a (R1a is as defined herein In certain embodiments, R 3 is -C(S)OR 1a (R 1a is defined herein as In certain embodiments, R 3 is -C(S)NR 1b R 1c (R 1b and R 1c and In certain embodiments, R 3 -OR 1a (R 1a is defined herein In certain embodiments, R 3 is optionally substituted with one or more substituents Q TaC 1-6 In certain embodiments, R 3 is optionally one or more substituents Q In certain embodiments, R 3 is -OC(O)R 1a (R 1 a is as defined herein. In certain embodiments, R 3 teeth, -OC(O)OR 1a (R 1a is as defined herein. In certain embodiments, R 3 is -OC(O)NR 1b R 1c (R 1b and R 1c are respectively , as defined herein). In certain embodiments, R 3 -O C(O)SR 1a (R 1a is as defined herein). In embodiments, R 3 is -OC(=NR 1a )NR 1b R 1c (R 1a , R 1b , and R 1c and each are as defined herein. In certain embodiments, , R 3 is -OC(S)R 1a (R 1a is as defined herein) In certain embodiments, R 3 is -OC(S)OR 1a (R 1a is defined herein In certain embodiments, R 3 is -OC(S)NR 1b R 1c (R 1b and R 1c and In certain embodiments, R 3 is -OS(O)R 1a (R 1a is defined herein In certain embodiments, R 3 is -OS(O)2R 1a (R 1 a is as defined herein. In certain embodiments, R 3 teeth, -OS(O)NR 1b R 1c (R 1b and R 1c are each defined herein In certain embodiments, R 3 is -OS(O)2NR 1b R 1c ( R 1b and R 1care each as defined herein. In embodiments, R 3 is -NR 1b R 1c (R 1b and R 1c are defined herein. In certain embodiments, R 3 is -NR 1a C(O) R 1d (R 1a and R 1d and In certain embodiments, R 3 is -NR 1a C(O)OR 1d (R 1a and R 1d is that (each as defined herein). In certain embodiments, R 3 teeth, -NR 1a C(O)NR 1b R 1c (R 1a , R 1b , and R 1c are the same as those in this specification. In certain embodiments, R 3 is -NR 1a C( O)SR 1d (R 1a and R 1d are each as defined herein) In certain embodiments, R 3 is -NR 1a C(=NR 1d )NR 1b R 1c (R 1a , R 1b , R 1c , and R 1d are each as defined herein In certain embodiments, R3 is -NR 1a C(S)R 1d (R 1a and R 1d and each are as defined herein. In certain embodiments, R 3 is -NR 1a C(S)OR 1d (R 1a and R 1d are each defined herein. In certain embodiments, R 3 is -NR 1a C(S)NR 1 b R 1c (R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, R 3 is -NR 1a S(O)R 1d (R 1a and R 1d and each are as defined herein. In certain embodiments, , R 3 is -NR 1a S(O)2R 1d (R 1a and R 1d are each defined herein. In certain embodiments, R 3 is one or more substituents Q Optionally substituted C 1-6 In certain embodiments, R 3 teeth , -NR 1a S(O)NR 1b R 1c (R 1a , R 1b , and R 1c are the same as those in this specification. In certain embodiments, R 3 is -NR 1a S (O)2NR 1b R 1c (R 1a , R 1b , and R 1c are each defined herein. In certain embodiments, R 3 is -S(O)R 1a (R 1a is as defined herein. In certain embodiments, R 3 teeth,- S(O)2R 1a (R 1a is as defined herein). In embodiments, R 3 is -S(O)NR 1b R 1c (R 1b and R 1c are respectively In certain embodiments, R 3 is -S(O) 2NR 1b R 1c (R 1b and R 1c are each as defined herein. (This is the case.)

[0087] In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is deuterium In certain embodiments, R 4 is cyano. In certain embodiments, R 4 Is full-on It is Ro.

[0088] In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is deuterium In certain embodiments, R 5 is cyano. In certain embodiments, R 5 Ha, Hello In certain embodiments, R 5 is fluoro, chloro, or bromo. In the embodiment, R 5 is chloro. In certain embodiments, R 5 is nitro. In an embodiment of the present invention, R 5 is C optionally substituted with one or more substituents Q 1-6 Alkyl In certain embodiments, R 5 is methyl optionally substituted with one or more substituents Q In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 2-6 Arke In certain embodiments, R 5 is a C2 optionally substituted with one or more substituents Q -6 In certain embodiments, R is alkynyl. 5 is optionally substituted with one or more substituents Q C 3-10 In certain embodiments, R 5 is one or more substitutions C optionally substituted with a group Q 6-14 In certain embodiments, R 5 is one C optionally substituted with the above substituent Q 7-15 In certain embodiments, R 5 is heteroaryl optionally substituted with one or more substituents Q. So, R 5 is heterocyclyl optionally substituted with one or more substituents Q.

[0089] In certain embodiments, R 5 is -C(O)R 1a (R 1ais defined herein In certain embodiments, R 5 is -C(O)OR 1a (R 1a teeth , as defined herein). In certain embodiments, R 5 -C (O)NR 1b R 1c (R 1b and R 1c are each as defined herein In certain embodiments, R 5 is -C(O)SR 1a (R 1a This specification In certain embodiments, R 5 is -C(NR 1 a )NR 1b R 1c (R 1a , R 1b , and R 1c are each defined herein. In certain embodiments, R 5 is -C(S)R 1a (R 1a teeth, As defined herein. In certain embodiments, R 5 is -C( S)OR 1a (R 1a is as defined herein. In terms of form, R 5 is -C(S)NR 1b R 1c (R 1b and R 1c are the same as those in this specification. In certain embodiments, R 5 -OR 1a (R 1ais as defined herein. In certain embodiments, R 5 teeth , C optionally substituted with one or more substituents Q 1-6 In certain embodiments, is R 5 is methoxy optionally substituted with one or more substituents Q. In certain embodiments, is R 5 is -OC(O)R 1a (R 1a are as defined herein) In certain embodiments, R 5 is -OC(O)OR 1a (R 1a is defined herein as In certain embodiments, R 5 is -OC(O)NR 1 b R 1c (R 1b and R 1c are each as defined herein) In certain embodiments, R 5 is -OC(O)SR 1a (R 1a is defined herein In certain embodiments, R 5 is -OC(=NR 1a )N R 1b R 1c (R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, R 5 is -OC(S)R 1a (R 1a is Honmei In certain embodiments, R 5 is -OC(S ) OR 1a (R 1ais as defined herein. In this state, R 5 is -OC(S)NR 1b R 1c (R 1b and R 1c are the same as those in this specification. In certain embodiments, R 5 is -OS(O)R 1a (R 1a is as defined herein). In certain embodiments , R 5 is -OS(O)2R 1a (R 1a are as defined herein) In certain embodiments, R 5 is -OS(O)NR 1b R 1c (R 1b and R 1c and each are as defined herein. In certain embodiments, R 5 is -OS(O)2NR 1b R 1c (R 1b and R 1c are each defined herein. In certain embodiments, R 5 is -NR 1b R 1c (R 1 b and R 1c and (wherein each is as defined herein). In terms of form, R 5 is -NR 1a C(O)R 1d (R 1a and R 1d are the same as those in this specification. In certain embodiments, R 5 is -NR 1a C( O)OR 1d (R 1a and R 1d are each as defined herein) In certain embodiments, R 5 is -NR 1a C(O)NR 1b R 1c (R 1a , R 1b , and R 1c are each as defined herein. In embodiments, R 5 is -NR 1a C(O)SR 1d (R 1a and R 1d are the books respectively. (as defined herein). In certain embodiments, R 5 is -NR 1 a C(=NR 1d )NR 1b R 1c (R 1a , R 1b , R 1c , and R 1d are respectively, As defined herein. In certain embodiments, R 5 is -NR 1a C(S)R 1d (R 1a and R 1d are each as defined herein. In certain embodiments, R 5 is -NR 1a C(S)OR 1d (R 1a and R 1d and each are as defined herein. In certain embodiments, is R 5 is -NR 1a C(S)NR 1b R 1c(R 1a , R 1b , and R 1c Each and as defined herein. In certain embodiments, R 5 teeth,- NR 1a S(O)R 1d (R 1a and R 1d are each as defined herein. In certain embodiments, R 5 is -NR 1a S(O)2R 1d (R 1a and R 1d and each are as defined herein. In this state, R 5 is -NR 1a S(O)NR 1b R 1c (R 1a , R 1b , and R 1c Haso and , each as defined herein. In certain embodiments, R 5 teeth , -NR 1a S(O)NR 1b R 1c (R 1a , R 1b , and R 1c are respectively In certain embodiments, R 5 is -S(O) R 1a (R 1a is as defined herein. In certain embodiments, is R 5 is -S(O)2R 1a (R 1a are as defined herein) In certain embodiments, R 5 is -S(O)NR 1b R 1c (R1b and R 1c teeth each as defined herein). In certain embodiments, R 5 is -S(O)NR 1b R 1c (R 1b and R 1c are each defined herein. (As stated above).

[0090] In certain embodiments, R 6 is hydrogen. In certain embodiments, R 6 is deuterium In certain embodiments, R 6 is cyano. In certain embodiments, R 6 Ha, Hello In certain embodiments, R 6 is fluoro, chloro, or bromo. In the embodiment, R 6 is chloro. In certain embodiments, R 6 is nitro. In an embodiment of the present invention, R 6 is C optionally substituted with one or more substituents Q 1-6 Alkyl In certain embodiments, R 6 is methyl optionally substituted with one or more substituents Q In certain embodiments, R 6 is C optionally substituted with one or more substituents Q 2-6 Arke In certain embodiments, R 6 is a C2 optionally substituted with one or more substituents Q -6 In certain embodiments, R is alkynyl. 6 is optionally substituted with one or more substituents Q C 3-10 In certain embodiments, R 6 is one or more substitutions C optionally substituted with a group Q6-14 In certain embodiments, R 6 is one C optionally substituted with the above substituent Q 7-15 In certain embodiments, R 6 is heteroaryl optionally substituted with one or more substituents Q. So, R 6 is heterocyclyl optionally substituted with one or more substituents Q.

[0091] In certain embodiments, R 6 is -C(O)R 1a (R 1a is defined herein In certain embodiments, R 6 is -C(O)OR 1a (R 1a teeth , as defined herein). In certain embodiments, R 6 -C (O)NR 1b R 1c (R 1b and R 1c are each as defined herein In certain embodiments, R 6 is -C(O)SR 1a (R 1a This specification In certain embodiments, R 6 is -C(NR 1 a )NR 1b R 1c (R 1a , R 1b , and R 1c are each defined herein. In certain embodiments, R 6 is -C(S)R 1a (R 1a teeth, As defined herein. In certain embodiments, R 6 is -C( S)OR 1a (R 1a is as defined herein. In terms of form, R 6 is -C(S)NR 1b R 1c (R 1b and R 1c are the same as those in this specification. In certain embodiments, R 6 -OR 1a (R 1a is as defined herein. In certain embodiments, R 6 teeth , -OC(O)R 1a (R 1a is as defined herein. In certain embodiments, R 6 is -OC(O)OR 1a (R 1a is defined herein In certain embodiments, R 6 is -OC(O)NR 1b R 1c ( R 1b and R 1c are each as defined herein. In embodiments, R 6 is -OC(O)SR 1a (R 1a is as defined herein In certain embodiments, R 6 is -OC(=NR 1a )NR 1b R 1 c (R 1a , R 1b , and R 1c are each as defined herein) In certain embodiments, R 6 is -OC(S)R 1a (R 1a is defined herein In certain embodiments, R 6 is -OC(S)OR 1a (R 1a is as defined herein. In certain embodiments, R 6 is -OC(S)NR 1b R 1c (R 1b and R 1c are each defined herein. In certain embodiments, R 6 is -OS(O)R 1a (R 1 a is as defined herein. In certain embodiments, R 6 teeth, -OS(O)2R 1a (R 1a is as defined herein. In certain embodiments, R 6 is -OS(O)NR 1b R 1c (R 1b and R 1c are respectively , as defined herein). In certain embodiments, R 6 -O S(O)NR 1b R 1c (R 1b and R 1c are each defined herein. In certain embodiments, R 6 is -NR 1b R 1c (R 1b and R 1 cand each are as defined herein. In certain embodiments, R 6 is -NR 1a C(O)R 1d (R 1a and R 1d are each defined herein. In certain embodiments, R 6 is -NR 1a C(O)OR 1 d (R 1a and R 1d and each are as defined herein. In certain embodiments, R 6 is -NR 1a C(O)NR 1b R 1c (R 1a , R 1b , and R 1c and each are as defined herein. In certain embodiments, is R 6 is -NR 1a C(O)SR 1d (R 1a and R 1d are defined herein. In certain embodiments, R 6 is -NR 1a C(=N R 1d )NR 1b R 1c (R 1a , R 1b , R 1c , and R 1d are respectively used herein In certain embodiments, R 6 is -NR 1a C(S )R 1d (R 1a and R 1d are each as defined herein) In certain embodiments, R 6 is -NR 1a C(S)OR 1d (R 1a and R 1d Haso and , each as defined herein. In certain embodiments, R 6 teeth , -NR 1a C(S)NR 1b R 1c (R 1a , R 1b , and R 1c are the same as those in this specification. In certain embodiments, R 6 is -NR 1a S (O)R 1d (R 1a and R 1d are each as defined herein) In certain embodiments, R 6 is -NR 1a S(O)2R 1d (R 1a and R 1d and each are as defined herein. In certain embodiments, R 6 is -NR 1a S(O)NR 1b R 1c (R 1a , R 1b , and R 1c are the books respectively. (as defined herein). In certain embodiments, R 6 is -NR 1 a S(O)NR 1b R 1c (R 1a , R 1b , and R 1c are each defined herein. In certain embodiments, R 6 is -S(O)R1a (R 1a is as defined herein. In certain embodiments, R 6 teeth , -S(O)2R 1a (R 1a is as defined herein. In certain embodiments, R 6 is -S(O)NR 1b R 1c (R 1b and R 1c are respectively, As defined herein. In certain embodiments, R 6 is -S( O)2NR 1b R 1c (R 1b and R 1c are each as defined herein (That is).

[0092] In certain embodiments, R X is hydrogen. In certain embodiments, R X is deuterium In certain embodiments, R X is cyano. In certain embodiments, R X Ha, Hello In certain embodiments, R X is nitro. In certain embodiments, R X is one C optionally substituted with the above substituent Q 1-6 In certain embodiments, R X is methyl optionally substituted with one or more substituents Q. In certain embodiments, R X teeth , C optionally substituted with one or more substituents Q 2-6 In certain embodiments, is R X is C optionally substituted with one or more substituents Q 2-6 Alkynyl. In embodiments, R X is C optionally substituted with one or more substituents Q 3-10 Cycloalkane In certain embodiments, R X is C optionally substituted with one or more substituents Q 6- 14 In certain embodiments, R X is optionally substituted with one or more substituents Q C 7-15 In certain embodiments, R X is one or more substituents Q In certain embodiments, R is an optionally substituted heteroaryl. X is one or more substitutions The group Q is an optionally substituted heterocyclyl.

[0093] In certain embodiments, R X is -C(O)R 1a (R 1a is defined herein In certain embodiments, R X is -C(O)OR 1a (R 1a teeth , as defined herein). In certain embodiments, R X -C (O)NR 1b R 1c (R 1b and R 1c are each as defined herein In certain embodiments, R X is -C(O)SR 1a (R 1a This specification In certain embodiments, R X is -C(NR 1 a )NR 1b R 1c (R 1a , R 1b, and R 1c are each defined herein. In certain embodiments, R X is -C(S)R 1a (R 1a teeth, As defined herein. In certain embodiments, R X is -C( S)OR 1a (R 1a is as defined herein. In terms of form, R X is -C(S)NR 1b R 1c (R 1b and R 1c are the same as those in this specification. In certain embodiments, R X -OR 1a (R 1a is as defined herein. In certain embodiments, R X teeth , -OC(O)R 1a (R 1a is as defined herein. In certain embodiments, R X is -OC(O)OR 1a (R 1a is defined herein In certain embodiments, R X is -OC(O)NR 1b R 1c ( R 1b and R 1c are each as defined herein. In embodiments, R X is -OC(O)SR 1a (R 1a is as defined herein In certain embodiments, R X is -OC(=NR 1a)NR 1b R 1 c (R 1a , R 1b , and R 1c are each as defined herein) In certain embodiments, R X is -OC(S)R 1a (R 1a is defined herein In certain embodiments, R X is -OC(S)OR 1a (R 1a is as defined herein. In certain embodiments, R X is -OC(S)NR 1b R 1c (R 1b and R 1c are each defined herein. In certain embodiments, R X is -OS(O)R 1a (R 1 a is as defined herein. In certain embodiments, R X teeth, -OS(O)2R 1a (R 1a is as defined herein. In certain embodiments, R X is -OS(O)NR 1b R 1c (R 1b and R 1c are respectively , as defined herein). In certain embodiments, R X -O S(O)NR 1b R 1c (R 1b and R 1c are each defined herein. In certain embodiments, R X is -NR 1b R 1c (R 1b and R 1 c and each are as defined herein. In certain embodiments, R X is -NR 1a C(O)R 1d (R 1a and R 1d are each defined herein. In certain embodiments, R X is -NR 1a C(O)OR 1 d (R 1a and R 1d and each are as defined herein. In certain embodiments, R X is -NR 1a C(O)NR 1b R 1c (R 1a , R 1b , and R 1c and each are as defined herein. In certain embodiments, is R X is -NR 1a C(O)SR 1d (R 1a and R 1d are defined herein. In certain embodiments, R X is -NR 1a C(=N R 1d )NR 1b R 1c (R 1a , R 1b , R 1c , and R 1d are respectively used herein In certain embodiments, R Xis -NR 1a C(S )R 1d (R 1a and R 1d are each as defined herein) In certain embodiments, R X is -NR 1a C(S)OR 1d (R 1a and R 1d Haso and , each as defined herein. In certain embodiments, R X teeth , -NR 1a C(S)NR 1b R 1c (R 1a , R 1b , and R 1c are the same as those in this specification. In certain embodiments, R X is -NR 1a S (O)R 1d (R 1a and R 1d are each as defined herein) In certain embodiments, R X is -NR 1a S(O)2R 1d (R 1a and R 1d and each are as defined herein. In certain embodiments, R X is -NR 1a S(O)NR 1b R 1c (R 1a , R 1b , and R 1c are the books respectively. (as defined herein). In certain embodiments, R X is -NR 1 a S(O)NR 1b R 1c (R1a , R 1b , and R 1c are each defined herein. In certain embodiments, R X is -S(O)R 1a (R 1a is as defined herein. In certain embodiments, R X teeth , -S(O)2R 1a (R 1a is as defined herein. In certain embodiments, R X is -S(O)NR 1b R 1c (R 1b and R 1c are respectively, As defined herein. In certain embodiments, R X is -S( O)2NR 1b R 1c (R 1b and R 1c are each as defined herein (That is).

[0094] In certain embodiments, m is 0. In certain embodiments, m is 1. In embodiments, m is 2. In certain embodiments, m is 3. So m is 4.

[0095] In certain embodiments, X is -SO2-. In certain embodiments, X is -NR X -(R X is as defined herein. In certain embodiments, X is -NH-.

[0096] In certain embodiments, Y is -SO2-. In certain embodiments, Y is -NR X -(R X is as defined herein. In certain embodiments, Y is -NH-.

[0097] In one embodiment, 4-(N-(3-(methylsulfonamido)phenyl)sulfamoyl)benzoic acid (A 1); 3-(N-(2-methyl-5-(trifluoromethyl)phenyl)sulfamoyl)ammonium Zozoic acid (A2); 3-(N-(3,5-dimethoxyphenyl)sulfamoyl)benzoic acid (A3); if Kuha 3-((2-Methoxy-5-nitrophenyl)sulfonamido)-4-methylbenzoic acid (A4); or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. Provided in the specification.

[0098] In another embodiment, 4-(N-(3-(methylsulfonamido)phenyl)sulfamoyl)benzoic acid (A 1); 3-(N-(2-methyl-5-(trifluoromethyl)phenyl)sulfamoyl)ammonium Zozoic acid (A2); 3-(N-(3,5-dimethoxyphenyl)sulfamoyl)benzoic acid (A3); 3-((2-Methoxy-5-nitrophenyl)sulfonamido)-4-methylbenzoic acid (A4); or 2-Fluoro-4-(N-(3-(methylsulfonamido)phenyl)sulfamoyl )benzoic acid (A5); or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. Provided in the specification.

[0099] In certain embodiments, the compounds provided herein are deuterium enriched. In embodiments, the compounds provided herein are carbon-13 enriched. In some embodiments, the compounds provided herein are carbon-14 enriched. In the case of nitrogen, the compounds provided herein are 15 N; for oxygen 17 O or 18 For O and sulfur, 33 S, 34 S, or 36 Including but not limited to S , containing one or more less common isotopes of other elements.

[0100] In certain embodiments, the compounds provided herein have a concentration of about 5 or more, about 10 or more, about 20 or more, about 30 or more, about 40 or more, about 50 or more, about 60 or more, about 70 or more, about 80 or more, about Over 90, over 100, over 200, over 500, over 1,000, over 2,000 0 or greater, about 5,000 or greater, or about 10,000 or greater. In any case, the isotopic enrichment factor for a particular isotope is determined by the chemical For a particular isotope, the isotopic enrichment factor is the isotopic enrichment factor when the compound is 100% enriched in that particular isotope. Therefore, the maximum isotopic enrichment factor varies depending on the isotope. The maximum isotopic enrichment factor is 6410 for deuterium and 90 for carbon-13. be.

[0101] In certain embodiments, the compounds provided herein have a deuterium enrichment of about 64 (about 1%). or more, about 130 (about 2% deuterium enrichment) or more, about 320 (about 5% deuterium enrichment) or more, about 640 (approximately 10% deuterium enrichment) or more, approximately 1,300 (approximately 20% deuterium enrichment) or more, approximately 3,200 (approximately 50% deuterium enrichment) or more, approximately 4,800 (approximately 75% deuterium enrichment) or more , approximately 5,130 (approximately 80% deuterium enrichment) or more, approximately 5,450 (approximately 85% deuterium enrichment) Above 5,770 (about 90% deuterium enrichment), above 6,090 (about 95% deuterium enrichment) 6,220 (approx. 97% deuterium enrichment) or more, approx. 6,280 (approx. 98% heavy water Deuterium enrichment) or more, about 6,350 (about 99% deuterium enrichment) or more, or about 6,380 (about 9 Deuterium enrichment is determined by mass spectrometry and It can be determined using conventional analytical methods known to those skilled in the art, including nuclear magnetic resonance spectroscopy. .

[0102] In certain embodiments, the compounds provided herein have a carbon-13 Concentration) or more, about 4.5 (about 5% carbon-13 concentration) or more, about 9 (about 10% carbon-13 concentration) 18 (approximately 20% carbon-13 enrichment) or more, approximately 45 (approximately 50% carbon-13 enrichment) or more 68 (approximately 75% carbon-13 enrichment), approximately 72 (approximately 80% carbon-13 enrichment) 77 (approximately 85% carbon-13 enrichment) or more, approximately 81 (approximately 90% carbon-13 enrichment) or more 86 (approximately 95% carbon-13 enrichment) or more, approximately 87 (approximately 97% carbon-13 enrichment) or more 88 (approximately 98% carbon-13 enrichment) or more, approximately 89 (approximately 99% carbon-13 enrichment) or more or a carbon-13 enrichment factor of about 90 (about 99.5% carbon-13 enrichment). Carbon-13 enrichment can be performed using methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy. The determination can be made using conventional analytical methods known in the art.

[0103] In certain embodiments, the compounds provided herein that are identified as being isotopically enriched are At least one of the atoms of the compound is about 1% or more, about 2% or more, about 5% or more, about 10% or more, approximately 20% or more, approximately 50% or more, approximately 70% or more, approximately 80% or more, approximately 90% or more or has an isotopic enrichment of about 98% or greater. In certain embodiments, the isotopically enriched The atoms of the compounds provided herein that are identified as having at least about 1%, at least about 2% Above, about 5% or more, about 10% or more, about 20% or more, about 50% or more, about 70% or more, about 80% or greater, about 90% or greater, or about 98% or greater isotopic enrichment. Isotopically enriched atoms of compounds provided in the specification are based on the natural abundance of the specified isotope. More than the amount available.

[0104] In certain embodiments, the compounds provided herein that are identified as being deuterium enriched are At least one of the atoms of the compound is about 1% or more, about 2% or more, about 5% or more, about 10% or more, approximately 20% or more, approximately 50% or more, approximately 70% or more, approximately 80% or more, approximately 90% or more or has a deuterium enrichment of about 98% or greater. In certain embodiments, the deuterium enriched The atoms of the compounds provided herein that are identified as having at least about 1%, at least about 2% Above, about 5% or more, about 10% or more, about 20% or more, about 50% or more, about 70% or more, about 80% or greater, about 90% or greater, or about 98% or greater deuterium enrichment.

[0105] In certain embodiments, 13C-enriched At least one of the atoms of the compound is about 2% or more, about 5% or more, about 10% or more, About 20% or more, about 50% or more, about 70% or more, about 80% or more, about 90% or more, or about 9 In certain embodiments, the carbon-13 enrichment is 8% or greater. 13 C-enriched and The atoms of the compounds provided herein identified as % or more, about 10% or more, about 20% or more, about 50% or more, about 70% or more, about 80% or more, about having a carbon-13 enrichment of 90% or greater, or about 98% or greater.

[0106] In certain embodiments, the compounds provided herein are isolated or purified. In embodiments, the compounds provided herein comprise at least about 50% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight %, at least about 98% by weight, at least about 99% by weight, or at least about 99.5% by weight It has a purity of % by volume.

[0107] The compounds provided herein represent all possible stereochemistry unless a particular stereochemistry is specified. Stereoisomers are intended to be encompassed. groups, the compounds may exist in one or more geometric cis / trans (or Z / E) isomers. Where structural isomers are interconvertible, the compounds may exist as a single tautomer. It may exist as a mixture of isomers or tautomers. This is the case, for example, with imino, keto groups. or proton tautomerism in compounds containing an oxime group; or aromatic moieties This can occur in the form of so-called valence tautomerism in compounds containing a single It follows that compounds may exhibit more than one type of isomerism.

[0108] The compounds provided herein may be single enantiomers or single diastereomers. It may be enantiomerically pure, such as , or a mixture of enantiomers, e.g. a racemic mixture of two enantiomers; or a mixture of two or more diastereomers Thus, one skilled in the art can distinguish between the (R) form of a compound and the stereoisomeric mixture of If the compound undergoes epimerization in vivo, administration of the (S) form of the compound Recognizing that administration is equivalent to conventional techniques for the preparation / isolation of individual enantiomers The techniques include synthesis from suitable optically pure precursors, asymmetric synthesis from asymmetric starting materials, or Resolution of enantiomeric mixtures, e.g., chiral chromatography, recrystallization, resolution, diastereomeric Formation of stereomeric salts or derivatization to diastereomeric adducts followed by separation Included.

[0109] When a compound provided herein contains an acidic or basic moiety, it also It may be provided as a pharmaceutically acceptable salt. Berge et al., J. Pharm Sci. 1977,66,1-19;Handbook of Pharmace utical Salts: Properties, Selection, and Use,2nd ed.;Stahl and Wermuth Eds.;Wiley -VCH and VHCA, Zurich, 2011. Certain embodiments Thus, pharmaceutically acceptable salts of the compounds provided herein are hydrates.

[0110] Suitable acids for use in preparing pharmaceutically acceptable salts include acetic acid, 2,2-dichlorobenzoic acid, Acetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-asparagine Acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphor Camphor acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, Capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexane Sulfamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2 -Hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glutamic acid Coheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglucan Taric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid , malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfo nicotine, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid Acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, Acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid , stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p - including but not limited to toluenesulfonic acid, undecylenic acid, and valenic acid In certain embodiments, the compounds provided herein are hydrochloride salts.

[0111] Suitable bases for use in preparing pharmaceutically acceptable salts include magnesium hydroxide, water, Inorganic bases such as calcium oxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide ; as well as L-arginine, benzamine, benzathine, choline, dianol, and diethanolamine Aminoamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine , 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine Amines, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazoline L-Lysine, Morpholine, 4-(2-hydroxyethyl)-morpholine, Methyl alcohol amine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)amine (ethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine Aminomethylamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-aminomethyl-D-glucamine Contains tromethamine, 2-(hydroxymethyl)-1,3-propanediol, and tromethamine These include organic bases such as primary, secondary, tertiary, and quaternary aliphatic and aromatic amines. These include, but are not limited to:

[0112] The compounds provided herein are also functional derivatives of compounds of Formula I, for example, and may be provided as a prodrug which is readily convertible in vivo into the parent compound. Prodrugs are often preferred because, in some situations, they may be easier to administer than the parent compound. They are often useful, for example, because they may be bioavailable by oral administration. Prodrugs also tend to be more readily available in pharmaceutical compositions than the parent compound, whereas the parent compound is not. Prodrugs may undergo various processes, including enzymatic processes and metabolic hydrolysis, and may have improved solubility. can be converted to the parent drug by various mechanisms. Drug Research 1962,4,221-294;Morozowich et al. in Design of Biopharmaceutical Pr operties through Prodrugs and Analogs,”R oche Ed.,APHA Acad. Pharm. Sci. 1977;“Bi oreversible Carriers in Drug in Drug Des ign,Theory and Application,”Roche Ed.,AP HA Acad. Pharm. Sci. 1987;“Design of Pro drugs,” Bundgaard,Elsevier,1985;Wang et al.,Curr. Pharm. Design 1999,5,265-287;P auletti et al.,Adv. Drug. Delivery Rev.1 997,27,235-256;Mizen et al.,Pharm. Biote ch. 1998,11,345-365;Gaignault et al.,Pra ct. Med. Chem. 1996,671-696;Asgharnejad in “Transport Processes in Pharmaceutica l Systems,” Amidon et al.,Ed.,Marcell De kker,185-218,2000;Balant et al.,Eur. J.D rug Metab. Pharmacokinet. 1990,15,143-53 ;Balimane and Sinko,Adv. Drug Delivery R ev. 1999,39,183-209;Browne,Clin. Neuroph armacol. 1997,20,1-12;Bundgaard,Arch. Ph arm. Chem. 1979,86,1-39;Bundgaard,Contro lled Drug Delivery 1987,17,179-96;Bundga ard,Adv. Drug Delivery Rev.1992,8,1-38;F leisher et al.,Adv. Drug Delivery Rev. 1 996,19,115-130;Fleisher et al.,Methods E nzymol.1985,112,360-381;Farquhar et al., J.Pharm. Sci. 1983,72,324-325;Freeman et al.,J.Chem.Soc.,Chem. Commun. 1991,875- 877;Friis and Bundgaard,Eur. J.Pharm. Sc i. 1996,4,49-59;Gangwar et al.,Des. Biop harm. Prop. Prodrugs Analogs,1977,409-42 1;Nathwani and Wood,Drugs 1993,45,866-94 ;Sinhababu and Thakker,Adv. Drug Deliver y Rev.1996,19,241-273;Stella et al.,Drug s 1985,29,455-73;Tan et al.,Adv. Drug De livery Rev.1999,39,117-151;Taylor,Adv. D rug Delivery Rev. 1996,19,131-148;Valent ino and Borchardt,Drug Discovery Today 1 997,2,148-155;Wiebe and Knaus,Adv. Drug Delivery Rev. 1999,39,63-80; and Waller et al.,Br. J. Clin. Pharmac. 1989,28,497-50 Please refer to 7.

[0113] The compounds provided herein may be prepared by any method known to one of skill in the art. In certain embodiments, the compound of Formula V can be isolated or obtained from a compound of Formula V shown in Scheme I. (L is a leaving group (e.g., chloro or bromo) and;R P is a carboxylic acid protecting group; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R X and m are each as defined herein). Compound 1 is reacted with Compound 2. Coupling followed by removal of the protecting group forms a compound of formula V. [ka]

[0114] In one embodiment, compounds A1 and A5 are synthesized as shown in Scheme II below. can be. [ka]

[0115] In one embodiment, compound A2 is synthesized as shown in Scheme III below. [ka]

[0116] In one embodiment, compound A3 is synthesized as shown in Scheme IV below. [ka]

[0117] In one embodiment, the pharmaceutical compositions provided herein comprise a compound provided herein. For example, a compound of formula I, or an enantiomer thereof, a mixture of enantiomers, or a mixture of two or more a mixture of the above diastereomers, tautomers, a mixture of two or more tautomers, or or a pharmaceutically acceptable salt, solvate, hydrate, or the like thereof. and a pharmaceutically acceptable excipient, can be.

[0118] In another embodiment, the pharmaceutical compositions provided herein comprise a compound provided herein. a compound of formula I, or an enantiomer thereof, a mixture of two enantiomers, A mixture of the above diastereomers, tautomers, a mixture of two or more tautomers, or or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates, or is formulated into a dosage form for parenteral administration, comprising a prodrug; and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical compositions provided herein are formulated for intravenous administration. In another embodiment, the pharmaceutical compositions provided herein are formulated for intramuscular administration. In yet another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for administration. The composition is formulated in a dosage form for subcutaneous administration.

[0119] In yet another embodiment, the pharmaceutical compositions provided herein comprise a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers thereof product, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof and a pharmaceutically acceptable excipient. It is formulated in

[0120] The compounds provided herein may be used alone or in combination with one or more other compounds provided herein. The compounds provided herein, such as compounds of Formula I, can be administered in combination with Pharmaceutical compositions containing the compounds are formulated in a variety of dosage forms for oral, parenteral, and topical administration. The pharmaceutical compositions may also be used to delay, extend, prolong, sustain, pulsatile, controlled, accelerated, fast acting, targeted, They can be formulated as modified release dosage forms, including programmed release and gastroretentive dosage forms. The dosage forms may be prepared according to conventional methods and techniques known to those skilled in the art (Reming ton: The Science and Practice of Pharmac. y,supra;Modified-Release Drug Delivery T echnology, 2nd Edition, Rathbone et al.,Ed. Marcel Dekker, Inc.: New York, NY, 2008. See the reference.

[0121] The pharmaceutical compositions provided herein may be provided in unit-dosage form or multi-dosage form. Dosage form, as used herein, refers to a physical unit suitable for administration to human and animal subjects. Individually packaged and individually individualized as known in the art. A dose is a predetermined amount of the active ingredient(s) required to produce the desired therapeutic effect. Examples of unit dosage forms include ampoules, syringes, and the like. Unit dosage forms include individual packaged tablets and capsules. Multiple dose forms may be administered in separate unit dosage forms in a single container. A packaged plurality of identical unit dosage forms. Examples of multiple-dosage forms include vials, tablets, or This includes bottles of capsules or bottles of pints or gallons.

[0122] The pharmaceutical compositions provided herein may be administered at once or multiple times at intervals of time. The exact dosage and duration of treatment will depend on the age, weight, and condition of the patient being treated. These may vary depending on the condition and may be determined empirically or in vivo using known testing protocols. or can be determined by in vitro testing or extrapolation from diagnostic data. It is understood that for any particular individual, the particular dosing regimen will depend on the individual's needs and the formulation. should be adjusted over time according to the professional judgment of the person administering or supervising the administration of It is further understood that

[0123] A. Oral Administration The pharmaceutical compositions provided herein for oral administration include solid, semi-solid, or steroid-resistant compositions for oral administration. As used herein, oral administration may also be provided in buccal or liquid form. Suitable oral dosage forms include tablets, fast dissolving tablets, chewable tablets, capsules, and nasal, lingual, and sublingual administration. Cells, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chews gums, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsifiers These include solutions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), pharmaceutical compositions may contain binders, fillers, , diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye transfer inhibitors, sweeteners, flavoring agents Flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and carbon dioxide sources containing one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, obtain.

[0124] Binders or granulating agents are compounds that are packed into the tablet to ensure that the tablet remains intact after compression. Suitable binders or granulating agents include starches, such as corn starch, Potato starch and pregelatinized starch (e.g., STARCH 150 0); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and raspberry natural and synthetic gums, e.g., acacia, alginic acid, alginates, iris Extracts of schmos, panwar gum, ghatti gum, isabgol Shell mucus, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (P VP), Veegum, Larch Aromatic Acid, Powdered Tragacanth, and Guar Gum cellulose, e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose; Calcium cellulose, sodium carboxymethylcellulose, methylcellulose, hydro Hydroxyethyl cellulose (HEC), Hydroxypropyl cellulose (HPC), Hydroxypropyl cellulose hydroxypropylmethylcellulose (HPMC); microcrystalline cellulose, e.g., AVICEL -PH-101, AVICEL-PH-103, AVICEL RC-581, AVIC EL-PH-105 (FMC Corp., Marcus Hook, PA); and Suitable fillers include, but are not limited to, talc, calcium carbonate, and mixtures thereof. Calcium, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof Binders in the pharmaceutical compositions provided herein include, but are not limited to, Alternatively, the amount of filler will vary depending on the type of formulation and is readily discernible to one skilled in the art. The binder or filler may be present in the pharmaceutical compositions provided herein in an amount ranging from about 50% to about 99% by weight. It may be present in a weight percent.

[0125] Suitable diluents include dicalcium phosphate, calcium sulfate, lactose, and sorbitol. , sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, These include, but are not limited to, dry starch, and powdered sugar. Certain diluents, such as sorbitol, sucrose, and inositol, are present in sufficient quantities. Some compressed tablets, when present, have properties that allow them to disintegrate in the mouth by chewing. Such compressed tablets may be used as chewable tablets. The amount of diluent in a pharmaceutical composition to be used varies depending on the type of formulation and is readily apparent to those skilled in the art. can be identified as

[0126] Suitable disintegrants include agar; bentonite; methylcellulose and carboxymethylcellulose. cellulose such as cellulose;wood products;natural sponges;cation exchange resins;alginic acid;glucan Gums such as Argum and Veegum HV; citrus pulp; croscarmellose Cross-linked cellulose; cross-linked polymers such as crospovidone; cross-linked starch; calcium carbonate; Microcrystalline cellulose such as sodium starch glycolate; polacrilin potassium; starch, potato starch, tapioca starch, and pregelatinized starch clays; algin; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation. The disintegrating agent in the pharmaceutical compositions provided herein is readily identifiable to one skilled in the art. The amount of disintegrant varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions provided herein may contain from about 0.5% to about 15% by weight or from about 1% to about 5% by weight. % by weight of a disintegrant.

[0127] Suitable lubricants include calcium stearate; magnesium stearate; mineral oil; light Mineral oil; glycerin; sorbitol; mannitol; glycerol behenate and polyethylene Glycols such as ethylene glycol (PEG); stearic acid; sodium lauryl sulfate; Talc; peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil Hydrogenated vegetable oil containing oil; Zinc stearate; Ethyl oleate; Ethyl laurate; Agar; Starch; Lycopodium; AEROSIL® 200 (WR Grace Co. Baltimore, MD) and CAB-O-SIL® (Boston Silica or silica gel, such as Cabot Co., MA; and mixtures thereof. The pharmaceutical compositions provided herein include, but are not limited to, about 0.1 to It may contain about 5% by weight of a lubricant.

[0128] Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® ( Cabot Co. of Boston, MA), and asbestos-free talc. Suitable coloring agents include, but are not limited to, approved and certified water-soluble FD&C dyes; and water-insoluble FD&C dyes and color lakes suspended in alumina hydrate and Color lakes include, but are not limited to, any mixture of water-soluble dyes. Combination by adsorption onto hydrous oxides of the metal, resulting in an insoluble form of the dye Suitable flavoring agents include natural flavors extracted from fruits and other plants, as well as peppermint. These include synthetic mixtures of compounds that produce a pleasant taste sensation, such as methyl salicylate and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, sucrose, and the like. Contains cereals containing gluten, glycerin, and artificial sweeteners such as saccharin and aspartame Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, benzyl alcohol, PEG-40, PEG-45, PEG-46, PEG-47, PEG-48, PEG-49 ... Tonite, and surfactants such as polyoxyethylene sorbitan monooleate (T WEEN® 20), polyoxyethylene sorbitan monooleate 80 (TW EEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, phenoxyethanol, PEG-10 ... Cutin, Tragacanth, Veegum, Acacia, Carbomethylcellulose Sodium, These include, but are not limited to, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propyl paraben, benzoic acid Suitable wetting agents include, but are not limited to, sodium benzoate and alcohol. Contains propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and Suitable non-aqueous emulsions include, but are not limited to, syrups and syrups. Liquids include, but are not limited to, mineral oil and cottonseed oil. Suitable carbon dioxide sources include, but are not limited to, sodium bicarbonate, acetic acid, and tartaric acid. These include, but are not limited to, thorium and sodium carbonate.

[0129] Many carriers and excipients may serve several functions, even within the same formulation. It should be understood.

[0130] The pharmaceutical compositions provided herein for oral administration include compressed tablets, powder tablets, chewable tablets, and the like. Lozenges, fast-dissolving tablets, multiple compressed tablets, or enteric-coated tablets, sugar-coated tablets They may be provided as enteric-coated or film-coated tablets. The tablets resist the action of stomach acid but dissolve or disintegrate in the intestine, thereby absorbing the acidic environment of the stomach. It is a compressed tablet coated with a substance that protects the active ingredient. , fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac and cellulose acetate phthalate. Coated tablets are compressed tablets surrounded by a sugar coating that can have an objectionable taste. or may be beneficial in masking odors and protecting tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of water-soluble material. The film coating contains hydroxyethyl cellulose, carboxymethylcellulose, and Sodium ethyl cellulose, polyethylene glycol 4000, and cellulose acetate Film coatings include, but are not limited to, sugar coatings. Multiple compressed tablets are layered tablets and press coated tablets. or tablets produced by multiple compression cycles, including dry-coated tablets. It is a compressed tablet.

[0131] Tablet dosage forms consist of active ingredients in powder, crystalline, or granular form, either alone or in combination. The compositions described herein may include a disintegrant, a controlled release polymer, a lubricant, a diluent, and / or a coloring agent. They may be prepared in combination with one or more of the carriers or excipients described. It is particularly useful in forming chewable tablets and lozenges.

[0132] The pharmaceutical compositions provided herein for oral administration may contain gelatin, methylcellulose, It is presented as a soft or hard capsule which may be made from starch, calcium alginate, or Hard gelatin capsules, also known as dry-filled capsules (DFCs), are available in two sections, one sliding over the other, thereby completely enclosing the active ingredient. A soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, that Plasticized by the addition of serine, sorbitol, or similar polyols The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives include methyl- and propyl-paraben, and sorbic acid. As described herein, the liquid, semi-solid, and solid dosage forms Suitable liquid and semi-solid dosage forms include propylene carbonate, vegetable oil, or triglyceride solutions and suspensions. Capsules containing such solutions are U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,5 Capsules may also be prepared as described in US Pat. No. 45,855, which is incorporated herein by reference. Capsules may also be prepared by modifying or dissolving the active ingredient. For example, the adhesive may be coated to provide a permanent seal or to provide a permanent seal, as known to those skilled in the art.

[0133] The pharmaceutical compositions provided herein for oral administration may be in the form of emulsions, solutions, suspensions, or the like. They can be provided in liquid and semisolid dosage forms, including emulsions, elixirs, and syrups. An oil-in-water mixture is a two-phase system in which one liquid is dispersed in the form of small droplets throughout another liquid. Emulsions can be of the water-in-oil or oil-in-water type. Suspensions may contain pharmaceutically acceptable suspending agents and solvents, emulsifying agents, and preservatives. The aqueous alcoholic solution may contain a pharmaceutically acceptable acetal, e.g., Di(lower alkyl) acetals of lower alkyl aldehydes, for example, acetaldehyde di ethyl acetal; and water-miscible solvents having one or more hydroxyl groups, such as It may contain propylene glycol and ethanol. Elixirs are clear, sweetened, hydrous liquids. Syrup is a concentrated aqueous solution of a sugar, e.g., sucrose, and is a preservative. In the case of a liquid dosage form, for example, a solution in polyethylene glycol may be used at the time of administration. and diluting with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to conveniently measure the amount of It can be done.

[0134] Other useful liquid and semisolid dosage forms include those containing the active ingredient(s) provided herein and 1,2-Dimethoxymethane, Diglyme, Triglyme, Tetraglyme, Polyethylene Glyco Glycol-350-dimethyl ether, Polyethylene glycol-550-dimethyl ether , polyethylene glycol-750-dimethyl ether (350, 550, and 750 refers to the approximate average molecular weight of polyethylene glycol) These include, but are not limited to, those containing alkylene or polyalkylene glycols. These formulations contain butylated hydroxytoluene (BHT), butylated hydroxyanisole, BHA, Propyl Gallate, Vitamin E, Hydroquinone, Hydroxycoumarin , ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol , phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters , as well as one or more antioxidants such as dithiocarbamates.

[0135] The pharmaceutical compositions provided herein for oral administration may also be formulated in liposomes, micelles, macrophages, or other microspheres. Micellar dosage forms may be provided in the form of microspheres, or nanosystems. Micellar dosage forms are described in U.S. Pat. They can be prepared as described in US Pat. No. 6,350,458.

[0136] The pharmaceutical compositions provided herein for oral administration are non-steroidal anti-inflammatory drugs that are reconstituted into a liquid dosage form. It may be provided as effervescent or effervescent granules and powders. Pharmaceutically acceptable carriers and excipients may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders include organic acids and diacids. The feed may contain a source of oxidized carbon.

[0137] Coloring and flavoring agents may be used in all of the above dosage forms.

[0138] The pharmaceutical compositions provided herein for oral administration may be administered in delayed, sustained, pulsed, controlled, or They may be formulated as immediate or modified release dosage forms, including targeted and programmed release forms.

[0139] B. Parenteral Administration The pharmaceutical compositions provided herein can be administered by injection, infusion, or other suitable means for local or systemic administration. The drug may be administered parenterally by injection or implantation. In case of intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrathoracic, intracranial, intramuscular, These include intravesical, intravesical, and subcutaneous administration.

[0140] The pharmaceutical compositions provided herein for parenteral administration may be administered as a solution in liquid prior to injection or Suitable for suspensions, solutions, suspensions, emulsions, micelles, liposomes, microspheres They can be formulated in any dosage form suitable for parenteral administration, including as nanosystems, and solid forms. Such dosage forms may be prepared according to conventional methods known to those skilled in the art of pharmaceutical science. (Remington: The Science and Practice of (See Pharmacy, supra).

[0141] Pharmaceutical compositions for parenteral administration may be formulated in aqueous vehicles, water-miscible vehicles, or non-aqueous vehicles. antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, tonicity agents, buffers anti-oxidant, local anesthetic, suspending and dispersing agent, wetting or emulsifying agent, complexing agent, sequestering or Chelating agents, cryoprotectants, lyoprotectants, thickeners, pH adjusters, and inert gases The composition may include one or more pharmaceutically acceptable carriers and excipients, including but not limited to:

[0142] Suitable aqueous vehicles include water, saline, normal saline, or phosphate buffered saline (PB S), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection Injectable solutions include, but are not limited to, dextrose and lactated Ringer's injection. Suitable non-aqueous vehicles include fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, Peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil and medium chain triglycerides of coconut oil, and palm kernel oil. Suitable water-miscible vehicles include ethanol, 1,3-butanediol, liquid polyisoprene, and ethanol. Ethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N -including but not limited to dimethylacetamide, and dimethyl sulfoxide .

[0143] Suitable antimicrobial or antiseptic agents include phenols, cresols, mercurials, benzyl alcohols, and the like. Cholesterol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl para Suitable tonicity agents include, but are not limited to, sorbic acid, sorbic acid, and sorbic acid. Examples of suitable glycerides include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffers include, but are not limited to, phosphate and citrate. Antioxidants include bisulfites and sodium metabisulfite, as described herein. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are sodium carboxymethylcellulose, hydroxypropyl cellulose, propyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include polyoxyethylene sorbitan monolaurate, Polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate Suitable sequestering or chelating agents include those described herein, including E Suitable pH adjusters include, but are not limited to, sodium hydroxide, salts Suitable complexing agents include, but are not limited to, α-citric acid, citric acid, and lactic acid. Cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin Phosphorus, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7- β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Cyclodextrins, including but not limited to cyclodextrins containing KS, are also suitable.

[0144] When the pharmaceutical compositions provided herein are formulated for multiple dose administration: Multi-dose parenteral formulations must contain the antimicrobial agent in a bacteriostatic or bactericidal concentration. All parenteral formulations must be sterile, as known and practiced in the art. Not possible.

[0145] In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is a lyophilized formulation that is reconstituted with a vehicle prior to use. It is provided as a sterile, dry, soluble product, including a powder and a hypodermic tablet. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. The pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle before use. In another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion. It is served.

[0146] The pharmaceutical compositions provided herein for parenteral administration may be administered in a delayed, sustained, pulsed, controlled or controlled manner. They can be formulated as immediate or modified release dosage forms, including targeted and programmed release forms. .

[0147] The pharmaceutical compositions provided herein for parenteral administration are administered as implanted depots. The formulation may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for In embodiments, the pharmaceutical compositions provided herein are insoluble in body fluids, but are insoluble in aqueous solutions. A solid interior surrounded by an outer polymeric membrane that allows the active ingredient in the composition to diffuse through. are dispersed in the matrix.

[0148] Suitable inner matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate Polyisoprene, polyisobutylene, polybutadiene, polyethylene Ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone Corn carbonate copolymer, hydrogels of esters of acrylic and methacrylic acid, etc. Any hydrophilic polymer, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed These include, but are not limited to, degraded polyvinyl acetate.

[0149] Suitable outer polymeric membranes include polyethylene, polypropylene, ethylene / propylene copolymers, Polymer, Ethylene / Ethyl Acrylate Copolymer, Ethylene / Vinyl Acetate Copolymer , silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, poly vinyl chloride, vinyl acetate, vinylidene chloride, vinyl chloride copolymers with ethylene and propylene Polymer, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin Ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers, Not limited to:

[0150] C. Topical Administration The pharmaceutical compositions provided herein may be administered topically to the skin, orifices, or mucous membranes. Topical administration, as used herein, includes (intra)dermal, conjunctival, intracorneal, intraocular, ocular, This includes otic, transdermal, nasal, vaginal, urethral, ​​respiratory, and rectal administration.

[0151] The pharmaceutical compositions provided herein may be in the form of emulsions, solutions, suspensions, creams, gels, or the like. , hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tins ointments, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and Formulated in any dosage form suitable for topical administration for local or systemic effect, including skin patches Topical formulations of the pharmaceutical compositions provided herein may also be formulated in liposomes, micelles, , microspheres, nanosystems, and mixtures thereof.

[0152] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein The agents include aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobials against microbial growth, agents or preservatives, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, Suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, freezing These include, but are not limited to, antiseptics, lyoprotectants, thickening agents, and inert gases. stomach.

[0153] The pharmaceutical compositions may also be used in conjunction with other methods such as electroporation, iontophoresis, phonophoresis, and the like. thrombus formation, sonophoresis, or microneedle or needle-free injection, e.g., POWDE RJECT™ (Chiron Corp., Emeryville, CA), and BIOJECT(TM)(Bioject Medical Technologies It can be administered topically by a steroid agonist (Inc., Tualatin, OR).

[0154] The pharmaceutical compositions provided herein may be provided in the form of ointments, creams, and gels. Suitable ointment vehicles include lard, benzoinated lard, olive oil, cottonseed oil, and Oily or hydrocarbon vehicles, including other oils, white petrolatum; hydrophilic petrolatum, sulfated hydrochloride emulsifying or absorbing vehicles such as stearin, and anhydrous lanolin; hydrophilic ointments, etc. Water-removable vehicle; water-soluble ointment vehicle containing polyethylene glycols of various molecular weights Contains cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid Emulsion vehicle (water-in-oil (W / O) emulsion or oil-in-water (O / W) emulsion) (Remington: The Science (See Pharmacy Practice, supra.) These vehicles are emollient but generally require the addition of antioxidants and preservatives. Let's say.

[0155] Suitable cream bases can be oil-in-water or water-in-oil. Suitable Cream Vehicles The emulsion may be water washable and contains an oil phase, an emulsifier, and a water phase. The oil phase is referred to as the "internal" phase. Also called oleic acid, it is commonly made from petrolatum and fatty alcohols such as cetyl or stearyl alcohol. The aqueous phase usually (but not necessarily) exceeds the oil phase in volume. Generally, they contain moisturizing agents. Emulsifiers in cream formulations are nonionic and anionic. The surfactant may be a cationic, cationic, or amphoteric surfactant.

[0156] Gels are semi-solid suspension-type systems. Single-phase gels are composed of a substantially uniformly distributed mass of solids throughout the liquid carrier. Suitable gelling agents include carbomers, carboxypolyalkylenes, and hydroxypropyl methylcelluloses. cross-linked acrylic polymers such as polyethylene glycols and CARBOPOL®; oxide, polyoxyethylene-polyoxypropylene copolymer, and polyvinyl alcohol Hydrophilic polymers such as cellulose; hydroxypropyl cellulose, hydroxyethyl cellulose Hydroxypropyl methylcellulose, Hydroxypropyl methylcellulose phthalate cellulose-based polymers such as cellulose, cellulose acetate, and methylcellulose; tragacanth and xanthan gum gums such as gum; sodium alginate; and gelatin. To prepare a uniform gel, dispersing agents such as alcohol or glycerin are added. The gelling agent may be dispersed by trituration, mechanical mixing, and / or agitation. It can be dispersed.

[0157] The pharmaceutical compositions provided herein may be in the form of a suppository, pessary, bougie, compress or patch. ointments, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions into the rectum in the form of a solution, suspension, tampon, gel, foam, spray, or enema These dosage forms may be administered intraurethrally, vaginally, or perivaginally. The Science and Practice of Pharmacy,su It can be prepared using conventional processes as described in pra.

[0158] Rectal, urethral, ​​and vaginal suppositories are solid objects for insertion into body orifices that, at room temperature, Solid, but melts or softens at body temperature to release the active ingredient(s) into the opening Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories are those provided herein. The pharmaceutical composition may contain a base such as a curing agent that produces a melting temperature close to body temperature when formulated with the pharmaceutical composition. materials or vehicles; and bisulfites and sodium metabisulfite, Suitable vehicles include cocoa butter (theobroma oil, ), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti , paraffins, white and yellow waxes, and mono-, di-, and triglycerides of fatty acids. and mixtures of polyvinyl alcohol, hydroxyethyl methacrylate, and poly Various vehicle combinations include, but are not limited to, hydrogels such as acrylic acid. Combinations may also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a vaginal suppository is about 2 to about 3 g.

[0159] The pharmaceutical compositions provided herein may be in the form of solutions, suspensions, ointments, emulsions, gel-forming They may be administered ophthalmically in the form of solutions, powders for solutions, gels, intraocular inserts, and implants.

[0160] The pharmaceutical compositions provided herein may be administered intranasally or by inhalation into the respiratory tract. The pharmaceutical composition can be administered in a pressurized container, pump, spray, nebulizer, e.g., a fine mist. A sprayer, or nebulizer, that uses electrohydrodynamics to generate is 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-hepta It can be used in combination with a suitable propellant, such as fluoropropane, to form an aerosol or The pharmaceutical composition may also be provided in the form of a solution, either alone or in the presence of lactose or It is offered as a dry powder for insufflation in combination with an inert carrier such as a phospholipid; and as a nasal spray. For nasal use, the powder may be administered in a bioadhesive containing chitosan or cyclodextrin. It may contain an adhesive.

[0161] Solutions or preparations for use in pressurized containers, pumps, sprays, atomizers, or nebulizers The suspension may be in ethanol, aqueous ethanol, or a mixture of the active ingredients provided herein. Suitable alternatives for dispersing, solubilizing, or extended release; propellants as solvents; and / or or surfactants such as sorbitan trioleate, oleic acid, or oligolactic acid. It can be formulated to have

[0162] The pharmaceutical compositions provided herein may be about 50 microns or less, or about 10 microns or less. The particles may be micronized to a size suitable for delivery by inhalation, such as a micrometer or less. Particles of this size can be formed by spiral jet milling, fluidized bed jet milling, or nanoparticle formation. To prepare the powder, methods known to those skilled in the art, such as supercritical fluid processing, high pressure homogenization, or spray drying, may be used. It can be prepared using pulverization methods.

[0163] Capsules, blisters and cartridges for use in inhalers or insufflators are a pharmaceutical composition provided herein; a suitable powder base such as lactose or starch; and and powder of performance modifiers such as l-leucine, mannitol, or magnesium stearate Lactose may be formulated to contain a powder mixture. Lactose may be in the form of anhydrous or monohydrate. Other suitable excipients or carriers include dextran, glucose, maltose, , sorbitol, xylitol, fructose, sucrose, and trehalose Pharmaceutical compositions provided herein for inhaled / intranasal administration include, but are not limited to: The product may contain suitable flavorings such as menthol and levomenthol; and / or saccharin and It may further comprise a sweetener such as sodium saccharin.

[0164] The pharmaceutical compositions provided herein for topical administration may be administered in a delayed, sustained, pulsed, controlled, or Can be formulated for immediate or modified release, including targeted and programmed release .

[0165] D. Modified release The pharmaceutical compositions provided herein may be formulated as modified release dosage forms. As used herein, the term "modified release" refers to a compound that, when administered by the same route, refers to a dosage form in which the rate or place of release of the active ingredient(s) differs from that of an immediate dosage form. Modified release dosage forms include delayed, extended, prolonged, sustained, pulsatile, controlled, accelerated and fast-acting, targeted These include, but are not limited to, modified release, programmed release, and gastroretentive dosage forms. Modified release pharmaceutical compositions can be prepared using a variety of modified release devices and formulations known to those skilled in the art. The methods can be prepared using matrix controlled release devices, osmotic controlled release devices, Devices, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings These include, but are not limited to, capsules, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) may also depend on the particle size of the active ingredient(s). and can be modified by changing polymorphism.

[0166] Examples of modified release include U.S. Pat. Nos. 3,845,770; 3,916,899. ; No. 3,536,809; No. 3,598,123; No. 4,008,719; No. 5, No. 674,533; No. 5,059,595; No. 5,591,767; No. 5,120, No. 548; No. 5,073,543; No. 5,639,476; No. 5,354,556 ; No. 5,639,480; No. 5,733,566; No. 5,739,108; No. 5, No. 891,474; No. 5,922,356; No. 5,972,891; No. 5,980, No. 945; No. 5,993,855; No. 6,045,830; No. 6,087,324 ; No. 6,113,943; No. 6,197,350; No. 6,248,363; No. 6, No. 264,970; No. 6,267,981; No. 6,376,461; No. 6,419, Nos. 961; 6,589,548; 6,613,358; and 6,699,50 These include, but are not limited to, those listed in Issue 0.

[0167] 1. Matrix controlled release devices The pharmaceutical compositions provided herein in modified release dosage form may be administered in any suitable form known to those skilled in the art. The device can be fabricated using a TRIXX controlled release device (Takada et al. n “Encyclopedia of Controlled Drug Deliv. ery,” Vol. 2, Mathiowitz Ed., Wiley, 1999 (I want to be).

[0168] In certain embodiments, the pharmaceutical compositions provided herein in modified release dosage form are These include synthetic polymers, as well as naturally occurring polymers and derivatives such as polysaccharides and proteins. Erodible matrices that are water-swellable, erodible, or soluble polymers, including, but not limited to, It is formulated using a fluoroscopy device.

[0169] Materials useful for forming the erodible matrix include chitin, chitosan, dextran, , and pullulan; agar gum, gum arabic, karaya gum, locust bean gum, tiger gum Canth gum, carrageenan, ghatti gum, guar gum, xanthan gum, and sclero Glucans; starches such as dextrin and maltodextrin; hydrophilic materials such as pectin Colloids; phosphatides such as lecithin; alginates; propylene glycol arginine gelatin; collagen; ethyl cellulose (EC), methyl ethyl cellulose (M EC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA ), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate Cetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate Hydroxyethylcellulose (Hydroxyethylcellulose, PEG-1000), and ethylhydroxyethylcellulose (EHE C) Cellulose derivatives such as polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl Glycerol fatty acid esters; Polyacrylamide; Polyacrylic acid; Ethylene Copolymers of acrylic or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ; Poly(2-hydroxyethyl ether) ethyl-methacrylate); polylactide; L-glutamic acid and ethyl-L-glutamate Degradable lactic acid-glycolic acid copolymer; Poly-D-(-)-3-hydroxybenzoate copolymer Butyl methacrylate, methyl methacrylate, ethyl methacrylate acrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethyl Other acrylates such as homopolymers and copolymers of (ethylaminoethyl) methacrylate chloride These include, but are not limited to, acrylic acid derivatives.

[0170] In certain embodiments, the pharmaceutical compositions provided herein comprise a non-erodible matrix. The active ingredient(s) are dissolved or dispersed in an inert matrix. Once dispersed and administered, they are released primarily by diffusion through the inert matrix. Suitable materials for use as erodible matrix devices include insoluble plastics, For example, polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene Diene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, Polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene vinyl acetate Nyl copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer vinyl chloride copolymers with ethylene and propylene, vinyl acetate, vinylidene chloride, and vinyl chloride copolymers with ethylene and propylene , ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, Ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer Polymer, Ethylene / Vinyloxyethanol Copolymer, Polyvinyl Chloride, Plasticized Nylon Plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane oxane, and silicone carbonate copolymers; hydrophilic polymers, such as ethylcellulose cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate and fatty compounds such as carnauba wax, microcrystalline wax, and triglycerides. These include, but are not limited to:

[0171] In matrix controlled release systems, the desired release kinetics can be determined, for example, by the polymer employed. type of polymer, viscosity of polymer, particle size of polymer and / or active ingredient(s), activity The ratio of the active ingredient(s) to the polymer, as well as other excipients or carriers in the composition, can be controlled. It can be controlled.

[0172] The pharmaceutical compositions provided herein in modified release dosage form may be directly compressed, dry or wet. granulation followed by compression, and melt granulation followed by compression. It can be prepared by the method.

[0173] 2. Osmotic Controlled Release Devices The pharmaceutical compositions provided herein in modified release dosage form are suitable for use in single-chamber systems, dual-chamber systems, and Including, but not limited to, Asymmetric Membrane Technology (AMT), and Extruded Core System (ECS) In general, such devices may be fabricated using osmotic controlled release devices that are not The present invention relates to a capsule having at least two components: (a) a core containing an active ingredient; and (b) an encapsulating core. The semipermeable membrane has at least one delivery port. The core is then extracted from the aqueous environment to induce drug release via extrusion through the membrane(s). Control the inflow of water into the

[0174] In addition to the active ingredient(s), the core of the osmotic device optionally may be configured to protect the device from the environment of use. They contain osmotic agents that create the driving force for water transport into the core of the saccharin. One class of osmotic agents is , which are water-swellable hydrophilic polymers also known as "osmopolymers" and "hydrogels." Suitable water-swellable hydrophilic polymers as osmotic agents include hydrophilic vinyl and acrylic polymers. , polysaccharides, such as calcium alginate, polyethylene oxide (PEO), polyethylene Polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxybenzoates) Diethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinyl Polyvinyl alcohol (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymer Polymers, PVA / with hydrophobic monomers such as methyl methacrylate and vinyl acetate PVP copolymer, hydrophilic polyurethane containing large PEO blocks, cross-linked Sodium cellulose, carrageenan, hydroxyethyl cellulose (HEC), hydroxy Propyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), Carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), Sodium glutamate, polycarbophil, gelatin, xanthan gum, and starch These include, but are not limited to, sodium glycolate.

[0175] Another class of osmotic agents affects the osmotic pressure gradient across the barrier of the surrounding coating. The preferred osmogen is an osmogen capable of absorbing water to Gen includes inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, salt Sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sulfite sodium, lithium sulfite, potassium chloride, and sodium sulfate; sugars, e.g., dextran; Trose, fructose, glucose, inositol, lactose, maltose, mannitol toll, raffinose, sorbitol, sucrose, trehalose, and xylitol; Organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, These include, but are not limited to, citric acid, and tartaric acid; urea; and mixtures thereof. .

[0176] Osmotic agents with different dissolution rates affect how rapidly the active ingredient(s) initially dissolves from the dosage form. For example, MANNOGEM™ E Amorphous sugars such as Z (SPI Pharma, Lewis, DE) tend to be more soluble in water within the first few hours. It provides rapid delivery to quickly produce the desired therapeutic effect and gradually and continuously releases the remaining amount. These drugs are used to release the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) may be released at such a rate that they are metabolized and excreted. This replaces the amount of active ingredient used.

[0177] The core may also be used to enhance the performance of the dosage form or to facilitate stability or processing. , may include a wide variety of other excipients and carriers as described herein.

[0178] Materials useful for forming semipermeable membranes include those that are water-permeable and water-insoluble at physiologically relevant pH. Various grades that are water-soluble or susceptible to chemical changes such as crosslinking acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives. Examples of suitable polymers useful in forming the coating include plasticized and unplasticized , and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate acetate, CA propionate, cellulose nitrate, cellulose acetate butylate CA ethyl carbamate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA sucrose cellulose acetate trimellitate (CAT), CA dimethylaminoacetate CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA Methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar agar Acetate, Amylose Triacetate, Beta Glucan Acetate, Beta Glucan Triacetate Acetate, Acetaldehyde Dimethyl Acetate, Triacetate of Locust Bean Gum hydroxylated ethylene vinyl acetate, EC, PEG, PPG, PEG / PPG copolymer Rimmer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMC AS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and their copolymers, starch, dextran, dextrin, chitosan, Collagen, gelatin, polyalkene, polyether, polysulfone, polyethersulfone Polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural rubber Includes waxes and synthetic waxes.

[0179] Semipermeable membranes may also be used, as disclosed in U.S. Pat. No. 5,798,119, in which the pores are gas-filled. A porous material that is substantially filled and impermeable to water vapor but not wetted by aqueous media. Such hydrophobic but water vapor permeable membranes are typically hydrophobic. Water-soluble polymers, such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, Polyethylene, polyacrylic acid derivatives, polyether, polysulfone, polyethersulfone Polystyrene, polyvinyl halide, polyvinylidene fluoride, polyvinyl ester It is composed of alcohols and ethers, natural waxes, and synthetic waxes.

[0180] Delivery port(s) on the semipermeable membrane coated by mechanical or laser drilling The delivery port(s) may also be formed later by erosion of a plug of water-soluble material. Or it can be formed in situ by rupture of a thinner portion of the membrane above a depression in the core. Also, the types disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220 As in the case of asymmetric membrane coating of It is possible.

[0181] The total amount and release rate of the active ingredient(s) released depend on the thickness and porosity of the semipermeable membrane, the core The amount of blood flow can be substantially controlled by the composition of the blood and the number, size, and location of the delivery ports.

[0182] Osmotically controlled release pharmaceutical compositions may be prepared using the methods of the present invention to facilitate formulation performance or processing. It may further include additional conventional excipients or carriers as described herein.

[0183] Osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. (Remington: The Science and Practice of Pharmacy,supra;Santus and Baker,J.Contr olled Release 1995,35,1-21;Verma et al., Drug Development and Industrial Pharmacy 2000,26,695-708;Verma et al.,J.Controll ed Release 2002,79,7-27).

[0184] In certain embodiments, the pharmaceutical compositions provided herein comprise an active ingredient(s) and An asymmetric osmotic membrane coating a core containing other pharmaceutically acceptable excipients or carriers. The compound is formulated as a controlled release dosage form containing AMT. 2002 / 17918. AMT controlled release dosage forms are available by direct compression, dry granulation, wet granulation, and Conventional methods and techniques known to those skilled in the art, including granulation, and dip coating methods. It can be prepared according to

[0185] In certain embodiments, the pharmaceutical compositions provided herein comprise an active ingredient(s), a core comprising hydroxyethylcellulose, and other pharmaceutically acceptable excipients or carriers; The ESC is formulated as a controlled release dosage form containing a coating permeable membrane.

[0186] 3. Multiparticulate controlled release devices The pharmaceutical compositions provided herein in modified release dosage form have a diameter of about 10 μm to about 3 μm. a large number of particles ranging from about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm; It may be fabricated as a multiparticulate controlled release device, including granules, or pellets. Multiparticulates can be prepared by any method known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compaction, and melt congealing. by a process known as For example, Multiparticulate Oral Drug Delivery ry;Marcel Dekker: 1994;andPharmaceutical Pelletization Technology;Marcel Dekker: See 1989.

[0187] Other excipients or carriers, as described herein, may aid in the processing and formation of the multiparticulates. The resulting particles may themselves be mixed with a pharmaceutical composition to form a multiparticulate device. or a variety of polymers such as enteric polymers, water-swellable polymers, and water-soluble polymers. The multiparticulates may be packaged as capsules or tablets. It can be further processed.

[0188] 4. Targeted delivery The pharmaceutical compositions provided herein also include liposomes, resealed erythrocytes, and antibody-based compositions. The present invention relates to a method for treating a subject's body comprising administering a therapeutic agent to a specific tissue, receptor, or other part of the body of the subject being treated, including a delivery system for the treatment of a subject's body. Examples include those described in U.S. Patent No. 6,316,652; No. 6,274,552; No. 6,271,359; No. 6,253,872; No. 6,13 No. 9,865; No. 6,131,570; No. 6,120,751; No. 6,071,49 No. 5; No. 6,060,082; No. 6,048,736; No. 6,039,975; No. No. 6,004,534; No. 5,985,307; No. 5,972,366; No. 5,90 Nos. 0,252; 5,840,674; 5,759,542; and 5,709, Examples include, but are not limited to, those disclosed in US Pat. No. 6,874.

[0189] How to use In one embodiment, the compound is used to treat, ameliorate, or prevent a disorder, disease, or condition in a subject. The method comprises administering to a subject a compound provided herein, e.g., a compound of Formula I, or Enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer isomers, mixtures of two or more tautomers, or isotopic variants; or A therapeutically effective amount of a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof

[0023] Methods are provided herein that include administering

[0190] In another embodiment, the method comprises treating or ameliorating one or more symptoms of a disorder, disease, or condition in a subject. A method for improving or preventing a disease comprising administering to a subject a pharmaceutical composition provided herein, e.g., A compound of formula I, or an enantiomer thereof, a mixture of enantiomers, two or more diastereoisomers A mixture of tautomers, tautomers, a mixture of two or more tautomers, or an isotopic variant or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof and a pharmaceutically acceptable excipient. Methods are provided herein.

[0191] In certain embodiments, the disorder, disease, or condition is a neurological disease. In certain embodiments, the disorder, disease, or condition is a neurodegenerative disease. The disease or condition is an ocular disorder. In certain embodiments, the disorder, disease, or condition is: He has Down syndrome.

[0192] In certain embodiments, the disorder, disease, or condition is Parkinson's disease (PD), Alzheimer's disease (ALD), or Parkinson's disease (PD). AD, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), multiple sclerosis In certain embodiments, the disorder, disease, or condition is: In certain embodiments, the disorder, disease, or condition is Parkinson's disease. In certain embodiments, the disorder, disease, or condition is amyotrophic lateral sclerosis. In certain embodiments, the disorder, disease, or condition is multiple sclerosis. In certain embodiments, the disorder, disease, or condition is dementia. The condition is frontotemporal dementia.

[0193] In certain embodiments, the disorder, disease, or condition is mediated by tau protein. In certain embodiments, the disorder, disease, or condition is mediated by tau protein. In certain embodiments, the disorder, disease, or condition is a tauopathy. A disorder, disease, or condition mediated by quality is Alzheimer's disease.

[0194] In certain embodiments, the disorder, disease, or condition is Alzheimer's disease. In embodiments, the Alzheimer's disease is Stage 1 AD (no impairment). In this case, the Alzheimer's disease is stage 2 AD (very mild decline). In certain embodiments, the Alzheimer's disease is stage 3 AD (mild decline). In some embodiments, the Alzheimer's disease is stage 4 AD (moderate decline). In certain embodiments, the Alzheimer's disease is stage 5 AD (moderate to severe decline). In certain embodiments, the Alzheimer's disease is stage 6 AD (severe decline). , Alzheimer's disease is stage 7AD (very severe decline).

[0195] The methods provided herein encompass treating subjects regardless of the patient's age. However, some diseases or disorders are more common in certain age groups.

[0196] Depending on the disease to be treated and the condition of the subject, compounds provided herein, such as those of Formula I, or its enantiomers, mixtures of enantiomers, two or more diastereomers Mixtures of tautomers, tautomers, mixtures of two or more tautomers, or isotopic variants or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof , oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, dermal Injection into the abdomen or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or The active ingredient may be administered by any of the following routes of administration: Administration of a compound or pharmaceutical composition provided herein in a depot formulation for release is described herein. The compounds provided herein, such as compounds of Formula I, or enantiomers thereof, are Thiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers , a mixture of two or more tautomers, or isotopic variants; or pharmaceutical compositions thereof The compound may be administered alone or in a suitable dosage form, such as a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. and pharmaceutically acceptable excipients, carriers, adjuvants and vehicles appropriate for each administration route. It may be formulated together with acetaminophen.

[0197] In one embodiment, a compound provided herein, e.g., a compound of Formula I, or an enzyme thereof, Nanantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers a tautomer, a mixture of two or more tautomers, or an isotopic variant; or A physiologically acceptable salt, solvate, hydrate, or prodrug is administered orally. In some embodiments, the compounds provided herein, e.g., compounds of Formula I, or enamels thereof, enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers a mixture of two or more tautomers, or isotopic variants; or pharmaceutical compositions thereof A physiologically acceptable salt, solvate, hydrate, or prodrug may be administered parenterally. In yet another embodiment, a compound provided herein, e.g., a compound of Formula I, or enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or A pharmaceutically acceptable salt, solvate, hydrate, or prodrug of In yet another embodiment, the compounds provided herein, e.g., compounds of Formula I, or its enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers a tautomer, a mixture of two or more tautomers, or an isotopic variant; or Pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof may be administered intramuscularly. In yet another embodiment, a compound provided herein, e.g., a compound of Formula I, a substance, or its enantiomer, a mixture of enantiomers, or two or more diastereomers mixtures of tautomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered subcutaneously. In another embodiment, a compound provided herein, e.g., a compound of Formula I, is administered to or its enantiomer, mixture of enantiomers, two or more diastereomers mixtures, tautomers, mixtures of two or more tautomers, or isotopic variants; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is It is administered to the affected area.

[0198] The compounds provided herein, e.g., compounds of Formula I, or their enantiomers, mixture of anantiomers, mixture of two or more diastereomers, tautomers, mixture of two or more a mixture of tautomers, or isotopic variants; or pharmaceutically acceptable salts thereof The salts, solvates, hydrates, or prodrugs may be administered, for example, by a single bolus injection or orally. As a single dose, such as a tablet or pill; or over time or in divided doses, e.g., by continuous infusion The compounds provided herein can be administered over time, such as in a bolus dose over time. Depending on the condition, for example, until the subject experiences stable disease or regression, or until the subject experiences a relapse of the disease Repeated doses may be administered until progression of disease or unacceptable toxicity is experienced. The presence or absence thereof can be assessed by methods known in the art, such as evaluation of the subject's symptoms and physical examination. It is determined by law.

[0199] The compounds provided herein, e.g., compounds of Formula I, or their enantiomers, mixture of anantiomers, mixture of two or more diastereomers, tautomers, mixture of two or more a mixture of tautomers, or isotopic variants; or pharmaceutically acceptable salts thereof The salts, solvates, hydrates, or prodrugs may be administered once daily (QD) or or divided into multiple daily doses, e.g., twice daily (BID), and three times daily (TID). Administration can also be continuous, i.e., every day, or intermittent. When used, the terms "intermittent" or "intermittently" refer to either regular or irregular For example, in this specification, Provided are compounds, for example, compounds of formula I, or enantiomers thereof, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers mixtures, or isotopic variants; or pharmaceutically acceptable salts, solvates thereof Intermittent administration of , hydrate, or prodrugs is recommended for 1-6 days per week, and for cycled administration. (e.g., 2 to 8 consecutive weeks of daily dosing followed by up to 1 week of no dosing rest period) ), or every other day.

[0200] In certain embodiments, a compound provided herein, e.g., a compound of Formula I, or enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or A pharmaceutically acceptable salt, solvate, hydrate, or prodrug of Cycling therapy involves the administration of an active agent for a period of time, followed by a period of rest, Cycling therapy involves the treatment of refractory to one or more of the therapies. to reduce the occurrence of a particular gene, to avoid or reduce a side effect of one of the therapies, and / or to improve the efficacy of the treatment. It can be improved.

[0201] In certain embodiments, the therapeutically effective amount is about 0.001 kg of subject body weight per day. ~Approx. 100mg (mg / kg / day), Approx. 0.01~Approx. 75mg / kg / day, Approx. 0.1~Approx. 50 mg / kg / day, about 0.5 to about 25 mg / kg / day, or about 1 to about 20 mg / kg / day, which can be administered in single or multiple doses. , dosage is about 0.005 to about 0.05, about 0.05 to about 0.5, about 0.5 to about 5.0, It can range from about 1 to about 15, about 1 to about 20, or about 1 to about 50 mg / kg / day.

[0202] However, the specific dose level and dosing frequency for any particular subject may vary. the activity of the particular compound employed, the metabolic stability and length of action of that compound, age, body weight, General health, sex, diet, mode and time of administration, rate of excretion, drug combinations, especially It is understood that the effectiveness of the treatment will depend on a variety of factors, including the severity of the particular condition, as well as the host receiving the treatment. can be.

[0203] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. be.

[0204] The compounds provided herein, e.g., compounds of Formula I, or their enantiomers, mixture of anantiomers, mixture of two or more diastereomers, tautomers, mixture of two or more a mixture of tautomers, or isotopic variants; or pharmaceutically acceptable salts thereof The salts, solvates, hydrates, or prodrugs may also be used to treat the disorders, diseases, and conditions described herein. may be combined or used in combination with other therapeutic agents useful in the treatment and / or prevention of It can be used.

[0205] As used herein, the term "in combination" refers to multiple therapies (e.g., one or more However, the use of the term "in combination" The use of the present invention is directed to administering a therapy (e.g., a prophylactic and / or therapeutic agent) to a subject with a disease or disorder. The order in which the first therapy (e.g., a prophylactic agent, such as a compound provided herein) is administered is not limited. a second therapy (e.g., a prophylactic or therapeutic agent) is administered to the subject prior to administration of the second therapy (e.g., a prophylactic or therapeutic agent) For example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6, 8, or 12 weeks before), at the same time, or after (e.g., 5 minutes, 1 5 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks later). Triple therapy is also contemplated herein.

[0206] A compound provided herein, for example, a compound of formula I, or an enantiomer thereof, mixtures of enantiomers or diastereomers; or their pharmaceutical equivalents The route of administration of the acceptable salt, solvate, or prodrug may be the same as the route of administration of the second therapy. are independent. In one embodiment, the compounds provided herein, e.g., compounds of Formula I or its enantiomers, mixtures of enantiomers, or diastereomers or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In another embodiment, a compound provided herein, e.g., a compound of Formula I, is administered orally. or its enantiomer, mixture of enantiomers, or diastereomer or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Thus, in accordance with these embodiments, the compounds provided herein are administered intravenously. , for example, a compound of formula I, or an enantiomer thereof, a mixture of enantiomers, if or a mixture of diastereomers; or a pharmaceutically acceptable salt, solvate, or The first or prodrug is administered orally or intravenously, and the second therapy is administered orally or parenterally. , intraperitoneally, intravenously, intraarterially, percutaneously, sublingually, intramuscularly, rectally, transbuccally, intranasally in liposomes, via inhalation, vaginally, intraocularly, via catheter or stent Via local delivery, subcutaneously, intraadiposally, intra-articularly, In one embodiment, the compounds provided herein are administered intrathecally or in a delayed release dosage form. a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers, or a mixture of diastereomers; or a pharmaceutically acceptable salt, solvate thereof, or prodrug and the second therapy in the same dosage form, either orally or by IV. In another embodiment, a compound provided herein, e.g., a compound of Formula I, is administered Compounds (enantiomers, mixtures of enantiomers, or mixtures of diastereomers) or a pharmaceutically acceptable salt, solvate, or prodrug thereof) The second agent is administered by one mode of administration, e.g., IV, while the second agent is administered by another The mode of administration is, for example, oral administration.

[0207] In certain embodiments, each of the methods provided herein independently comprises administering a second therapeutic agent. The method may further include the step of:

[0208] The compounds provided herein may also be prepared using packaging materials familiar to those skilled in the art. For example, U.S. Patent Nos. 5,323,907; 5,052,5 58; and 5,033,252. Examples of pharmaceutical packaging materials include Bliss Turpacks, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging materials appropriate for the selected formulation and intended mode of administration and treatment. These include, but are not limited to:

[0209] In certain embodiments, when used by a healthcare practitioner, the appropriate administration of the active ingredient to a subject Also provided herein are kits that can simplify the administration of the doses. The kits provided in include a container and a compound provided herein (single enantiomers thereof). or a mixture of diastereomers; or a pharmaceutically acceptable salt, solvate thereof, or prodrugs).

[0210] In certain embodiments, the kit may further comprise one or more other therapeutic agent(s) described herein. In a container containing a compound provided herein, e.g., a compound of Formula I, or an enantiomer thereof, Thiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers , a mixture of two or more tautomers, or isotopic variants; or pharmaceutical compositions thereof The present invention includes a container containing a dosage form of a therapeutically acceptable salt, solvate, hydrate, or prodrug.

[0211] The kits provided herein may further include a device used to administer the active ingredient. Examples of such devices include syringes, needleless injectors, drip bags, patches, The kits provided herein also include, but are not limited to, active ingredients, and inhalers. A condom for administration of the sexual component may be included.

[0212] The kits provided herein include pharmaceutical compositions that can be used to administer one or more active ingredients. For example, if the active ingredient is administered parenterally, the active ingredient may further comprise a physiologically acceptable vehicle. If provided in a solid form that must be reconstituted, the kit may contain a composition suitable for parenteral administration. A sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particle-free sterile solution. Examples of pharmaceutically acceptable vehicles include water for injection, USP, sodium chloride injection, Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection aqueous vehicles, including but not limited to, ethyl alcohol; including, but not limited to, glycol, polyethylene glycol, and polypropylene glycol water-miscible vehicles; as well as corn oil, cottonseed oil, peanut oil, sesame oil, oleic acid including, but not limited to, ethyl myristate, isopropyl myristate, and benzyl benzoate Non-aqueous vehicles include, but are not limited to, non-aqueous vehicles.

[0213] In one embodiment, a method for inhibiting amyloid-beta production in a subject is provided, comprising administering to a subject a compound of formula Compound I, or its enantiomers, mixtures of enantiomers, two or more diastereomeric Mixtures of tautomers, tautomers, mixtures of two or more tautomers, or isotopic barriers or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof Provided herein are methods comprising administering to a subject a therapeutically effective amount of In one embodiment, the methods provided herein inhibit the total production of amyloid beta in a subject. This is for the purpose.

[0214] In another embodiment, a method for reducing amyloid beta levels in a subject comprises: , a compound of formula I, or an enantiomer thereof, a mixture of enantiomers, two or more diastereomeric Mixtures of stereomers, tautomers, mixtures of two or more tautomers, or isotopic variations or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof Provided herein are methods for administering to a subject a therapeutically effective amount of a given In embodiments, the methods provided herein reduce total amyloid beta levels in a subject. It is intended to make it so.

[0215] In yet another embodiment, the amyloid beta-induced signaling pathway in a subject or cell 1. A method for reducing the activity of a compound of formula I, or an enantiomer thereof, mixture of tautomers, mixture of two or more diastereomers, tautomers, two or more tautomers or a pharmaceutically acceptable salt, solution, or mixture thereof. administering a therapeutically effective amount of the solvate, hydrate, or prodrug to a subject or cell. In certain embodiments, the methods provided herein include , for reducing total amyloid beta levels in a subject.

[0216] In yet another embodiment, there is provided a method of inhibiting amyloid beta production in a cell, comprising: A compound of formula I, or an enantiomer thereof, a mixture of enantiomers, two or more diastereoisomers A mixture of tautomers, tautomers, a mixture of two or more tautomers, or an isotopic variant or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof Methods are provided herein that include contacting a cell with an effective amount of a medicament. In some embodiments, the methods provided herein involve administering a compound to inhibit the total production of amyloid beta in a cell. This is what we want to achieve.

[0217] In one embodiment, the amyloid beta is amyloid beta 36, ​​amyloid beta 37, amyloid β38, amyloid β39, amyloid β40, amyloid β41, amyloid β42, Amyloid beta 43, amyloid beta 44, amyloid beta 45, amyloid beta 46, amyloid amyloid β47, amyloid β48, amyloid β49, amyloid β50, amyloid β51 In another embodiment, the antibody is amyloid β52, or amyloid β52, or a combination thereof. In yet another embodiment, the amyloid beta is amyloid beta 40. It is myloid beta 42.

[0218] In one embodiment, there is provided a method of inhibiting the production of tau protein in a subject, comprising administering to a subject a compound of formula I A compound, or its enantiomer, a mixture of enantiomers, two or more diastereomeric mixture of tautomers, tautomers, mixture of two or more tautomers, or isotopic variants or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof Methods are provided herein that include administering to a subject a therapeutically effective amount of In accordance with the present invention, the methods provided herein include administering a tau protein comprising phosphorylated tau protein to a subject. It is intended to inhibit the total production of protein.

[0219] In another embodiment, there is provided a method of reducing tau protein levels in a subject, comprising administering to a subject a compound of formula Compound I, or its enantiomers, mixtures of enantiomers, two or more diastereomeric Mixtures of tautomers, tautomers, mixtures of two or more tautomers, or isotopic barriers or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof Provided herein are methods comprising administering to a subject a therapeutically effective amount of In one embodiment, the methods provided herein include methods for reducing total tau protein levels in a subject. It is intended to make it possible.

[0220] In yet another embodiment, there is provided a method of inhibiting the production of tau protein in a cell, , a compound of formula I, or an enantiomer thereof, a mixture of enantiomers, two or more diastereomeric Mixtures of stereomers, tautomers, mixtures of two or more tautomers, or isotopic variations or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof Provided herein are methods for treating a cell comprising contacting the cell with an effective amount of a compound selected from the group consisting of: In one embodiment, the methods provided herein include detecting tau protein in a cell, the tau protein comprising phosphorylated tau protein. It is intended to inhibit the total production of proteins.

[0221] In one embodiment, the tau protein is phosphorylated tau protein. In yet another embodiment, the tau protein is hyperphosphorylated tau protein. In another embodiment, the tau protein is a human tau protein. , human isoforms 0N3R, 0N4R, 1N3R, 1N4R, 2N3R, or 2N It's the 4th round.

[0222] In one embodiment, there is provided a method of inhibiting production of phosphorylated tau protein in a subject, , a compound of formula I, or an enantiomer thereof, a mixture of enantiomers, two or more diastereomeric Mixtures of stereomers, tautomers, mixtures of two or more tautomers, or isotopic variations or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof Methods are provided herein that include administering to a subject a therapeutically effective amount of a compound selected from the group consisting of:

[0223] In another embodiment, the method is for reducing phosphorylated tau protein levels in a subject. Thus, a compound of formula I, or an enantiomer thereof, a mixture of enantiomers, or two or more Mixtures of diastereomers, tautomers, mixtures of two or more tautomers, or isomers or a pharmaceutically acceptable salt, solvate, hydrate, or protease thereof. Methods are provided herein that include administering to a subject a therapeutically effective amount of a drug.

[0224] In yet another embodiment, a method of inhibiting production of phosphorylated tau protein in a cell includes: a compound of formula I, or an enantiomer thereof, a mixture of enantiomers, or a mixture of two or more a mixture of the above diastereomers, tautomers, a mixture of two or more tautomers, or or a pharmaceutically acceptable salt, solvate, hydrate, or the like thereof. Methods are provided herein that include contacting a cell with an effective amount of a prodrug.

[0225] In one embodiment, the method is a method of inhibiting the production of hyperphosphorylated tau protein in a subject. and a compound of formula I, or an enantiomer thereof, a mixture of enantiomers, two or more dimers thereof, Mixture of asastereomers, tautomers, mixture of two or more tautomers, or isotopes or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. Methods are provided herein that include administering to a subject a therapeutically effective amount of Ragg.

[0226] In another embodiment, the method for reducing hyperphosphorylated tau protein levels in a subject comprises: a compound of formula I, or an enantiomer thereof, a mixture of two or more enantiomers thereof a mixture of diastereomers, tautomers, a mixture of two or more tautomers, or or a pharmaceutically acceptable salt, solvate, hydrate, or protease thereof. Methods are provided herein that include administering to a subject a therapeutically effective amount of a prodrug.

[0227] In yet another embodiment, the method for inhibiting the production of hyperphosphorylated tau protein in a cell is 1. A method for producing a compound of formula I, or an enantiomer thereof, a mixture of enantiomers, or a mixture of two A mixture of the above diastereomers, tautomers, a mixture of two or more tautomers, or or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates, or Provided herein are methods comprising contacting the cell with an effective amount of a prodrug.

[0228] In yet another embodiment, the method comprises reducing tau protein-induced signaling in a subject or cell. 10. A method for reducing the pH of a compound of formula I, or an enantiomer thereof, or a mixture of enantiomers thereof, mixture, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, water The method includes contacting a subject or cell with an effective amount of a compound, a solvate, or a prodrug of the present invention. Provided in the specification.

[0229] The present disclosure will be further understood by the following non-limiting examples. [Example]

[0230] As used herein, whether or not a particular abbreviation is specifically defined, The symbols and notations used in these processes, schemes and examples are consistent with those of contemporary scientific literature, For example, the Journal of the American Chemical Society, the Journal of Medicinal Chemistry try, or the Journal of Biological Chemist matches that used in ry.

[0231] Example 1 Decreasing amyloid beta 40 levels It is caused by familial Alzheimer's disease patients who carry a copy of the amyloid precursor protein gene. The resulting induced pluripotent stem cells were differentiated into neurons using standard protocols. Rael et al.,Nature 2012,482,216-220. Neural precursors Somatic cells were plated in 24-well plates and allowed to differentiate into neurons for 3 weeks. From day 4 onwards, there was an exponential increase in the levels of Aβ secreted by these cells. Media from the wells was collected on day 6 for Aβ40 analysis and on day 39 for Aβ42 analysis. The cells were harvested and replaced with medium containing compound or phosphate buffered saline (PBS) solution. After 24 hours, the medium was collected from each well and analyzed using a commercially available ELISA kit. The effect of test compounds on Aβ levels was determined over a period of 24 hours. The effects of compounds A1–A4 on the levels of Aβ40 secreted by neurons are shown. Figure 2 shows the levels of Aβ40 secreted by neurons after 24 hours of treatment. The effects of compounds A1 to A3 on

[0232] Example 2 Compound characterization Compound A1 was synthesized and analyzed by mass spectrometry at 371.0 (M H + ) Mass and HPLC Compound A2 was synthesized and analyzed by HPLC. 360.0 (MH) by mass spectrum + ) by mass and 98% by HPLC at 230 nm Compound A3 was synthesized and determined to have a purity of 338% by mass spectrometry. .0(MH + ) and a purity of greater than 99% by HPLC. .

[0233] Example 3 Metabolic stability of compounds A1-A3 in fresh human plasma Compounds A1-A3 were individually analyzed in fresh human plasma with sodium heparin as an anticoagulant. Each compound was added independently to the lot to give a final assay concentration of 1.00 μM. After incubation at room temperature for 0, 0.5, 1, 2, and 4 hours, the samples were removed and , and an aliquot was made for analysis. Valacyclovir was used as a positive control. Plasma samples containing the compounds were processed by protein precipitation.

[0234] A 1.00 mM primary stock solution of test compound in acetonitrile or The acetonitrile used in the human plasma stability study was prepared in either acetonitrile or water (1:1, v / v). Prepare a 0.200 mM working stock from the primary stock in Trillium:water (1:1, v / v) The primary and working stock solutions were stored at -20°C when not in use. When used for sei, the working stock was kept at room temperature for as short a time as possible.

[0235] Human plasma stability testing was performed using 0.995 mL of human plasma in a 1.7 mL snap tube. Plasma (sodium heparin) was spiked with 5.00 μL of test compound stock solution. After the start of each incubation, duplicate 50.0 μL aliquots of plasma were The zero time point was determined by immediately removing the sample and quenching it in 150 μL of methanol. The plasma incubation tubes were capped and kept at room temperature between time points.

[0236] After 0.5, 1, 2, and 4 hours of incubation, duplicate 50.0 μL aliquots were Each time point was immediately removed and placed in an extraction tube containing 150 μL of methanol. Extraction was performed by lutex mixing, centrifugation, and the supernatant was transferred to an HPLC vial for analysis. After extraction of all samples, the extracts were analyzed by LC / MS / MS.

[0237] LC / MS / MS analysis of the incubation solution involves chromatographic analysis prior to detection by mass spectrometry. This was achieved by initial separation of the test compound peaks using LC / MS system. The system is an HPLC coupled to a TQS-Micro or Quattro Premier. The electrochemical analysis consisted of either positive or negative ionization mode. Atomize the mobile phase using heated nitrogen at the Z spray source / interface set to spray The ionized compounds were detected using MS / MS. The data were analyzed by MassL Obtained using ynx.

[0238] The peak heights for compounds A1-A3 are shown in Table 1, while the peak heights for the positive control are shown in Table 2. The peak heights are shown in Table 2. In fresh human plasma, compounds A1 to A3 were It was not metabolized intentionally. Table 1. Peak heights of compounds A1–A3 in fresh human plasma [Table 1] Table 2. Peak heights of the positive control valacyclovir in fresh human plasma [Table 2]

[0239] Example 4 Pharmacokinetic study of Compound A2 in rats Pharmacokinetic studies for Compound A2 were conducted in rats, and the results are summarized in Table 3. Table 3. PK parameters of compound A2 in rats [Table 3]

[0240] Compound A2 was also analyzed in the CSF of rats, and the results are shown in Table 4 below. BQL represents below the quantifiable limit of 2.0 ng / mL. Table 4. Compound A2 in CSF [Table 4] *****

[0241] The above examples provide a complete disclosure and description of how to make and use the claimed embodiments. These are provided to provide guidance to those skilled in the art and are not intended to limit the scope of what is disclosed herein. Modifications obvious to one skilled in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited herein are the property of their respective owners. Each such publication, patent, or patent application is hereby incorporated by reference. and are incorporated herein by reference as if specifically and individually indicated to be incorporated by reference.

Claims

1. Compounds of Formula I: 【Chemistry 1】 or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or and pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof; and pharmaceutically Pharmaceutical compositions comprising excipients acceptable to (In the formula: X is -SO ２ - and Y is -NR Ｘ or X is -NR Ｘ - and Y is -SO ２ - and; Each R １ are independently (a) cyano, halo, or nitro; (b) C １－６ Al Kill, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１ ４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl; or (c)-C(O)R １ａ 、-C(O)OR １ａ 、-C(O)NR １ｂ R １ｃ 、-C(O) SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ａ 、-C(S)OR １ａ 、 -C(S)NR １ｂ R １ｃ 、-OR １ａ 、-OC(O)R １ａ 、-OC(O)OR １ａ 、 -OC(O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC(=NR １ａ )NR １ｂ R １ｃ 、-OC(S)R １ａ 、-OC(S)OR １ａ 、-OC(S)NR １ｂ R １ｃ 、-O S (O) R １ａ ,-OS(O) ２ R １ａ ,-OS(O)NR １ｂ R １ｃ ,-OS(O) ２ NR １ｂ R １ｃ 、-NR １ｂ R １ｃ 、-NR １ａ C(O)R １ｄ 、-NR １ａ C(O)O R １ｄ 、-NR １ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C(O)SR １ｄ 、-NR １ａ C(=NR １ｄ )NR １ｂ R １ｃ 、-NR １ａ C(S)R １ｄ 、-NR １ａ C(S)OR １ｄ 、-NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O)R １ｄ 、-NR １ａ S( O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ ｃ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ , or -S (O) ２ NR １ｂ R １ｃ and R ２ , R ５ , R ６ , and R Ｘ are each independently: (a) hydrogen, deuterium, cyano, halo b) nitro; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkini Lu, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ Aralkyl, Heteroa aryl, or heterocyclyl; or (c) —C(O)R １ａ , -C(O)OR １ａ 、-C(O)NR １ｂ R １ｃ 、-C(O)SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、 -C(S)R １ａ 、-C(S)OR １ａ 、-C(S)NR １ｂ R １ｃ 、-OR １ａ 、-O C(O)R １ａ 、-OC(O)OR １ａ 、-OC(O)NR １ｂ R １ｃ 、-OC(O)S R １ａ 、-OC(=NR １ａ )NR １ｂ R １ｃ 、-OC(S)R １ａ 、-OC(S)OR １ａ ,-OC(S)NR １ｂ R １ｃ ,-OS(O)R １ａ ,-OS(O) ２ R １ａ 、-O S(O)NR １ｂ R １ｃ ,-OS(O) ２ NR １ｂ R １ｃ ,-NR １ｂ R １ｃ ,-NR １ ａ C(O)R １ｄ 、-NR １ａ C(O)OR １ｄ 、-NR １ａ C(O)NR １ｂ R １ｃ 、 -NR １ａ C(O)SR １ｄ 、-NR １ａ C(=NR) １ｄ )NR １ｂ R １ｃ 、-NR １ａ C(S)R １ｄ 、-NR １ａ C(S)OR １ｄ 、-NR １ａ C(S)NR １ｂ R １ｃ 、- NR １ａ S(O)R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ｃ 、-S(O)R １ａ 、-S(O) ２ R １ａ 、 -S(O)NR １ｂ R １ｃ , or -S(O) ２ NR １ｂ R １ｃ and R ３ is (a) cyano, halo, or nitro; (b) C １－６ Alkyl, C ２－６ a Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７ －１５ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O) R １ａ 、-C(O)OR １ａ 、-C(O)NR １ｂ R １ｃ 、-C(O)SR １ａ 、-C( NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ａ 、-C(S)OR １ａ 、-C(S)NR １ ｂ R １ｃ 、-OR １ａ 、-OC(O)R １ａ 、-OC(O)OR １ａ 、-OC(O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC(=NR １ａ )NR １ｂ R １ｃ 、-OC(S )R １ａ 、-OC(S)OR １ａ 、-OC(S)NR １ｂ R １ｃ 、-OS(O)R １ａ 、 -OOS(O) ２ R １ａ ,-OS(O)NR １ｂ R １ｃ ,-OS(O) ２ NR １ｂ R １ｃ 、 -NR １ｂ R １ｃ 、-NR １ａ C(O)R １ｄ 、-NR １ａ C(O)OR １ｄ 、-NR １ ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C(O)SR １ｄ 、-NR １ａ C(=NR １ｄ ) NR １ｂ R １ｃ 、-NR １ａ C(S)R １ｄ 、-NR １ａ C(S)OR １ｄ 、-NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O)R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、- NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ｃ 、-S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ , or -S(O) ２ NR １ｂ R １ｃ and R ４ is hydrogen, deuterium, cyano, or fluoro; Each R １ａ , R １ｂ , R １ｃ , and R １ｄ are independently hydrogen, deuterium, C １－６ a Lukil, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－ １４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl or R １ａ and R １ｃ together with the C and N atoms to which they are attached form a hetero forming a cyclyl; or R １ｂ and R １ｃ together with the N atoms to which they are attached. to form a heterocyclyl; m is an integer of 0, 1, 2, 3, or 4; However, the compound is 4-((4'-((4-(2,4-dichlorophenyl)-1-ethoxyphenyl)-4-methyl-2,4-dichlorophenyl)-1-ethoxyphenyl. (methyl-1H-imidazol-2-yl)methyl)-[1,1'-biphenyl]-4-yl )oxy)-3-((3-(trifluoromethyl)phenyl)-sulfonamido)benzoin In acid, 3-(N-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)- Neither 2-methylphenyl)sulfamoyl)benzoic acid; Each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, Heteroaryl and heterocyclyl may be one or more, in one embodiment 1, 2, 3 or or four substituents Q, each Q being independently selected from: (a) deuterium, cyano, halo, and nitro; (b) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Shik Roalkyl, C ６－１４ Aryl, C ７－１５ Aralkyl, heteroaryl, and heteroaryl cyclyl (each of which has one or more, in one embodiment 1, 2, 3, or 4, substituents); Substituent Q ａ (c) —C(O)R ａ , —C(O) OR ａ 、-C(O)NR ｂ R ｃ 、-C(O)SR ａ 、-C(NR ａ )NR ｂ R ｃ 、-C( S)R ａ 、-C(S)OR ａ 、-C(S)NR ｂ R ｃ 、-OR ａ 、-OC(O)R ａ 、- OC(O)OR ａ 、-OC(O)NR ｂ R ｃ 、-OC(O)SR ａ 、-OC(=NR ａ ) NR ｂ R ｃ 、-OC(S)R ａ 、-OC(S)OR ａ 、-OC(S)NR ｂ R ｃ 、-OS (O)R ａ ,-OS(O) ２ R ａ ,-OS(O)NR ｂ R ｃ ,-OS(O) ２ NR ｂ R ｃ 、-NR ｂ R ｃ 、-NR ａ C(O)R ｄ 、-NR ａ C(O)OR ｄ 、-NR ａ C(O)N R ｂ R ｃ 、-NR ａ C(O)SR ｄ 、-NR ａ C(=NR ｄ )NR ｂ R ｃ 、-NR ａ C( S)R ｄ 、-NR ａ C(S)OR ｄ 、-NR ａ C(S)NR ｂ R ｃ 、-NR ａ S(O)R ｄ 、-NR ａ S(O) ２ R ｄ 、-NR ａ S(O)NR ｂ R ｃ 、-NR ａ S(O) ２ NR ｂ R ｃ 、 - SR ａ 、 - S(O)R ａ 、 - S(O) ２ R ａ 、 - S(O)NR ｂ R ｃ 、 and - S (O) ２ NR ｂ R ｃ (Each R ａ , R ｂ , R ｃ , and R ｄ are independently: (i) hydrogen or (ii) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ Aralkyl, heteroaryl or heterocyclyl (each of which may be one or more, in one embodiment 1, 2, 3 , or four substituents Q ａ (iii) optionally substituted with R ｂ and R ｃ together with the N atoms to which they are attached, form one or more, in one embodiment, , 2, 3, or 4 substituents Q ａ forming an optionally substituted heterocyclyl) optionally substituted with (selected from); Each Q ａ are independently selected from: (a) deuterium, cyano, halo, and nitro; (b) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６ －１４ Aryl, C ７－１５ aralkyl, heteroaryl, and heterocyclyl; and に(c)-C(O)R ｅ 、-C(O)OR ｅ 、-C(O)NR ｆ R ｇ 、-C(O)SR ｅ 、-C(NR ｅ )NR ｆ R ｇ 、-C(S)R ｅ 、-C(S)OR ｅ 、-C(S)NR ｆ R ｇ 、-OR ｅ 、-OC(O)R ｅ 、-OC(O)OR ｅ 、-OC(O)NR ｆ R ｇ 、-O C(O)SR ｅ 、-OC(=NR ｅ )NR ｆ R ｇ 、-OC(S)R ｅ 、-OC(S)OR ｅ ,-OC(S)NR ｆ R ｇ ,-OS(O)R ｅ ,-OS(O) ２ R ｅ ,-OS(O)N R ｆ R ｇ ,-OS(O) ２ NR ｆ R ｇ ,-NR ｆ R ｇ ,-NR ｅ C(O)R ｈ ,-NR ｅ C(O)OR ｆ 、-NR ｅ C(O)NR ｆ R ｇ 、-NR ｅ C(O)SR ｆ 、-NR ｅ C( =NR ｈ )NR ｆ R ｇ 、-NR ｅ C(S)R ｈ 、-NR ｅ C(S)OR ｆ 、-NR ｅ C( S)NR ｆ R ｇ 、-NR ｅ S(O)R ｈ 、-NR ｅ S(O) ２ R ｈ 、-NR ｅ S(O)N R ｆ R ｇ 、-NR ｅ S(O) ２ NR ｆ R ｇ 、-SR ｅ 、-S(O)R ｅ 、-S(O) ２ R ｅ , -S(O)NR ｆ R ｇ , and -S(O) ２ NR ｆ R ｇ (Each R ｅ , R ｆ , R ｇ , and BiR ｈ are independently (i) hydrogen or deuterium; (ii) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl; or (iii) ) R ｆ and R ｇ together with the N atom to which they are attached form a heterocyclyl. (selected from the group consisting of).

2. The compound is a compound of formula II: 【Chemistry 2】 or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or is a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. Item 1. The pharmaceutical composition according to item 1.

3. The compound has the formula III: 【Transformation 3】 or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or is a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. Item 1. The pharmaceutical composition according to item 1.

4. The compound has the formula IV: 【Chemistry 4】 or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or is a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. Item 3. The pharmaceutical composition according to item 3.

5. X is -SO ２ - and Y is -NR Ｘ - according to any one of claims 1 to 4. The pharmaceutical composition described above.

6. X is -SO ２ 6. The pharmaceutical composition of claim 5, wherein Y is - and Y is -NH-.

7. X is -NR Ｘ - and Y is -SO ２ - according to any one of claims 1 to 4. The pharmaceutical composition described above.

8. X is —NH— and Y is —SO ２ The pharmaceutical composition of claim 7, wherein

9. Each R １ are independently (a) cyano, halo, or nitro; (b) C １－６ Al Kill, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１ ４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl; or (c)-C(O)R １ａ 、-C(O)OR １ａ 、-C(O)NR １ｂ R １ｃ 、-C(O) SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ａ 、-C(S)OR １ａ 、 -C(S)NR １ｂ R １ｃ , C １－６ Alkoxy, —OC(O)R １ａ , -OC(O)O R １ａ 、-OC(O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC(=NR １ａ )N R １ｂ R １ｃ 、-OC(S)R １ａ 、-OC(S)OR １ａ 、-OC(S)NR １ｂ R １ ｃ ,-OS(O)R １ａ ,-OS(O) ２ R １ａ ,-OS(O)NR １ｂ R １ｃ ,-OS (O) ２ NR １ｂ R １ｃ 、-NR １ｂ R １ｃ 、-NR １ａ C(O)R １ｄ 、-NR １ａ C (O)OR １ｄ 、-NR １ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C(O)SR １ｄ 、- NR １ａ C(=NR) １ｄ )NR １ｂ R １ｃ ,-NR １ａ C(S)R １ｄ ,-NR １ａ C( S)OR １ｄ 、-NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O)R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ｃ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ ,if Kuha -S(O) ２ NR １ｂ R １ｃ wherein the alkoxy is optionally substituted with one or more substituents Q. The pharmaceutical composition according to any one of claims 1 to 8, wherein

10. Each R １ is independently halo or C optionally substituted with one or more substituents Q １－６ The pharmaceutical composition of claim 9, wherein the alkyl is alkyl.

11. Each R １ is fluoro or methyl optionally substituted with one or more substituents Q; 10. The pharmaceutical composition of claim 9.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein m is an integer of 1.

13. The pharmaceutical composition according to any one of claims 1 to 8, wherein m is an integer of 0.

14. R ２ The pharmaceutical composition of any one of claims 1 to 13, wherein is hydrogen.

15. R ４ The pharmaceutical composition of any one of claims 1 to 14, wherein is hydrogen.

16. R ３ is (a) cyano, halo, or nitro; (b) C １－６ Alkyl, C ２－６ a Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７ －１５ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O) -C １－６ Alkyl, —C(O)OR １ａ , —C(O)NHR １ｃ , -C(O)SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ａ 、-C(S)OR １ａ 、-C(S )NR １ｂ R １ｃ 、-OR １ａ 、-OC(O)R １ａ 、-OC(O)OR １ａ 、-OC( O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC(=NR １ａ )NR １ｂ R １ｃ 、- OC(S)R １ａ 、-OC(S)OR １ａ 、-OC(S)NR １ｂ R １ｃ 、-OS(O) R １ａ ,-OS(O) ２ R １ａ ,-OS(O)NR １ｂ R １ｃ ,-OS(O) ２ NR １ｂ R １ｃ 、-NR １ｂ R １ｃ 、-NR １ａ C(O)R １ｄ 、-NR １ａ C(O)OR １ｄ 、 -NR １ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C(O)SR １ｄ 、-NR １ａ C(=N R １ｄ )NR １ｂ R １ｃ 、-NR １ａ C(S)R １ｄ 、-NR １ａ C(S)OR １ｄ 、- NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O)R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ｃ 、-S (O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ , or -S(O) ２ NR １ｂ R １ｃ (each alkyl, alkenyl, alkynyl, cycloalkyl, aryl , aralkyl, heteroaryl, and heterocyclyl may independently and optionally be one or more The pharmaceutical composition according to any one of claims 1 to 15, wherein Finished product.

17. R ３ Nitro, C １－６ Alkyl, -OR １ａ , or -NR １ａ S (O) ２ R １ｄ wherein the alkyl is optionally substituted with one or more substituents Q. The pharmaceutical composition described.

18. R ３ Nitro, C １－６ Alkyl, C １－６ Alkoxy, or C １－６ Alkyls sulfonamides, each of which alkyl and alkoxy is optionally substituted with one or more substituents Q.

17. The pharmaceutical composition of claim 16, wherein

19. R ３ is nitro, trifluoromethyl, methoxy, or methylsulfonamido 17. The pharmaceutical composition of claim 16.

20. R ５ is hydrogen or -OR １ａ The pharmaceutical composition according to any one of claims 1 to 19, composition.

21. R ５ is hydrogen or C １－６ Alkoxy, wherein the alkoxy is optionally substituted with one or more substituents Q.

21. The pharmaceutical composition of claim 20, wherein:

22. R ５ 21. The pharmaceutical composition of claim 20, wherein is hydrogen or methoxy.

23. R ６ is hydrogen, C １－６ Alkyl, or -OR １ａ Any one of claims 1 to 22, 1. The pharmaceutical composition according to claim 1.

24. R ６ is hydrogen, C １－６ Alkyl, or C １－６ Alkoxy (the above alkyl and alkoxy) Each koxy is optionally substituted with one or more substituents Q. The pharmaceutical composition described.

25. R ６ 24. The pharmaceutical composition of claim 23, wherein is hydrogen, methyl, or methoxy.

26. Each R １ are independently (a) cyano, halo, or nitro; (b) C １－６ Al Kill, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１ ４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl; or (c)-C(O)R １ａ 、-C(O)OR １ａ 、-C(O)NR １ｂ R １ｃ 、-C(O) SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ａ 、-C(S)OR １ａ 、 -C(S)NR １ｂ R １ｃ , C １－６ Alkoxy, —OC(O)R １ａ , -OC(O)O R １ａ 、-OC(O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC(=NR １ａ )N R １ｂ R １ｃ 、-OC(S)R １ａ 、-OC(S)OR １ａ 、-OC(S)NR １ｂ R １ ｃ ,-OS(O)R １ａ ,-OS(O) ２ R １ａ ,-OS(O)NR １ｂ R １ｃ ,-OS (O) ２ NR １ｂ R １ｃ 、-NR １ｂ R １ｃ 、-NR １ａ C(O)R １ｄ 、-NR １ａ C (O)OR １ｄ 、-NR １ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C(O)SR １ｄ 、- NR １ａ C(=NR) １ｄ )NR １ｂ R １ｃ ,-NR １ａ C(S)R １ｄ ,-NR １ａ C( S)OR １ｄ 、-NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O)R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ｃ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ ,if Kuha-S(O) ２ NR １ｂ R １ｃ and R ２ and R ４ are each hydrogen; R ３ is (a) cyano, halo, or nitro; (b) C １－６ Alkyl, C ２－６ a Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７ －１５ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O) -C １－６ Alkyl, —C(O)OR １ａ , —C(O)NHR １ｃ , -C(O)SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ａ 、-C(S)OR １ａ 、-C(S )NR １ｂ R １ｃ 、-OR １ａ 、-OC(O)R １ａ 、-OC(O)OR １ａ 、-OC( O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC(=NR １ａ )NR １ｂ R １ｃ 、- OC(S)R １ａ 、-OC(S)OR １ａ 、-OC(S)NR １ｂ R １ｃ 、-OS(O) R １ａ ,-OS(O) ２ R １ａ ,-OS(O)NR １ｂ R １ｃ ,-OS(O) ２ NR １ｂ R １ｃ 、-NR １ｂ R １ｃ 、-NR １ａ C(O)R １ｄ 、-NR １ａ C(O)OR １ｄ 、 -NR １ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C(O)SR １ｄ 、-NR １ａ C(=N R １ｄ )NR １ｂ R １ｃ 、-NR １ａ C(S)R １ｄ 、-NR １ａ C(S)OR １ｄ 、- NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O)R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ｃ 、-S (O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ , or -S(O) ２ NR １ｂ R １ｃ and R ５ and R ６ are each independently (a) hydrogen, deuterium, cyano, halo, or nitro Toro; (b) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, or is heterocyclyl; or (c) —C(O)R １ａ , -C(O)OR １ａ , -C(O)N R １ｂ R １ｃ 、-C(O)SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ ａ 、-C(S)OR １ａ 、-C(S)NR １ｂ R １ｃ 、-OR １ａ 、-OC(O)R １ａ 、-OC(O)OR １ａ 、-OC(O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC (=NR １ａ )NR １ｂ R １ｃ 、-OC(S)R １ａ 、-OC(S)OR １ａ 、-OC( S)NR １ｂ R １ｃ ,-OS(O)R １ａ ,-OS(O) ２ R １ａ ,-OS(O)NR １ ｂ R １ｃ ,-OS(O) ２ NR １ｂ R １ｃ ,-NR １ｂ R １ｃ ,-NR １ａ C(O)R １ ｄ 、-NR １ａ C(O)OR １ｄ 、-NR １ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C( O)SR １ｄ 、-NR １ａ C(=NR １ｄ )NR １ｂ R １ｃ 、-NR １ａ C(S)R １ｄ 、-NR １ａ C(S)OR １ｄ 、-NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O )R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ ａ S(O) ２ NR １ｂ R １ｃ 、-S(O)R １ａ 、-S(O) ２ R １ａ 、-S(O)NR １ｂ R １ｃ , or -S(O) ２ NR １ｂ R １ｃ and Each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, Heteroaryl and heterocyclyl may independently and optionally be one or more of the following: is substituted with 1, 2, 3 or 4 substituents Q, The pharmaceutical composition according to claim 1.

27. Each R １ are independently (a) cyano, halo, or nitro; (b) C １－６ Al Kill, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１ ４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl; or (c)-C(O)R １ａ 、-C(O)OR １ａ 、-C(O)NR １ｂ R １ｃ 、-C(O) SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ａ 、-C(S)OR １ａ 、 -C(S)NR １ｂ R １ｃ , C １－６ Alkoxy, —OC(O)R １ａ , -OC(O)O R １ａ 、-OC(O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC(=NR １ａ )N R １ｂ R １ｃ 、-OC(S)R １ａ 、-OC(S)OR １ａ 、-OC(S)NR １ｂ R １ ｃ ,-OS(O)R １ａ ,-OS(O) ２ R １ａ ,-OS(O)NR １ｂ R １ｃ ,-OS (O) ２ NR １ｂ R １ｃ 、-NR １ｂ R １ｃ 、-NR １ａ C(O)R １ｄ 、-NR １ａ C (O)OR １ｄ 、-NR １ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C(O)SR １ｄ 、- NR １ａ C(=NR) １ｄ )NR １ｂ R １ｃ ,-NR １ａ C(S)R １ｄ ,-NR １ａ C( S)OR １ｄ 、-NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O)R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ｃ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ ,if Kuha-S(O) ２ NR １ｂ R １ｃ and R ２ and R ４ are each hydrogen; R ３ Nitro, C １－６ Alkyl, -OR １ａ , or -NR １ａ S (O) ２ R １ｄ and R ５ is hydrogen or -OR １ａ and R ６ is hydrogen, C １－６ Alkyl, or -OR １ａ and m is an integer of 0, 1, 2, or 3; Each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, Heteroaryl and heterocyclyl may independently and optionally be one or more of the following: is substituted with 1, 2, 3 or 4 substituents Q, The pharmaceutical composition according to claim 1.

28. Each R １ are independently halo or C １－６ is alkyl; R ２ and R ４ are each hydrogen; R ３ Nitro, C １－６ Alkyl, C １－６ Alkoxy, or C １－６ Alkyls sulfonamide; R ５ is hydrogen or C １－６ is alkoxy; R ６ is hydrogen, C １－６ Alkyl, or C １－６ is alkoxy; m is an integer of 0, 1, or 2; Each of alkyl, alkoxy, and C １－６ The alkyl sulfonamide may comprise one or more In one embodiment, the compound of claim 1 is optionally substituted with 1, 2, 3, or 4 substituents Q.

9. A pharmaceutical composition according to any one of claims 1 to 8.

29. R １ is fluoro or methyl; R ２ and R ４ are each hydrogen; R ３ is nitro, trifluoromethyl, methoxy, or methylsulfonamide ； R ５ is hydrogen or methoxy; R ６ is hydrogen, methyl, or methoxy; The pharmaceutical composition according to any one of claims 1 to 8, wherein m is an integer of 0 or 1.

30. The compound is 4-(N-(3-(methylsulfonamido)phenyl)sulfamoyl ) benzoic acid; 3-(N-(2-methyl-5-(trifluoromethyl)phenyl)sulfamoyl)ammonium Zozoic acid; 3-(N-(3,5-dimethoxyphenyl)sulfamoyl)benzoic acid; 3-((2-methoxy-5-nitrophenyl)sulfonamido)-4-methylbenzoic acid ； or 2-fluoro-4-(N-(3-(methylsulfonamido)phenyl)sulfamoyl ) benzoic acid; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; a or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, The pharmaceutical composition according to any one of claims 1 to 8.

31. The pharmaceutical composition according to any one of claims 1 to 30, wherein the pharmaceutical composition is in a single dosage form. composition.

32. 32. The pharmaceutical composition according to any one of claims 1 to 31, wherein the pharmaceutical composition is in oral, parenteral, or intravenous dosage form. The pharmaceutical composition according to any one of claims 1 to 4.

33. 33. The pharmaceutical composition of claim 32, wherein the composition is in an oral dosage form.

34. 34. The pharmaceutical composition of claim 33, wherein the oral dosage form is a tablet, capsule, or solution. thing.

35. 35. The pharmaceutical composition of any one of claims 1 to 34, further comprising a second therapeutic agent.

36. 35. A method of treating one or more symptoms of a neurodegenerative disease in a subject, comprising administering to a subject a compound of claim 1 to claim 35. The method comprises administering to the subject a pharmaceutical composition according to any one of claims 1 to 4.

37. 37. The method of claim 36, wherein the neurodegenerative disease is Alzheimer's disease.

38. 38. The method of claim 37, wherein the neurodegenerative disease is stage 1 Alzheimer's disease.

39. 38. The method of claim 37, wherein the neurodegenerative disease is stage 2 Alzheimer's disease.

40. 38. The method of claim 37, wherein the neurodegenerative disease is stage 3 Alzheimer's disease.

41. 38. The method of claim 37, wherein the neurodegenerative disease is stage 4 Alzheimer's disease.

42. 38. The method of claim 37, wherein the neurodegenerative disease is stage 5 Alzheimer's disease.

43. 38. The method of claim 37, wherein the neurodegenerative disease is stage 6 Alzheimer's disease.

44. 38. The method of claim 37, wherein the neurodegenerative disease is stage 7 Alzheimer's disease.

45. The neurodegenerative diseases include Parkinson's disease, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and the like.

37. The method of claim 36, wherein the condition is rheumatoid arthritis or dementia.

46. 1. A method of treating one or more symptoms of a disorder, disease, or condition in a subject, comprising:

36. A method for treating a patient with a rheumatoid arthritis comprising administering to the subject the pharmaceutical composition according to any one of items 1 to 35, The method, wherein the disorder, disease, or condition is an eye disorder or Down's syndrome.

47. A method for inhibiting amyloid β production in a subject, comprising administering to a subject a compound according to any one of claims 1 to 35. The method comprises administering to the subject the pharmaceutical composition of claim 1.

48. A method for reducing amyloid beta levels in a subject, comprising administering to a subject a compound according to any one of claims 1 to 35. The method comprises administering to the subject the pharmaceutical composition of any one of claims 1 to 4.

49. 49. The method of claim 47 or 48, wherein the amyloid beta is amyloid beta 40.

50. 49. The method of claim 47 or 48, wherein the amyloid beta is amyloid beta 42.

51. 1. A method of inhibiting amyloid beta production in a cell, comprising administering to a patient a compound of formula I: 【Transformation 5】 or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof with said cells. contacting said method (In the formula: X is -SO ２ - and Y is -NR Ｘ or X is -NR Ｘ - and Y is -SO ２ - and; Each R １ are independently (a) cyano, halo, or nitro; (b) C １－６ Al Kill, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１ ４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl; or (c)-C(O)R １ａ 、-C(O)OR １ａ 、-C(O)NR １ｂ R １ｃ 、-C(O) SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ａ 、-C(S)OR １ａ 、 -C(S)NR １ｂ R １ｃ 、-OR １ａ 、-OC(O)R １ａ 、-OC(O)OR １ａ 、 -OC(O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC(=NR １ａ )NR １ｂ R １ｃ 、-OC(S)R １ａ 、-OC(S)OR １ａ 、-OC(S)NR １ｂ R １ｃ 、-O S (O) R １ａ ,-OS(O) ２ R １ａ ,-OS(O)NR １ｂ R １ｃ ,-OS(O) ２ NR １ｂ R １ｃ 、-NR １ｂ R １ｃ 、-NR １ａ C(O)R １ｄ 、-NR １ａ C(O)O R １ｄ 、-NR １ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C(O)SR １ｄ 、-NR １ａ C(=NR １ｄ )NR １ｂ R １ｃ 、-NR １ａ C(S)R １ｄ 、-NR １ａ C(S)OR １ｄ 、-NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O)R １ｄ 、-NR １ａ S( O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ ｃ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ , or -S (O) ２ NR １ｂ R １ｃ and R ２ , R ５ , R ６ , and R Ｘ are each independently: (a) hydrogen, deuterium, cyano, halo b) nitro; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkini Lu, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ Aralkyl, Heteroa aryl, or heterocyclyl; or (c) —C(O)R １ａ , -C(O)OR １ａ 、-C(O)NR １ｂ R １ｃ 、-C(O)SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、 -C(S)R １ａ 、-C(S)OR １ａ 、-C(S)NR １ｂ R １ｃ 、-OR １ａ 、-O C(O)R １ａ 、-OC(O)OR １ａ 、-OC(O)NR １ｂ R １ｃ 、-OC(O)S R １ａ 、-OC(=NR １ａ )NR １ｂ R １ｃ 、-OC(S)R １ａ 、-OC(S)OR １ａ ,-OC(S)NR １ｂ R １ｃ ,-OS(O)R １ａ ,-OS(O) ２ R １ａ 、-O S(O)NR １ｂ R １ｃ ,-OS(O) ２ NR １ｂ R １ｃ ,-NR １ｂ R １ｃ ,-NR １ ａ C(O)R １ｄ 、-NR １ａ C(O)OR １ｄ 、-NR １ａ C(O)NR １ｂ R １ｃ 、 -NR １ａ C(O)SR １ｄ 、-NR １ａ C(=NR) １ｄ )NR １ｂ R １ｃ 、-NR １ａ C(S)R １ｄ 、-NR １ａ C(S)OR １ｄ 、-NR １ａ C(S)NR １ｂ R １ｃ 、- NR １ａ S(O)R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ｃ 、-S(O)R １ａ 、-S(O) ２ R １ａ 、 -S(O)NR １ｂ R １ｃ , or -S(O) ２ NR １ｂ R １ｃ and R ３ is (a) cyano, halo, or nitro; (b) C １－６ Alkyl, C ２－６ a Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７ －１５ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O) R １ａ 、-C(O)OR １ａ 、-C(O)NR １ｂ R １ｃ 、-C(O)SR １ａ 、-C( NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ａ 、-C(S)OR １ａ 、-C(S)NR １ ｂ R １ｃ 、-OR １ａ 、-OC(O)R １ａ 、-OC(O)OR １ａ 、-OC(O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC(=NR １ａ )NR １ｂ R １ｃ 、-OC(S )R １ａ 、-OC(S)OR １ａ 、-OC(S)NR １ｂ R １ｃ 、-OS(O)R １ａ 、 -OOS(O) ２ R １ａ ,-OS(O)NR １ｂ R １ｃ ,-OS(O) ２ NR １ｂ R １ｃ 、 -NR １ｂ R １ｃ 、-NR １ａ C(O)R １ｄ 、-NR １ａ C(O)OR １ｄ 、-NR １ ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C(O)SR １ｄ 、-NR １ａ C(=NR １ｄ ) NR １ｂ R １ｃ 、-NR １ａ C(S)R １ｄ 、-NR １ａ C(S)OR １ｄ 、-NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O)R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、- NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ｃ 、-S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ , or -S(O) ２ NR １ｂ R １ｃ and R ４ is hydrogen, deuterium, cyano, or fluoro; Each R １ａ , R １ｂ , R １ｃ , and R １ｄ are independently hydrogen, deuterium, C １－６ a Lukil, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－ １４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl or R １ａ and R １ｃ together with the C and N atoms to which they are attached form a hetero forming a cyclyl; or R １ｂ and R １ｃ together with the N atoms to which they are attached. to form a heterocyclyl; m is an integer of 0, 1, 2, 3, or 4; However, the compound is 4-((4'-((4-(2,4-dichlorophenyl)-1-ethoxyphenyl)-4-methyl-2,4-dichlorophenyl)-1-ethoxyphenyl. (methyl-1H-imidazol-2-yl)methyl)-[1,1'-biphenyl]-4-yl )oxy)-3-((3-(trifluoromethyl)phenyl)-sulfonamido)benzoin In acid, 3-(N-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)- Neither 2-methylphenyl)sulfamoyl)benzoic acid; Each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, Heteroaryl and heterocyclyl may be one or more, in one embodiment 1, 2, 3 or or four substituents Q, each Q being independently selected from: (a) deuterium, cyano, halo, and nitro; (b) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Shik Roalkyl, C ６－１４ Aryl, C ７－１５ Aralkyl, heteroaryl, and heteroaryl cyclyl (each of which has one or more, in one embodiment 1, 2, 3, or 4, substituents); Substituent Q ａ (c) —C(O)R ａ , —C(O) OR ａ 、-C(O)NR ｂ R ｃ 、-C(O)SR ａ 、-C(NR ａ )NR ｂ R ｃ 、-C( S)R ａ 、-C(S)OR ａ 、-C(S)NR ｂ R ｃ 、-OR ａ 、-OC(O)R ａ 、- OC(O)OR ａ 、-OC(O)NR ｂ R ｃ 、-OC(O)SR ａ 、-OC(=NR ａ ) NR ｂ R ｃ 、-OC(S)R ａ 、-OC(S)OR ａ 、-OC(S)NR ｂ R ｃ 、-OS (O)R ａ ,-OS(O) ２ R ａ ,-OS(O)NR ｂ R ｃ ,-OS(O) ２ NR ｂ R ｃ 、-NR ｂ R ｃ 、-NR ａ C(O)R ｄ 、-NR ａ C(O)OR ｄ 、-NR ａ C(O)N R ｂ R ｃ 、-NR ａ C(O)SR ｄ 、-NR ａ C(=NR ｄ )NR ｂ R ｃ 、-NR ａ C( S)R ｄ 、-NR ａ C(S)OR ｄ 、-NR ａ C(S)NR ｂ R ｃ 、-NR ａ S(O)R ｄ 、-NR ａ S(O) ２ R ｄ 、-NR ａ S(O)NR ｂ R ｃ 、-NR ａ S(O) ２ NR ｂ R ｃ 、 - SR ａ 、 - S(O)R ａ 、 - S(O) ２ R ａ 、 - S(O)NR ｂ R ｃ 、及び - S (O) ２ NR ｂ R ｃ (Each R ａ , R ｂ , R ｃ , and R ｄ are independently: (i) hydrogen or (ii) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ Aralkyl, heteroaryl or heterocyclyl (each of which may be one or more, in one embodiment 1, 2, 3 , or four substituents Q ａ (iii) optionally substituted with R ｂ and R ｃ together with the N atoms to which they are attached, form one or more, in one embodiment, , 2, 3, or 4 substituents Q ａ forming an optionally substituted heterocyclyl) optionally substituted with (selected from); Each Q ａ are independently selected from: (a) deuterium, cyano, halo, and nitro; (b) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６ －１４ Aryl, C ７－１５ aralkyl, heteroaryl, and heterocyclyl; and に(c)-C(O)R ｅ 、-C(O)OR ｅ 、-C(O)NR ｆ R ｇ 、-C(O)SR ｅ 、-C(NR ｅ )NR ｆ R ｇ 、-C(S)R ｅ 、-C(S)OR ｅ 、-C(S)NR ｆ R ｇ 、-OR ｅ 、-OC(O)R ｅ 、-OC(O)OR ｅ 、-OC(O)NR ｆ R ｇ 、-O C(O)SR ｅ 、-OC(=NR ｅ )NR ｆ R ｇ 、-OC(S)R ｅ 、-OC(S)OR ｅ ,-OC(S)NR ｆ R ｇ ,-OS(O)R ｅ ,-OS(O) ２ R ｅ ,-OS(O)N R ｆ R ｇ ,-OS(O) ２ NR ｆ R ｇ ,-NR ｆ R ｇ ,-NR ｅ C(O)R ｈ ,-NR ｅ C(O)OR ｆ 、-NR ｅ C(O)NR ｆ R ｇ 、-NR ｅ C(O)SR ｆ 、-NR ｅ C( =NR ｈ )NR ｆ R ｇ 、-NR ｅ C(S)R ｈ 、-NR ｅ C(S)OR ｆ 、-NR ｅ C( S)NR ｆ R ｇ 、-NR ｅ S(O)R ｈ 、-NR ｅ S(O) ２ R ｈ 、-NR ｅ S(O)N R ｆ R ｇ 、-NR ｅ S(O) ２ NR ｆ R ｇ 、-SR ｅ 、-S(O)R ｅ 、-S(O) ２ R ｅ , -S(O)NR ｆ R ｇ , and -S(O) ２ NR ｆ R ｇ (Each R ｅ , R ｆ , R ｇ , and BiR ｈ are independently (i) hydrogen or deuterium; (ii) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl; or (iii) ) R ｆ and R ｇ together with the N atom to which they are attached form a heterocyclyl. (selected from the group consisting of).

52. The compound is a compound of formula II: 【Transformation 6】 or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or is a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. Item 52. The method according to item 51.

53. The compound has the formula III: 【Transformation 7】 or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or is a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. Item 52. The method according to item 51.

54. The compound has the formula IV: 【Transformation 8】 or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers a compound, tautomer, mixture of two or more tautomers, or isotopic variant; or is a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. Item 53. The method according to item 53.

55. X is -SO ２ - and Y is -NR Ｘ - any one of claims 51 to 54 The method described below.

56. X is -SO ２ - and Y is -NH-.

57. X is -NR Ｘ - and Y is -SO ２ - any one of claims 51 to 54 The method described below.

58. X is —NH— and Y is —SO ２ The method of claim 57, wherein

59. Each R １ are independently (a) cyano, halo, or nitro; (b) C １－６ Al Kill, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１ ４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl; or (c)-C(O)R １ａ 、-C(O)OR １ａ 、-C(O)NR １ｂ R １ｃ 、-C(O) SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ａ 、-C(S)OR １ａ 、 -C(S)NR １ｂ R １ｃ , C １－６ Alkoxy, —OC(O)R １ａ , -OC(O)O R １ａ 、-OC(O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC(=NR １ａ )N R １ｂ R １ｃ 、-OC(S)R １ａ 、-OC(S)OR １ａ 、-OC(S)NR １ｂ R １ ｃ ,-OS(O)R １ａ ,-OS(O) ２ R １ａ ,-OS(O)NR １ｂ R １ｃ ,-OS (O) ２ NR １ｂ R １ｃ 、-NR １ｂ R １ｃ 、-NR １ａ C(O)R １ｄ 、-NR １ａ C (O)OR １ｄ 、-NR １ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C(O)SR １ｄ 、- NR １ａ C(=NR) １ｄ )NR １ｂ R １ｃ ,-NR １ａ C(S)R １ｄ ,-NR １ａ C( S)OR １ｄ 、-NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O)R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ｃ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ ,if Kuha-S(O) ２ NR １ｂ R １ｃ wherein the alkoxy is optionally substituted with one or more substituents Q. The method according to any one of claims 51 to 58, wherein

60. Each R １ is independently halo or C optionally substituted with one or more substituents Q １－６ 60. The method of claim 59, wherein the alkyl is alkyl.

61. Each R １ is fluoro or methyl optionally substituted with one or more substituents Q; 60. The method of claim 59.

62. 62. The method of any one of claims 51 to 61, wherein m is an integer equal to 1.

63. 59. The method of any one of claims 51 to 58, wherein m is an integer equal to 0.

64. R ２ The method of any one of claims 51 to 63, wherein is hydrogen.

65. R ４ The method of any one of claims 51 to 64, wherein is hydrogen.

66. R ３ is (a) cyano, halo, or nitro; (b) C １－６ Alkyl, C ２－６ a Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７ －１５ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O) -C １－６ Alkyl, —C(O)OR １ａ , —C(O)NHR １ｃ , -C(O)SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ａ 、-C(S)OR １ａ 、-C(S )NR １ｂ R １ｃ 、-OR １ａ 、-OC(O)R １ａ 、-OC(O)OR １ａ 、-OC( O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC(=NR １ａ )NR １ｂ R １ｃ 、- OC(S)R １ａ 、-OC(S)OR １ａ 、-OC(S)NR １ｂ R １ｃ 、-OS(O) R １ａ ,-OS(O) ２ R １ａ ,-OS(O)NR １ｂ R １ｃ ,-OS(O) ２ NR １ｂ R １ｃ 、-NR １ｂ R １ｃ 、-NR １ａ C(O)R １ｄ 、-NR １ａ C(O)OR １ｄ 、 -NR １ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C(O)SR １ｄ 、-NR １ａ C(=N R １ｄ )NR １ｂ R １ｃ 、-NR １ａ C(S)R １ｄ 、-NR １ａ C(S)OR １ｄ 、- NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O)R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ｃ 、-S (O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ , or -S(O) ２ NR １ｂ R １ｃ (each alkyl, alkenyl, alkynyl, cycloalkyl, aryl , aralkyl, heteroaryl, and heterocyclyl may independently and optionally be one or more 66. The method of any one of claims 51 to 65, wherein the group is substituted with a substituent Q of the formula:

67. R ３ Nitro, C １－６ Alkyl, -OR １ａ , or -NR １ａ S (O) ２ R １ｄ wherein the alkyl is optionally substituted with one or more substituents Q. The method described.

68. R ３ Nitro, C １－６ Alkyl, C １－６ Alkoxy, or C １－６ Alkyls sulfonamides, each of which alkyl and alkoxy is optionally substituted with one or more substituents Q.

67. The method of claim 66, wherein

69. R ３ is nitro, trifluoromethyl, methoxy, or methylsulfonamido 67. The method of claim 66.

70. R ５ is hydrogen or -OR １ａ The method according to any one of claims 51 to 69, 。

71. R ５ is hydrogen or C １－６ Alkoxy, wherein the alkoxy is optionally substituted with one or more substituents Q.

71. The method of claim 70, wherein:

72. R ５ 71. The method of claim 70, wherein is hydrogen or methoxy.

73. R ６ is hydrogen, C １－６ Alkyl, or -OR １ａ Any of claims 51 to 72, The method according to any one of claims 1 to 10.

74. R ６ is hydrogen, C １－６ Alkyl, or C １－６ Alkoxy (the above alkyl and alkoxy) 74. The method of claim 73, wherein each koxy is optionally substituted with one or more substituents Q. The method described.

75. R ６ is hydrogen, methyl, or methoxy.

76. Each R １ are independently (a) cyano, halo, or nitro; (b) C １－６ Al Kill, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１ ４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl; or (c)-C(O)R １ａ 、-C(O)OR １ａ 、-C(O)NR １ｂ R １ｃ 、-C(O) SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ａ 、-C(S)OR １ａ 、 -C(S)NR １ｂ R １ｃ , C １－６ Alkoxy, —OC(O)R １ａ , -OC(O)O R １ａ 、-OC(O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC(=NR １ａ )N R １ｂ R １ｃ 、-OC(S)R １ａ 、-OC(S)OR １ａ 、-OC(S)NR １ｂ R １ ｃ ,-OS(O)R １ａ ,-OS(O) ２ R １ａ ,-OS(O)NR １ｂ R １ｃ ,-OS (O) ２ NR １ｂ R １ｃ 、-NR １ｂ R １ｃ 、-NR １ａ C(O)R １ｄ 、-NR １ａ C (O)OR １ｄ 、-NR １ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C(O)SR １ｄ 、- NR １ａ C(=NR) １ｄ )NR １ｂ R １ｃ ,-NR １ａ C(S)R １ｄ ,-NR １ａ C( S)OR １ｄ 、-NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O)R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ｃ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ ,if Kuha-S(O) ２ NR １ｂ R １ｃ and R ２ and R ４ are each hydrogen; R ３ is (a) cyano, halo, or nitro; (b) C １－６ Alkyl, C ２－６ a Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７ －１５ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O) -C １－６ Alkyl, —C(O)OR １ａ , —C(O)NHR １ｃ , -C(O)SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ａ 、-C(S)OR １ａ 、-C(S )NR １ｂ R １ｃ 、-OR １ａ 、-OC(O)R １ａ 、-OC(O)OR １ａ 、-OC( O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC(=NR １ａ )NR １ｂ R １ｃ 、- OC(S)R １ａ 、-OC(S)OR １ａ 、-OC(S)NR １ｂ R １ｃ 、-OS(O) R １ａ ,-OS(O) ２ R １ａ ,-OS(O)NR １ｂ R １ｃ ,-OS(O) ２ NR １ｂ R １ｃ 、-NR １ｂ R １ｃ 、-NR １ａ C(O)R １ｄ 、-NR １ａ C(O)OR １ｄ 、 -NR １ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C(O)SR １ｄ 、-NR １ａ C(=N R １ｄ )NR １ｂ R １ｃ 、-NR １ａ C(S)R １ｄ 、-NR １ａ C(S)OR １ｄ 、- NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O)R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ｃ 、-S (O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ , or -S(O) ２ NR １ｂ R １ｃ and R ５ and R ６ are each independently (a) hydrogen, deuterium, cyano, halo, or nitro Toro; (b) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, or is heterocyclyl; or (c) —C(O)R １ａ , -C(O)OR １ａ , -C(O)N R １ｂ R １ｃ 、-C(O)SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ ａ 、-C(S)OR １ａ 、-C(S)NR １ｂ R １ｃ 、-OR １ａ 、-OC(O)R １ａ 、-OC(O)OR １ａ 、-OC(O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC (=NR １ａ )NR １ｂ R １ｃ 、-OC(S)R １ａ 、-OC(S)OR １ａ 、-OC( S)NR １ｂ R １ｃ ,-OS(O)R １ａ ,-OS(O) ２ R １ａ ,-OS(O)NR １ ｂ R １ｃ ,-OS(O) ２ NR １ｂ R １ｃ ,-NR １ｂ R １ｃ ,-NR １ａ C(O)R １ ｄ 、-NR １ａ C(O)OR １ｄ 、-NR １ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C( O)SR １ｄ 、-NR １ａ C(=NR １ｄ )NR １ｂ R １ｃ 、-NR １ａ C(S)R １ｄ 、-NR １ａ C(S)OR １ｄ 、-NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O )R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ ａ S(O) ２ NR １ｂ R １ｃ 、-S(O)R １ａ 、-S(O) ２ R １ａ 、-S(O)NR １ｂ R １ｃ , or -S(O) ２ NR １ｂ R １ｃ and Each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, Heteroaryl and heterocyclyl may independently and optionally be one or more of the following: substituted with 1, 2, 3 or 4 substituents Q.

1. The method according to claim 1.

77. Each R １ are independently (a) cyano, halo, or nitro; (b) C １－６ Al Kill, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１ ４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl; or (c)-C(O)R １ａ 、-C(O)OR １ａ 、-C(O)NR １ｂ R １ｃ 、-C(O) SR １ａ 、-C(NR １ａ )NR １ｂ R １ｃ 、-C(S)R １ａ 、-C(S)OR １ａ 、 -C(S)NR １ｂ R １ｃ , C １－６ Alkoxy, —OC(O)R １ａ , -OC(O)O R １ａ 、-OC(O)NR １ｂ R １ｃ 、-OC(O)SR １ａ 、-OC(=NR １ａ )N R １ｂ R １ｃ 、-OC(S)R １ａ 、-OC(S)OR １ａ 、-OC(S)NR １ｂ R １ ｃ ,-OS(O)R １ａ ,-OS(O) ２ R １ａ ,-OS(O)NR １ｂ R １ｃ ,-OS (O) ２ NR １ｂ R １ｃ 、-NR １ｂ R １ｃ 、-NR １ａ C(O)R １ｄ 、-NR １ａ C (O)OR １ｄ 、-NR １ａ C(O)NR １ｂ R １ｃ 、-NR １ａ C(O)SR １ｄ 、- NR １ａ C(=NR) １ｄ )NR １ｂ R １ｃ ,-NR １ａ C(S)R １ｄ ,-NR １ａ C( S)OR １ｄ 、-NR １ａ C(S)NR １ｂ R １ｃ 、-NR １ａ S(O)R １ｄ 、-NR １ａ S(O) ２ R １ｄ 、-NR １ａ S(O)NR １ｂ R １ｃ 、-NR １ａ S(O) ２ NR １ｂ R １ｃ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ｂ R １ｃ ,if Kuha-S(O) ２ NR １ｂ R １ｃ and R ２ and R ４ are each hydrogen; R ３ Nitro, C １－６ Alkyl, -OR １ａ , or -NR １ａ S (O) ２ R １ｄ and R ５ is hydrogen or -OR １ａ and R ６ is hydrogen, C １－６ Alkyl, or -OR １ａ and m is an integer of 0, 1, 2, or 3; Each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, Heteroaryl and heterocyclyl may independently and optionally be one or more of the following: is substituted with 1, 2, 3 or 4 substituents Q.

1. The method according to claim 1.

78. Each R １ are independently halo or C １－６ is alkyl; R ２ and R ４ are each hydrogen; R ３ Nitro, C １－６ Alkyl, C １－６ Alkoxy, or C １－６ Alkyls sulfonamide; R ５ is hydrogen or C １－６ is alkoxy; R ６ is hydrogen, C １－６ Alkyl, or C １－６ is alkoxy; m is an integer of 0, 1, or 2; Each of alkyl, alkoxy, and C １－６ The alkyl sulfonamide may comprise one or more In one embodiment, the compound of claim 5 is optionally substituted with 1, 2, 3, or 4 substituents Q.

59. The method of any one of 1 to 58.

79. R １ is fluoro or methyl; R ２ and R ４ are each hydrogen; R ３ is nitro, trifluoromethyl, methoxy, or methylsulfonamide ； R ５ is hydrogen or methoxy; R ６ is hydrogen, methyl, or methoxy; 59. The method of any one of claims 51 to 58, wherein m is an integer of 0 or 1.

80. The compound is 4-(N-(3-(methylsulfonamido)phenyl)sulfamoyl)benzoic acid; 3-(N-(2-methyl-5-(trifluoromethyl)phenyl)sulfamoyl)ammonium Zozoic acid; 3-(N-(3,5-dimethoxyphenyl)sulfamoyl)benzoic acid; 3-((2-methoxy-5-nitrophenyl)sulfonamido)-4-methylbenzoic acid ;or 2-fluoro-4-(N-(3-(methylsulfonamido)phenyl)sulfamoyl ) benzoic acid; or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. The method according to any one of claims 51 to 58,

81. The method according to any one of claims 51 to 80, wherein the amyloid β is amyloid β40. How to post.

82. The method according to any one of claims 51 to 80, wherein the amyloid β is amyloid β42. How to post.

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