Phosphorus-containing compounds for treatment of inflammatory bowel disease

Abstract

Provided herein are methods of treating, preventing, or ameliorating one or more symptoms of inflammatory bowel disease with a phosphorus-containing compound, e.g., a compound represented by Formula (I). # imgabs0 #

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. 119(a) to international patent application No. PCT / CN2022 / 132520, filed on November 17, 2022; the disclosure of that patent application is incorporated herein by reference in its entirety. Technical Field

[0002] Provided herein are methods of treating, preventing, or ameliorating one or more symptoms of inflammatory bowel disease using phosphorus-containing compounds. Background Art

[0003] Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic, progressive, immune-mediated, incurable gastrointestinal diseases. Torres et al., Lancet 2017, 389, 1741-55; Ungaro et al., Lancet 2017, 389, 1756-70; Agrawal et al., Gastroenterology 2021, 161, 47-65. IBDs are associated with significant morbidity, disability, and risk of complications. Torres et al., Lancet 2017, 389, 1741-55. Common symptoms of IBDs include abdominal pain, diarrhea, vomiting, fever, and weight loss. Although the cause of IBDs is unknown, genetic, environmental, and lifestyle factors are thought to contribute to IBDs.

[0004] Several immunomodulatory and anti-inflammatory therapies have been approved for the treatment of moderate to severe IBD. These therapies include biologics such as tumor necrosis factor-α (TNF-α) blockers (e.g., infliximab, adalimumab, and golimumab), anti-IL-23 / 12 (e.g., ustekinumab), and anti-integrin α4b7 (e.g., vedolizumab). Rutgeerts et al. N. Engl. J. Med. 2005, 353, 2462-76. Recently, small molecule therapies such as JAK inhibitors (e.g., tofacitinib and upadacitinib) and S1P1 inhibitors (e.g., ozanimod) have also been approved.

[0005] Although multiple therapies have been approved for the treatment and management of IBD, none of them has shown very high efficacy. Cai et al., J. Front. Med. 2021, 8, 765474. For example, approximately 40 to 50% of IBD patients do not respond to anti-TNF-α therapy. Leal et al., Gut 2015, 64, 233-42. In addition, most of these drugs are administered systemically and have significant exposure in tissues other than the intestine, resulting in significant systemic side effects. Therefore, other IBD therapies are needed to better serve IBD patients. Summary of the Invention

[0006] Provided herein are methods for treating, preventing, or ameliorating one or more symptoms of inflammatory bowel disease (IBD) in a subject, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: R 1 Yes (i) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (ii) –OR 1a ,–NR 1b R 1c or –SR 1a ; R 2 It is C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group; Each R 3 are independently (i) deuterium, cyano, halo or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, 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) –C(O)R 1a 、–C(O)OR 1a ,–C(O)NR 1b R1c 、–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(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 R1c ,–NR 1a S(O)2NR 1b R 1c ,–SR 1a ,–S(O)R 1a ,–S(O)2R 1a ,–S(O)NR 1b R 1c or –S(O)2NR 1b R 1c ; R 4 and R 6 are each independently (i) hydrogen; or (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group; R 5 Yes (i) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclic; or (ii) C 1-6 Alkylene-R 5a , where R 5a It is C 3-10 cycloalkyl, heteroaryl or heterocyclyl; X is a bond, –O–, –S–, –N(R 1b )–or C 1-6 alkylene; Z is –O–, –S–, or –N(R 1b )–、C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-10 cycloalkylene or heterocyclylene; Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C7-15 Aralkyl, heteroaryl or heterocyclic; or R 1b and R 1c Together with the nitrogen atom to which they are attached, they form a heterocyclyl; and m is an integer of 0, 1, 2, 3 or 4; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment, 1, 2, 3, or 4, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted by one or more, in one embodiment, 1, 2, 3 or 4 substituents Q a substitution; 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 、–OP(O)(OR b )OR 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)NR b R c ,–NR a C(O)SR d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–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)2NR 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 , where each R a 、R b 、R c and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15Aralkyl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more, in one embodiment, 1, 2, 3 or 4 substituents Q a or (iii) R b and R c Together with the nitrogen atom to which they are attached, they form a heterocyclic group, which is optionally substituted by one or more, in one embodiment, 1, 2, 3 or 4 substituents Q a replace; Each Q a are independently selected from: (a) deuterium, cyano, halo, nitro and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 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 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 、–OP(O)(OR f )OR g 、–OS(O)R e 、–OS(O)2R e 、–OS(O)NR f R g 、–OS(O)2NR f R g ,–NR f Rg ,–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(N(CN))R h ,–NR e C(N(CN))NR f R g ,–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 g ; where each R e 、R f 、R g and R 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 nitrogen atom to which they are attached they form a heterocyclyl. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1 Shown is the effect of compound A30 on body weight changes in mice with oxazolone-induced colitis in a murine colitis model, wherein the term "Tofa" represents tofacitinib.

[0008] Figure 2 Shown is the effect of compound A30 on the DAI score of oxazolone-induced colitis mice in a murine colitis model, wherein the term "Tofa" represents tofacitinib.

[0009] Figure 3 Shown are the effects of Compound A30 on colon weight in mice with oxazolone-induced colitis in a murine colitis model, wherein the term "Tofa" represents tofacitinib.

[0010] Figure 4 Shown is the effect of Compound A30 on colon length in mice with oxazolone-induced colitis in a murine colitis model, wherein the term "Tofa" represents tofacitinib.

[0011] Figure 5 Shown are the effects of Compound A30 on colon density in mice with oxazolone-induced colitis in a murine colitis model, where the term "Tofa" represents tofacitinib.

[0012] Figure 6 Shown are the effects of compound A30 on the pathological scores of oxazolone-induced colitis mice in a murine colitis model, wherein the term "Tofa" represents tofacitinib.

[0013] Figure 7 Shown is the effect of Compound A30 on TNF-α levels (intestinal mucosa) in mice with oxazolone-induced colitis in a murine colitis model, where the term "Tofa" represents tofacitinib.

[0014] Figure 8 Shown is the effect of compound A30 on IFN-γ levels (intestinal mucosa) in mice with oxazolone-induced colitis in a murine colitis model, where the term "Tofa" represents tofacitinib.

[0015] Figure 9 Shown is the effect of Compound A30 on TNF-α levels (serum) in mice with oxazolone-induced colitis in a murine colitis model, where the term "Tofa" represents tofacitinib.

[0016] Figure 10 Shown is the effect of compound A30 on IFN-γ levels (serum) in mice with oxazolone-induced colitis in a murine colitis model, wherein the term "Tofa" represents tofacitinib.

[0017] Figure 11 Shown are the effects of compound A30 on body weight changes in TNBS-induced colitis mice in a murine colitis model of Crohn's disease, wherein the term "Mesa" represents mesalamine.

[0018] Figure 12 Shown are the effects of compound A30 on the DAI score of TNBS-induced colitis mice in a murine colitis model of Crohn's disease, wherein the term "Mesa" represents mesalamine. DETAILED DESCRIPTION

[0019] To aid in understanding the disclosure described herein, certain terms are defined below.

[0020] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology and pharmacy described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

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

[0022] The term "treating" is meant to include alleviating or eliminating the disorder, disease or condition, or one or more symptoms associated with the disorder, disease or condition; or alleviating or eliminating the cause of the disorder, disease or condition itself.

[0023] The term "prevent" is meant to include methods of delaying and / or preventing the onset of a disorder, disease or condition and / or its attendant symptoms; rendering a subject free from the disorder, disease or condition; or reducing the risk of a subject developing a disorder, disease or condition.

[0024] The terms "alleviate" and "alleviating" refer to relieving or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. The term can also refer to reducing an adverse effect associated with an active ingredient. Sometimes, the beneficial effects a subject obtains from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.

[0025] The term "therapeutically effective amount" or "effective amount" is meant to include an amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" or "effective amount" also means an amount of a compound that is sufficient to elicit the biological or medical response of a biomolecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0026] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with tissues or organs of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit / risk ratio. See, for example, Remington: The Science and Practice of Pharmacy, 23rd ed.; Adejare, ed.; Academic Press, 2020; Handbook of Pharmaceutical Excipients, 9th ed.; Sheskey et al., eds.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash, eds.; Synapse Information Resources, 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson, ed.; CRC Press, 2009.

[0027] The term "about" or "approximately" means an acceptable error for a particular value as determined by one skilled in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, or 3 standard deviations. In certain embodiments, the term "about" or "approximately" means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0028] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon group, wherein the alkyl group is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1 to 6 (C 1-6 ) carbon atoms, or a straight-chain saturated monovalent hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. As used herein, a straight chain C 1-6 and branched C 3-6 Alkyl groups are also referred to as "lower alkyl groups." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., n-propyl and isopropyl), butyl (including all isomeric forms, e.g., n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (including all isomeric forms, e.g., n-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl), and hexyl (including all isomeric forms, e.g., n-hexyl, isohexyl, and sec-hexyl).

[0029] The terms "alkylene" and "alkanediyl" are used interchangeably herein to refer to a straight or branched chain saturated divalent hydrocarbon radical, wherein the alkanediyl radical is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkanediyl refers to a straight chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched chain saturated divalent hydrocarbon group having 3 to 6 carbon atoms. 1-30 ), 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1 to 6 (C 1-6 ) carbon atoms, or a straight-chain saturated divalent hydrocarbon group having 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. As used herein, a straight chain C 1-6 and branched C 3-6Alkanediyl groups are also referred to as "lower alkanediyl groups." Examples of alkanediyl groups include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms, for example, ethane-1,1-diyl and ethane-1,2-diyl), propanediyl (including all isomeric forms, for example, propane-1,1-diyl, propane-1,2-diyl and propane-1,3-diyl), butanediyl (including all isomeric forms, for example, butane-1,1-diyl, butane-1,2-diyl and butane-1,3-diyl), and methyl ... -diyl, butane-1,3-diyl and butane-1,4-diyl), pentanediyl (including all isomeric forms, for example, pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl and pentane-1,5-diyl) and hexanediyl (including all isomeric forms, for example, hexane-1,1-diyl, hexane-1,2-diyl, hexane-1,3-diyl and hexane-1,6-diyl). Examples of substituted alkanediyl groups include, but are not limited to, –C(O)CH2–, –C(O)(CH2)2–, –C(O)(CH2)3–, –C(O)(CH2)4–, –C(O)(CH2)5–, –C(O)(CH2)6–, –C(O)(CH2)7–, –C(O)(CH2)8–, –C(O)(CH2)9–, –C(O)(CH2) 10 –, –C(O)CH2C(O)–, –C(O)(CH2)2C(O)–, –C(O)(CH2)3C(O)–, –C(O)(CH2)4C(O)–, or –C(O)(CH2)5C(O)–.

[0030] The term "heteroalkyl" refers to a linear or branched saturated monovalent hydrocarbon group containing one or more heteroatoms in its backbone, each of which is independently selected from O, S, and N. The heteroalkyl group is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, heteroalkyl is a group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1 to 6 (C 1-6 ) carbon atoms, or a straight-chain saturated monovalent hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. As used herein, a straight chain C 1-6 and branched C 3-6Heteroalkyl groups are also referred to as “lower heteroalkyl”. Examples of heteroalkyl groups include, but are not limited to, –OCH3, –OCH2CH3, –CHOCH3, –NHCH3, –ONHCH3, –NHOCH3, –SCH3, –CH2NHCH2CH3, and –NHCH2CH2CH3. Examples of substituted heteroalkyl groups include, but are not limited to, –CH2NHC(O)CH3 and –NHC(O)CH2CH3.

[0031] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more, in one embodiment, 1, 2, 3 or 4, in another embodiment, 1 carbon-carbon double bond. The alkenyl group is optionally substituted with one or more substituents Q as described herein. The term "alkenyl" encompasses groups or mixtures thereof having a "cis" or "trans" configuration, or alternatively, a group or mixtures thereof having a "Z" or "E" configuration, as understood by those skilled in the art. For example, C 2-6 Alkenyl refers to a linear unsaturated monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon group having 3 to 6 carbon atoms. 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or a linear monovalent hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms, e.g., propen-1-yl, propen-2-yl, and allyl), and butenyl (including all isomeric forms, e.g., buten-1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl).

[0032] The terms "alkenylene" and "alkenediyl" are used interchangeably herein to refer to a straight or branched divalent hydrocarbon radical containing one or more, in one embodiment, 1, 2, 3, or 4, in another embodiment, 1 carbon-carbon double bond. The alkenediyl radical is optionally substituted with one or more substituents Q as described herein. The term "alkenediyl" encompasses radicals or mixtures thereof having a "cis" or "trans" configuration, or alternatively, a "Z" or "E" configuration, as understood by those skilled in the art. For example, C 2-6Alkenediyl refers to a straight chain unsaturated divalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, the alkenediyl group is a group having 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or a straight-chain divalent hydrocarbon group having 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. Examples of alkenediyl groups include, but are not limited to, ethylenediyl (including all isomeric forms, for example, ethylene-1,1-diyl and ethylene-1,2-diyl), propylenediyl (including all isomeric forms, for example, 1-propylene-1,1-diyl, 1-propylene-1,2-diyl, and 1-propylene-1,3-diyl), butenediyl (including all isomeric forms, for example, 1-butene-1,1-diyl, 1-butene-1,2-diyl, and 1-butene-1,3-diyl), -1,4-diyl), pentenediyl (including all isomeric forms, for example, 1-penten-1,1-diyl, 1-penten-1,2-diyl and 1-penten-1,5-diyl) and hexenediyl (including all isomeric forms, for example, 1-hexen-1,1-diyl, 1-hexen-1,2-diyl, 1-hexen-1,3-diyl, 1-hexen-1,4-diyl, 1-hexen-1,5-diyl and 1-hexen-1,6-diyl).

[0033] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more, in one embodiment, 1, 2, 3 or 4, in another embodiment, 1 carbon-carbon triple bond. Alkynyl groups do not contain carbon-carbon double bonds. The alkynyl group is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynyl refers to a linear unsaturated monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon group having 4 to 6 carbon atoms. 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or a linear monovalent hydrocarbon group having 4 to 20 (C 4-20 ), 4 to 15 (C 4-15 ), 4 to 10 (C 4-10 ) or 4 to 6 (C 4-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (—C≡CH), propynyl (including all isomeric forms, for example, 1-propynyl (—C≡CCH 3 ) and propargyl (—CH 2 C≡CH )), butynyl (including all isomeric forms, for example, 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomeric forms, for example, 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomeric forms, for example, 1-hexyn-1-yl and 2-hexyn-1-yl).

[0034] The terms "alkynylene" and "alkynediyl" are used interchangeably herein to refer to a straight or branched divalent hydrocarbon radical containing one or more, in one embodiment, 1, 2, 3, or 4, in another embodiment, 1 carbon-carbon triple bond. Alkynediyl groups do not contain carbon-carbon double bonds. The alkynediyl radical is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynediyl refers to a straight chain unsaturated divalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group having 4 to 6 carbon atoms. In certain embodiments, the alkynediyl group is a group having 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or a straight-chain divalent hydrocarbon group having 4 to 30 (C 4-30 ), 4 to 20 (C 4-20 ), 4 to 15 (C 4-15 ), 4 to 10 (C 4-10 ) or 4 to 6 (C 4-6 ) carbon atoms. Examples of alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, for example, 1-propyn-1,3-diyl and 1-propyn-3,3-diyl), butynediyl (including all isomeric forms, for example, 1-butyn-1,3-diyl, 1-butyn-1,4-diyl, and 2-butyn-1,1-diyl), pentynediyl (including all isomeric forms, for example, 1-pentyn-1,3-diyl, 1-pentyn-1,4-diyl, and 2-pentyn-1,1-diyl), and hexynediyl (including all isomeric forms, for example, 1-hexyn-1,3-diyl, 1-hexyn-1,4-diyl, and 2-hexyn-1,1-diyl).

[0035] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl radical is a saturated or unsaturated but non-aromatic, and / or bridged or non-bridged, and / or fused bicyclic radical. In certain embodiments, the cycloalkyl radical has 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 7 (C 3-7 ) carbon atoms. In one embodiment, the cycloalkyl group is monocyclic. In another embodiment, the cycloalkyl group is bicyclic. In yet another embodiment, the cycloalkyl group is tricyclic. In yet another embodiment, the cycloalkyl group is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]-octyl, decahydronaphthyl, and adamantyl.

[0036] The terms "cycloalkylene" and "cycloalkanediyl" are used interchangeably herein to refer to a cyclic divalent hydrocarbon radical that may be optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkanediyl radical may be a saturated or unsaturated but non-aromatic, and / or bridged, and / or non-bridged, and / or fused bicyclic radical. In certain embodiments, the cycloalkanediyl radical has 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 7 (C 3-7) carbon atoms. Examples of cycloalkanediyl groups include, but are not limited to, cyclopropanediyl (including all isomeric forms, for example, cyclopropane-1,1-diyl and cyclopropane-1,2-diyl), cyclobutanediyl (including all isomeric forms, for example, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl and cyclobutane-1,3-diyl), cyclopentanediyl (including all isomeric forms, for example, cyclopentane-1,1-diyl, cyclopentane-1,2-diyl and cyclopentane-1,3-diyl), cyclohexanediyl (including all isomeric forms, for example, cyclohexane-1,1-diyl, cyclohexane-1, cyclohexane-2-diyl, cyclohexane-1,3-diyl and cyclohexane-1,4-diyl), cycloheptane-1,1-diyl (including all isomeric forms, for example, cycloheptane-1,2-diyl, cycloheptane-1,3-diyl and cycloheptane-1,4-diyl), decahydronaphthalene-1,1-diyl (including all isomeric forms, for example, decahydronaphthalene-1,2-diyl and decahydronaphthalene-1,8-diyl) and adamantane-1,2-diyl, adamantane-1,3-diyl and adamantane-1,8-diyl).

[0037] The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon group and / or a monovalent polycyclic aromatic hydrocarbon group containing at least one aromatic hydrocarbon carbocyclic ring. In certain embodiments, the aryl group has 6 to 20 (C 6-20 ), 6 to 15 (C 6-15 ) or 6 to 10 (C 6-10 ) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to a bicyclic or tricyclic carbocyclic ring, wherein one of the rings is aromatic and the remaining rings can be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetrahydronaphthyl). In one embodiment, the aryl group is monocyclic. In another embodiment, the aryl group is bicyclic. In yet another embodiment, the aryl group is tricyclic. In yet another embodiment, the aryl group is polycyclic. In certain embodiments, the aryl group is optionally substituted with one or more substituents Q as described herein.

[0038] The terms "arylene" and "arene diyl" are used interchangeably herein to refer to a divalent monocyclic aromatic hydrocarbon group or a divalent polycyclic aromatic hydrocarbon group containing at least one aromatic hydrocarbon ring. In certain embodiments, the arylene group has 6 to 20 (C 6-20 ), 6 to 15 (C 6-15 ) or 6 to 10 (C 6-10) ring atoms. Examples of arylene groups include, but are not limited to, phenylene (including all isomeric forms, for example, benzene-1,2-diyl, benzene-1,3-diyl, and benzene-1,4-diyl), naphthylene (including all isomeric forms, for example, naphthalene-1,2-diyl, naphthalene-1,3-diyl, and naphthalene-1,8-diyl), fluorenylene (including all isomeric forms, for example, fluorene-1,2-diyl, fluorene-1,3-diyl, and fluorene-1,8-diyl), nitrenylene (including all isomeric forms, for example, nitrene-1,2-diyl, nitrene-1,3-diyl, and nitrene-1,8-diyl), anthracenylene (including all isomeric forms, for example, anthracene- 1,2-diyl, anthracene-1,3-diyl and anthracene-1,8-diyl), phenanthrenylene (including all isomeric forms, for example, phenanthren-1,2-diyl, phenanthren-1,3-diyl and phenanthren-1,8-diyl), pyrenylene (including all isomeric forms, for example, pyrene-1,2-diyl, pyrene-1,3-diyl and pyrene-1,8-diyl), biphenylene (including all isomeric forms, for example, biphenyl-2,3-diyl, biphenyl-3,4'-diyl and biphenyl-4,4'-diyl) and triphenylene (including all isomeric forms, for example, triphenyl-2,3-diyl, triphenyl-3,4'-diyl and triphenyl-4,4'-diyl). Arylene also refers to a bicyclic or tricyclic carbocyclic ring in which one of the rings is aromatic and the other ring can be saturated, partially unsaturated or aromatic, for example, dihydronaphthylene (including all isomeric forms, for example, dihydronaphthalene-1,2-diyl and dihydronaphthalene-1,8-diyl), indenylene (including all isomeric forms, for example, indene-1,2-diyl, indene-1,5-diyl and indene-1,7-diyl), indanylene (including all isomeric forms, for example, indane-1,2-diyl, indane-1,5-diyl and indane-1,7-diyl) or tetrahydronaphthylene (tetrahydronaphthylene) (including all isomeric forms, for example, tetrahydronaphthalene-1,2-diyl, tetrahydronaphthalene-1,5-diyl and tetrahydronaphthalene-1,8-diyl). In certain embodiments, arylene is optionally substituted with one or more substituents Q as described herein.

[0039] The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl group has 7 to 30 (C 7-30 ), 7 to 20 (C 7-20 ) or 7 to 16 (C 7-16 ) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl (including all isomeric forms, e.g., 1-phenethyl and 2-phenethyl), and phenylpropyl (including all isomeric forms, e.g., 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In certain embodiments, the aralkyl group is optionally substituted with one or more substituents Q as described herein.

[0040] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or a monovalent polycyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each of which is independently selected from O, S, and N. For heteroaryl groups containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heteroaryl group is not bonded to the rest of the molecule through its non-aromatic heterocyclic ring. Each ring of the heteroaryl group can contain one or two O atoms, one or two S atoms, and / or 1 to 4 N atoms; as long as the total number of heteroatoms in each ring is independently 4 or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl group has 5 to 20, 5 to 15, or 5 to 10 ring atoms. In one embodiment, the heteroaryl group is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl group is bicyclic.Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridinyl (including all isomeric forms, e.g., furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl) ), imidazopyridinyl (including all isomeric forms, for example, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, for example, imidazo[2,1-b]thiazolyl and imidazo[4,5-d]thiazolyl), indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzothiophenyl (i.e., benzo[c]thiophenyl), isoindolyl, isoquinazolyl, naphthyridinyl (including all isomeric forms, for example, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl and 1,8-naphthyridinyl), oxazolopyridinyl (including all isomeric forms, for example, oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridinyl (including all isomeric forms, for example, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2- b]pyridinyl and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl (including all isomeric forms, for example, [1,2,5]thiadiazolopyrimidinyl and [1,2,3]thiadiazolopyrimidinyl) and thienopyridinyl (including all isomeric forms, for example, thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl and thieno[3,2-c]pyridinyl). In another embodiment, the heteroaryl group is tricyclic. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, pyridinyl, phenanthrinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrinyl, 1,6-phenanthrinyl, 1,7-phenanthrinyl, 1,9-phenanthrinyl, and 2,10-phenanthrinyl), phenanthrinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthanyl. In certain embodiments, the heteroaryl group is optionally substituted with one or more substituents Q as described herein.

[0041] The term "heterocyclyl" or "heterocyclic" refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms is a heteroatom, each independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. For heterocyclyl groups containing heteroaromatic rings and non-aromatic heterocycles, the heterocyclyl group is not bonded to the rest of the molecule through a heteroaromatic ring. In certain embodiments, the heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some of the rings may be partially or fully saturated or aromatic. The heterocyclyl group may be attached to the main structure at any heteroatom or carbon atom that results in a stable compound. Examples of heterocyclic groups include, but are not limited to, azepine, benzodioxane, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzoisoxazine (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4-dihydrobenzo[c][1,2]oxazinyl, and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrobenzothiophenyl, dihydroisobenzofuranyl, dihydrobenzo[c]thiophenyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazine In some embodiments, the heterocyclyl group is optionally substituted with one or more substituents Q as described herein.

[0042] The term "heterocyclyl" refers to a divalent monocyclic non-aromatic ring system or a divalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S and N; and the remaining ring atoms are carbon atoms. For heterocyclyl groups containing heteroaromatic rings and non-aromatic heterocycles, the heterocyclyl group has at least one bond bonded to the rest of the molecule via its non-aromatic heterocycle. In certain embodiments, the heterocyclyl group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7 or 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can be fused or bridged and wherein the nitrogen or sulfur atom can be optionally oxidized, the nitrogen atom can be optionally quaternized and some rings can be partially or completely saturated or aromatic. The heterocyclyl can be connected to the main structure at any heteroatom or carbon atom that results in a stable compound. Examples of such heterocyclyl groups include, but are not limited to, azepindiyl, benzodioxanediyl, benzodioxoldiyl, benzofurandiyl, chromandiyl, decahydroisoquinolindiyl, dihydrobenzofurandiyl, dihydrobenzisothiazoldiyl, dihydrobenzoisoxazindiyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazindiyl, 3,4-dihydrobenzo[c][1,2]oxazindiyl, and 3,4-dihydrobenzo[d][1,2]oxazindiyl), dihydrobenzothiophendiyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiophendiyl, dihydrofurdiyl, dihydroisoindolediyl, dihydropyrandiyl, dihydropyrazoldiyl, dihydropyrazindiyl, dihydropyridinediyl, dihydrobenzothiophendiyl, dihydrobenzothiophendiyl, dihydrobenzofurandiyl, dihydrobenzo[c]thiophendiyl, dihydrofurandiyl, dihydroisoindolediyl, dihydropyrandiyl, dihydropyrazoldiyl, dihydropyrazindiyl, dihydropyridinediyl, dihydrobenzothiophen ... pyrimidinediyl, dihydropyrrolediyl, dioxolanediyl, 1,4-dithianediyl, furanonediyl, imidazolidinediyl, imidazolinediyl, dihydroindolediyl, isochromandiyl, isoindolediyl, isothiazolidinediyl, isoxazolidinediyl, morpholindiyl, octahydroindolediyl, octahydroisoindolediyl, oxazolidinonediyl, oxazolidinediyl, epoxy ethanediyl, piperazinediyl, piperidinediyl, 4-piperidonediyl, pyrazolidinediyl, pyrazolindiyl, pyrrolidinediyl, pyrrolinediyl, quinuclidinediyl, tetrahydrofurandiyl (tetrahydrofurdiyl), tetrahydroisoquinolindiyl, tetrahydropyrandiyl, tetrahydrothiophenediyl, thiomorpholindiyl, thiazolidinediyl, thiochromandiyl, tetrahydroquinolindiyl and 1,3,5-trithianediyl. In certain embodiments, the heterocyclyl group is optionally substituted with one or more substituents Q as described herein.

[0043] The term "halogen," "halide," or "halo" refers to fluoro, chloro, bromo, and / or iodo.

[0044] The term "optionally substituted" is intended to mean that a group or substituent, such as an alkyl, alkylene, heteroalkyl, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heterocyclyl or heterocyclylene, may be substituted with one or more, and in one embodiment, 1, 2, 3 or 4, substituents Q, each of which is independently selected from (for example) (a) deuterium (-D), cyano (-CN), halo, nitro (-NO2) and oxo (=O); (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted by one or more, in one embodiment, 1, 2, 3 or 4 substituents Q a substitution; 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 、–OP(O)(OR b )OR c 、–OS(O)R a 、–OS(O)2R a 、–OS(O)NR b R c 、–OS(O)2NR b R c ,–NR b Rc ,–NR a C(O)R d ,–NR a C(O)OR d ,–NR a C(O)NR b R c ,–NR a C(O)SR d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–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)2NR 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 , where each R a 、R b 、R c and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more, in one embodiment, 1, 2, 3 or 4 substituents Qa or (iii) R b and R c Together with the N atom to which they are attached, they form a group optionally substituted by one or more, in one embodiment, 1, 2, 3 or 4 substituents Q a Substituted heterocyclyl. As used herein, all groups that can be substituted are "optionally substituted."

[0045] In one embodiment, each Q a are independently selected from: (a) deuterium, cyano, halo, nitro and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 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 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 、–OP(O)(OR f )OR g 、–OS(O)R e 、–OS(O)2R e 、–OS(O)NR f R g 、–OS(O)2NR f R g ,–NR f Rg ,–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(N(CN))R h ,–NR e C(N(CN))NR f R g ,–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 g ; where each R e 、R f 、R g and R 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 nitrogen atom to which they are attached they form a heterocyclyl.

[0046] In certain embodiments, "optically active" and "enantiomerically active" refer to a range of molecules having an enantiomeric excess of not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, an optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound contains about 99% or more of one enantiomer and about 1% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question.

[0047] When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center. The prefixes (+) and (-) are used to denote the compound's optical rotation, i.e., the direction in which the optically active compound rotates the plane of polarized light. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left, or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right, or clockwise. However, the signs of optical rotation (+) and (-) have nothing to do with the absolute configuration, R or S, of the compound.

[0048] The term "isotopically enriched" refers to a compound that contains an unnatural proportion of isotopes in one or more of the atoms comprising the compound. In certain embodiments, an isotopically enriched compound contains an unnatural proportion of one or more isotopes, including but not limited to hydrogen ( 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 ( 18O), fluorine-17 ( 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), chlorine-36 ( 36 Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br), iodine-123 ( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and iodine-131( 131 I). In certain embodiments, the isotopically enriched compound is in a stable form, i.e., non-radioactive. In certain embodiments, the isotopically enriched compound contains unnatural proportions of one or more isotopes, including but not limited to 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-31 ( 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( 127I). In certain embodiments, the isotopically enriched compound is in an unstable form, i.e., radioactive. In certain embodiments, the isotopically enriched compound contains unnatural proportions of one or more isotopes, including but not limited to 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), iodine-129( 129 I) and iodine-131( 131 I). It will be understood that in the compounds provided herein, as an example, any hydrogen may be 2 H, or as an example, any carbon can be 13 C, or as an example, any nitrogen may be 15 N, or as an example, any oxygen may be 18 O.

[0049] The term "isotopically enriched" refers to the substitution of a less common isotope of an element (e.g., D for deuterium or hydrogen-2) for a more common isotope of an element (e.g., H for protium or hydrogen-1) at a given position in a molecule. 1 As used herein, when an atom at a particular position in a molecule is designated as a particularly uncommon isotope, it is understood that the abundance of that isotope at that position is significantly greater than its natural abundance.

[0050] The term "isotopic enrichment factor" refers to the ratio of the isotopic abundance in an isotopically enriched compound to the natural abundance of a particular isotope.

[0051] The term "hydrogen" or the symbol "H" refers to the composition of naturally occurring hydrogen isotopes in their natural abundance including protium ( 1 H), deuterium ( 2 H or D) and tritium ( 3 H). Protium is the most common hydrogen isotope with a natural abundance greater than 99.98%. Deuterium is a less common hydrogen isotope with a natural abundance of approximately 0.0156%.

[0052] The term "deuterium enrichment" refers to the percentage of incorporation of deuterium instead of hydrogen at a given position in a molecule. For example, a deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Since the naturally occurring distribution of deuterium averages about 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials averages about 0.0156%. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is significantly greater than its natural abundance (0.0156%).

[0053] The term "carbon" or the symbol "C" refers to the composition of naturally occurring carbon isotopes, which include carbon-12 ( 12 C) and carbon-13 ( 13 C). Carbon-12 is the most common carbon isotope with a natural abundance greater than 98.89%. Carbon-13 is a less common carbon isotope with a natural abundance of approximately 1.11%.

[0054] The term "carbon-13 enriched" or 13 "C-enrichment" refers to the percentage of carbon-13 incorporated in place of carbon at a given position in a molecule. For example, a 10% carbon-13 enrichment at a given position means that 10% of the molecules in a given sample contain carbon-13 at the specified position. Since the naturally occurring distribution of carbon-13 averages about 1.11%, the carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials averages about 1.11%. As used herein, when a particular position in an isotopically enriched compound is designated as having carbon-13, it is understood that the abundance of carbon-13 at that position in the compound is significantly greater than its natural abundance (1.11%).

[0055] The terms "substantially pure" and "substantially homogeneous" mean, when referring to a substance, sufficiently homogeneous to appear free of readily detectable impurities, as determined by standard analytical methods used by those skilled in the art, including but not limited to thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification does not detectably alter the physical, chemical, biological, and / or pharmacological properties of the substance, such as enzymatic and biological activities. In certain embodiments, "substantially pure" or "substantially homogeneous" refers to a collection of molecules wherein at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particularly uncommon isotope, then, relative to the isotopically enriched compound, molecules containing isotopes other than the designated isotope at the designated position are impurities. Thus, for a deuterated compound having an atom designated as deuterium at a particular position, compounds containing protium at the same position are impurities.

[0056] The term "solvate" refers to a complex or aggregate formed by one or more solute molecules, e.g., a compound as provided herein, and one or more solvent molecules, wherein the molecules are present in stoichiometric or non-stoichiometric amounts. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in crystalline form. In another embodiment, the complex or aggregate is in amorphous form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, and pentahydrates.

[0057] For divalent groups described herein, no orientation is indicated by the direction in which the divalent group exists. For example, the formula -C(O)NH- represents both -C(O)NH- and -NHC(O)- unless a specific orientation is specified.

[0058] The phrase “an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof” has the same meaning as the following phrases: “(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of a compound referred to therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of a compound referred to therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of a compound referred to therein.” Compound

[0059] In one embodiment, described herein are compounds of formula (I): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: R 1 Yes (i) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (ii) –OR 1a ,–NR 1b R 1c or –SR 1a ; R 2 It is C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group; Each R 3 are independently (i) deuterium, cyano, halo or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15an aralkyl, heteroaryl or heterocyclic group; or (iii) –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)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 [[ID=九十二]]、–NR 1a [[ID=九十四]]C(S)R 1d [[ID=九十六]]、–NR 1a [[ID=九十八]]C(S)OR 1d 、–NR 1a C(S)NR 1b R 1c 、–NR 1a S(O)R1d ,–NR 1a S(O)2R 1d ,–NR 1a S(O)NR 1b R 1c ,–NR 1a S(O)2NR 1b R 1c ,–SR 1a ,–S(O)R 1a ,–S(O)2R 1a ,–S(O)NR 1b R 1c or –S(O)2NR 1b R 1c ; R 4 and R 6 are each independently (i) hydrogen; or (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group; R 5 Yes (i) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclic; or (ii) C 1-6 Alkylene-R 5a , where R 5a It is C 3-10 Cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclic group; X is a bond, –O–, –S–, –N(R 1b )–or C 1-6 alkylene; Z is –O–, –S–, or –N(R 1b )–、C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-10 cycloalkylene or heterocyclylene; Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, deuterium, C1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic; or R 1b and R 1c Together with the nitrogen atom to which they are attached, they form a heterocyclyl; and m is an integer of 0, 1, 2, 3 or 4; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment, 1, 2, 3, or 4, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted by one or more, in one embodiment, 1, 2, 3 or 4 substituents Q a substitution; 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 、–OP(O)(ORb )OR 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)NR b R c ,–NR a C(O)SR d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–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)2NR 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 , where each R a 、R b 、R c and R d are independently (i) hydrogen or deuterium; (ii) C 1-6Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more, in one embodiment, 1, 2, 3 or 4 substituents Q a or (iii) R b and R c Together with the nitrogen atom to which they are attached, they form a heterocyclic group, which is optionally substituted by one or more, in one embodiment, 1, 2, 3 or 4 substituents Q a replace; Each Q a are independently selected from: (a) deuterium, cyano, halo, nitro and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 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 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 、–OP(O)(OR f )OR g 、–OS(O)R e 、–OS(O)2Re 、–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(N(CN))R h ,–NR e C(N(CN))NR f R g ,–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 g ; where each R e 、R f 、R g and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (iii) R f and R g Together with the nitrogen atom to which they are attached they form a heterocyclyl.

[0060] In certain embodiments, in Formula (I), R 2 is C optionally substituted by one or more substituents Q 6-14 In certain embodiments, in Formula (I), R 2 is C optionally substituted with one or more substituents Q 6-14 In certain embodiments, in Formula (I), R 2 is phenyl optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R 2 is phenyl optionally substituted with 1, 2 or 3 substituents, each of which is independently halo or -OR 1a ; where R 1a As defined herein. In certain embodiments, in Formula (I), R 2 is phenyl optionally substituted with one or two substituents, each of which is independently halo, hydroxy or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in Formula (I), R 2 is phenyl optionally substituted by one or two substituents, each of which is independently chloro, hydroxy or methoxy. In certain embodiments, in formula (I), R 2 is phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl or 3-chloro-4-hydroxyphenyl. In certain embodiments, in formula (I), R 2 It is 3-hydroxyphenyl.

[0061] In certain embodiments, in Formula (I), R 2 is a heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R 2 is a bicyclic heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R 2 is a 5,6-fused heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R 2 is benzofuranyl or indolyl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), R 2is benzofuran-2-yl, benzofuran-6-yl or indol-5-yl. In certain embodiments, in formula (I), R 2 It is phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 3-chloro-4-hydroxyphenyl, benzofuran-2-yl, benzofuran-6-yl or indol-5-yl.

[0062] In one embodiment, in formula (I), R 1 (i) C optionally substituted with one or more substituents Q 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl; or (ii) –OR a ; where R a As defined herein; R 2 is C optionally substituted by one or more substituents Q 6-14 aryl or heteroaryl; Each R 3 is independently (i) halo; or (ii) C optionally substituted with one or more substituents Q 1-6 alkyl; R 4 and R 6 are each independently hydrogen; R 5 is C optionally substituted by one or more substituents Q 1-6 Alkyl, C 7-15 Aralkyl, C 1-6 Alkylene-heteroaryl or C 1-6 alkylene-heterocyclyl; X is a bond or –O–; Z is C optionally substituted with one or more substituents Q 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 an alkynylene group; and m is an integer 0, 1, or 2.

[0063] In another embodiment, in Formula (I), R 1 is (i) hydroxy; or (ii) C optionally substituted with one or more substituents Q 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14 Aryl or C 1-6 alkoxy; R 2 is C optionally substituted by one or more substituents Q 6-14aryl or heteroaryl; Each R 3 are independently halogenated; R 4 and R 6 They are hydrogen; R 5 It is C 1-6 Alkyl, C 7-15 Aralkyl, C 1-6 Alkylene-heteroaryl or C 1-6 Alkylene-heterocyclyl, each group independently substituted with one or two substituents; wherein each substituent is independently -OR a ,–NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2R d or –S(O)2R a ; where each R a 、R b 、R c and R d As defined herein; X is a bond or –O–; Z is C optionally substituted with one or more substituents Q 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 an alkynylene group; and m is the integer 2.

[0064] In another embodiment, in formula (I), R 1 is methyl, ethyl, isopropyl, n-butyl, cyclopropyl, 3-hydroxyphenyl, hydroxy, methoxy or ethoxy; R 2 is phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 3-chloro-4-hydroxyphenyl, benzofuran-2-yl, benzofuran-6-yl or indol-5-yl; Each R 3 It is chlorinated; R 4 and R 6 They are hydrogen; R 53-Methylsulfonylaminopropyl, 4-methylsulfonylaminobutyl, thiophen-2-yl-carboxamidomethyl, ((S)-3-hydroxypyrrolidine-1-carboxamido)methyl, (E)-N'-cyano-3-hydroxy-pyrrolidine-1-carboxamidomethyl, (E)-N'-cyano-3,4-dihydroxypyrrolidine-1-carboxamidomethyl, 2-cyano-3,3-bis(2-hydroxyethyl)guanidinomethyl, 3-hydroxybenzyl, 3,5-dihydroxybenzyl, 3-methyl methyl, (1-(methylsulfonyl)pyrrol-3-yl)methyl, (1-(methylsulfonyl)pyrazol-3-yl)methyl, (1-(methylsulfonyl)pyrazol-4-yl)methyl, (5-(methylsulfonyl)pyridin-3-yl)methyl, (1-(methylsulfonyl)pyrrolidin-3-yl)methyl, or (1-(methylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl)methyl; X is a bond or –O–; Z is methanediyl, ethane-1,2-diyl, 1-hydroxyethane-1,2-diyl, ethylene-1,2-diyl, acetylene-1,2-diyl; and m is the integer 2.

[0065] In one embodiment, described herein is a compound of formula (II): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: R 2a is hydrogen or R 2b ; Each R 2b are independently (i) hydrogen, deuterium, cyano, halo or nitro; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is optionally substituted by one or more, in one embodiment, 1, 2, 3 or 4 substituents Q a substitution; and (c)–C(O)R a 、–C(O)OR a ,–C(O)NR b R c ,–C(O)SR a ,–C(NR a )NRb 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 、–OP(O)(OR b )OR 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)NR b R c 、–NR a C(O)SR d 、–NR a C(NR d )NR b R c 、–NR a C(N(CN))R d 、–NR a C(N(CN))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)Rd ,–NR a S(O)2R d ,–NR a S(O)NR b R c ,–NR a S(O)2NR 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 ; n is an integer 0, 1, 2, 3, or 4; and R 1 、R 3 、R 4 、R 5 、R 6 、R a 、R b 、R c 、R d , X, Z and m are each as defined herein.

[0066] In another embodiment, described herein is a compound of formula (III): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 3a and R 3b are independently hydrogen or R 3 ; and R 1 、R 3 、R 4 、R 5 、R 6 、R 2a 、R 2b , X, Z and n are each as defined herein.

[0067] In another embodiment, described herein is a compound of formula (IV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 、R 4 、R 5 、R 6 、R 2a 、R 2b 、R 3a 、R 3b , X, Z and n are each as defined herein.

[0068] In yet another embodiment, described herein are compounds of formula (V): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 、R 4 、R 5 、R 6 、R 2a 、R 2b 、R 3a 、R 3b , X, Z and n are each as defined herein.

[0069] In certain embodiments, in any one of Formulas (I) to (V), R 5 It is C 1-6 Alkyl, C 7-15 Aralkyl, C 1-6 Alkylene-heteroaryl or C 1-6 These groups are optionally substituted by one or more substituents Q. In certain embodiments, in any one of the chemical formulas (I) to (V), R 5 It is C 1-6 Alkyl, C 7-15 Aralkyl, C 1-6 Alkylene-heteroaryl or C 1-6 Alkylene-heterocyclyl, each optionally substituted by -OR a ,–NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2Rd or –S(O)2R a Replace; wherein each R a 、R b 、R c and R d As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (V), R 5 Is -NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c or –NR a S(O)2R d Substituted C 1-6 Alkyl; wherein each R a 、R b 、R c and R d As defined herein.

[0070] In certain embodiments, in any one of Formulas (I) to (V), R 5 is C optionally substituted with one or more substituents Q 7-15 In certain embodiments, in any one of Formulas (I) to (V), R 5 is a C substituted with one or two substituents 7-15 Aralkyl, each substituent is independently –OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a benzyl group optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (V), R 5 is benzyl substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is benzyl substituted with one or two substituents, each substituent being independently hydroxy or methylsulfonyl.

[0071] In certain embodiments, in any one of Formulas (I) to (V), R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (V), R 5 is a C substituted with one or two substituents 1-6 Alkylene-heteroaryl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is -CH2-heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a –CH2-heteroaryl substituted with one or two substituents, each of which is independently –OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a -CH2-heteroaryl group substituted with one or two substituents, each of which is independently hydroxy or methylsulfonyl.

[0072] In certain embodiments, in any one of Formulas (I) to (V), R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (V), R 5 is a C substituted with one or two substituents 1-6 Alkylene-monocyclic heteroaryl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a -CH2-monocyclic heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a –CH2-monocyclic heteroaryl substituted with one or two substituents, each of which is independently –OR a or –S(O)2R a ; where each R aAs defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a –CH2-monocyclic heteroaryl group substituted with one or two substituents, each of which is independently hydroxy or methylsulfonyl.

[0073] In certain embodiments, in any one of Formulas (I) to (V), R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (V), R 5 is a C substituted with one or two substituents 1-6 Alkylene-5-membered heteroaryl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a -CH2-5-membered heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a –CH2-5-membered heteroaryl substituted with one or two substituents, each of which is independently –OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a -CH2-5-membered heteroaryl substituted with one or two substituents, each of which is independently hydroxy or methylsulfonyl.

[0074] In certain embodiments, in any one of Formulas (I) to (V), R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (V), R 5 is a C substituted with one or two substituents 1-6 Alkylene-6-membered heteroaryl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a -CH2-6-membered heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (V), R 5is a –CH2-6-membered heteroaryl substituted with one or two substituents, each of which is independently –OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a -CH2-6-membered heteroaryl substituted with one or two substituents, each of which is independently hydroxy or methylsulfonyl.

[0075] In certain embodiments, in any one of Formulas (I) to (V), R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (V), R 5 is a C substituted with one or two substituents 1-6 Alkylene-heterocyclyl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is -CH2-heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a –CH2-heterocyclyl substituted with one or two substituents, each of which is independently –OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a -CH2-heterocyclyl substituted with one or two substituents, each of which is independently hydroxy or methylsulfonyl.

[0076] In certain embodiments, in any one of Formulas (I) to (V), R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (V), R 5 is a C substituted with one or two substituents 1-6 Alkylene - a monocyclic heterocyclyl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R5 is a -CH2-monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a –CH2-monocyclic heterocyclyl substituted with one or two substituents, each of which is independently –OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a -CH2-monocyclic heterocyclyl substituted by one or two substituents, each of which is independently hydroxy or methylsulfonyl.

[0077] In certain embodiments, in any one of Formulas (I) to (V), R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (V), R 5 is a C substituted with one or two substituents 1-6 Alkylene-5-membered heterocyclyl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a -CH2-5-membered heterocyclyl group optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a -CH2-5-membered heterocyclyl substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a -CH2-5-membered heterocyclic group substituted by one or two substituents, each of which is independently hydroxy or methylsulfonyl.

[0078] In certain embodiments, in any one of Formulas (I) to (V), R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (V), R 5 is a C substituted with one or two substituents 1-6Alkylene-6-membered heterocyclyl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a -CH2-6-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a -CH2-6-membered heterocyclyl substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (I) to (V), R 5 is a -CH2-6-membered heterocyclyl substituted by one or two substituents, each of which is independently hydroxy or methylsulfonyl.

[0079] In certain embodiments, in any one of Formulas (I) to (V), R 5 are 3-methylsulfonylaminopropyl, 4-methylsulfonylaminobutyl, thiophen-2-ylcarboxamidomethyl, ((S)-3-hydroxy-pyrrolidine-1-carboxamido)methyl, (E)-N'-cyano-3-hydroxypyrrolidine-1-carboxamido-methyl, (E)-N'-cyano-3,4-dihydroxypyrrolidine-1-carboxamido-methyl, 2-cyano-3,3-bis(2-hydroxyethyl)guanidinomethyl, 3-hydroxybenzyl, 3,5-dihydroxybenzyl, 3 -methylsulfonylbenzyl, 3,5-dimethylsulfonylbenzyl, (1-(methylsulfonyl)pyrrol-3-yl)methyl, (1-(methylsulfonyl)pyrazol-3-yl)methyl, (1-(methylsulfonyl)pyrazol-4-yl)methyl, (5-(methylsulfonyl)pyridin-3-yl)methyl, (1-(methylsulfonyl)pyrrolidin-3-yl)methyl, or (1-(methylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl)methyl.

[0080] In one embodiment, in any one of formulae (III) to (V), R 1 (i) C optionally substituted with one or more substituents Q 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl; or (ii) –OR a ; R 2a is hydrogen, halogen, or –OR a ; Each R2b are independently halo or –OR a ; R 3a and R 3b are independently (i) halo; or (ii) C optionally substituted with one or more substituents Q 1-6 alkyl; R 4 and R 6 They are hydrogen; R 5 is C optionally substituted by one or more substituents Q 1-6 Alkyl, C 7-15 Aralkyl, C 1-6 Alkylene-heteroaryl or C 1-6 alkylene-heterocyclyl; X is a bond or –O–; Z is C optionally substituted with one or more substituents Q 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene; m is an integer 0, 1, or 2; and n is an integer 0 or 1; Each R a 、R b 、R c and R d As defined herein.

[0081] In another embodiment, in any one of formulae (III) to (V), R 1 is (i) hydroxy; or (ii) C optionally substituted with one or more substituents Q 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14 Aryl or C 1-6 alkoxy; R 2a is (i) hydrogen, halo or hydroxy; or (ii) C optionally substituted with one or two substituents Q 1-6 alkoxy; Each R 2b is independently (i) halo or hydroxy; or (ii) C optionally substituted with one or two substituents Q 1-6 alkoxy; R 3a and R 3b are each independently halogenated; R 4 and R 6 They are hydrogen; R 5is independently substituted by one or two substituents 1-6 Alkyl, C 7-15 Aralkyl, C 1-6 Alkylene-heteroaryl or C 1-6 Alkylene-heterocyclyl, each substituent is independently -OR a ,–NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2R d or –S(O)2R a ; X is a bond or –O–; Z is C optionally substituted with one or more substituents Q 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene; m is the integer 2; and n is an integer 0 or 1; Each R a 、R b 、R c and R d As defined herein.

[0082] In another embodiment, in any one of formulae (III) to (V), R 1 is methyl, ethyl, isopropyl, n-butyl, cyclopropyl, 3-hydroxyphenyl, hydroxy, methoxy or ethoxy; R 2a is hydrogen, chloro, hydroxy or methoxy; Each R 2b are independently chloro, hydroxy or methoxy; R 3a and R 3b Each is chlorinated; R 4 and R 6 They are hydrogen; R 53-Methylsulfonylaminopropyl, 4-methylsulfonylaminobutyl, thiophen-2-yl-carboxamidomethyl, ((S)-3-hydroxypyrrolidine-1-carboxamido)methyl, (E)-N'-cyano-3-hydroxy-pyrrolidine-1-carboxamidomethyl, (E)-N'-cyano-3,4-dihydroxypyrrolidine-1-carboxamidomethyl, 2-cyano-3,3-bis(2-hydroxyethyl)guanidinomethyl, 3-hydroxybenzyl, 3,5-dihydroxybenzyl, 3-methylsulfonyl 1-(methylsulfonyl)pyrrolidin-3-yl)methyl, (1-(methylsulfonyl)pyrazol-3-yl)methyl, (1-(methylsulfonyl)pyrazol-4-yl)-methyl, (5-(methylsulfonyl)pyridin-3-yl)methyl, (1-(methylsulfonyl)pyrrolidin-3-yl)methyl, or (1-(methylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl)methyl; X is a bond or –O–; Z is methanediyl, ethane-1,2-diyl, 1-hydroxyethane-1,2-diyl, ethylene-1,2-diyl, acetylene-1,2-diyl; m is the integer 2; and n is an integer 0 or 1.

[0083] In one embodiment, described herein is a compound of formula (VI): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: R 5a (i) 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 arylalkyl, heteroaryl or heterocyclyl; or (ii) -NR a C(N(CN))R d or –NR a C(N(CN))NR b R c ; and R 1 、R 3 、R 4 、R 6 、R a 、R b 、R c 、R d 、R 2a、R 2b , X, Z, m and n are each as defined herein.

[0084] In another embodiment, described herein is a compound of formula (VII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 、R 4 、R 6 、R 2a 、R 2b 、R 3a 、R 3b 、R 5a , X, Z and n are each as defined herein.

[0085] In yet another embodiment, described herein is a compound of formula (VIII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 、R 4 、R 6 、R 2a 、R 2b 、R 3a 、R 3b 、R 5a , X, Z and n are each as defined herein.

[0086] In yet another embodiment, described herein is a compound of formula (IX): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 、R 4 、R 6 、R 2a 、R 2b 、R 3a 、R 3b 、R 5a , X, Z and n are each as defined herein.

[0087] In certain embodiments, in any one of Formulas (VII) to (IX), R 2a is hydrogen, halogen, or –OR 1a , where R 1a As defined herein. In certain embodiments, in any one of Formulas (VII) to (IX), R 2a is hydrogen, halo, hydroxy or C optionally substituted by one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (VII) to (IX), R 2a is hydrogen, chloro, hydroxy or methoxy. In certain embodiments, in any one of formulas (VII) to (IX), R 2a is chloro, hydroxy or methoxy. In certain embodiments, in any one of formulas (VII) to (IX), R 2a It is a hydroxyl group.

[0088] In certain embodiments, in any one of Formulas (VII) to (IX), R 2b Is halogenated or –OR 1a , where R 1a As defined herein. In certain embodiments, in any one of Formulas (VII) to (IX), R 2b is halogenated, hydroxyl or C optionally substituted by one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (VII) to (IX), R 2b is chloro, hydroxy or methoxy.

[0089] In certain embodiments, in any one of Formulas (VII) to (IX), n is an integer of 0 or 1. In certain embodiments, in any one of Formulas (VII) to (IX), n is an integer of 0. In certain embodiments, in any one of Formulas (VII) to (IX), n is an integer of 1.

[0090] In certain embodiments, in any one of Formulas (III) to (V) and (VII) to (IX), R 3a C is halogenated or optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (III) to (V) and (VII) to (IX), R 3a In certain embodiments, in any one of Formulas (III) to (V) and (VII) to (IX), R 3ais fluoro, chloro or bromo. In certain embodiments, in any one of formulas (III) to (V) and (VII) to (IX), R 3a In certain embodiments, in any one of Formulas (III) to (V) and (VII) to (IX), R 3a is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (III) to (V) and (VII) to (IX), R 3a is methyl or trifluoromethyl.

[0091] In certain embodiments, in any one of Formulas (III) to (V) and (VII) to (IX), R 3b C is halogenated or optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (III) to (V) and (VII) to (IX), R 3b In certain embodiments, in any one of Formulas (III) to (V) and (VII) to (IX), R 3b is fluoro, chloro or bromo. In certain embodiments, in any one of formulas (III) to (V) and (VII) to (IX), R 3b In certain embodiments, in any one of Formulas (III) to (V) and (VII) to (IX), R 3b is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (III) to (V) and (VII) to (IX), R 3b is methyl or trifluoromethyl.

[0092] In certain embodiments, in any one of Formulas (III) to (V) and (VII) to (IX), R 3a and R 3b In certain embodiments, in any one of Formulas (III) to (V) and (VII) to (IX), R 3a and R 3b Each is chlorinated.

[0093] In certain embodiments, in any one of Formulas (VI) to (IX), R 5a (i) each independently substituted with one or more substituents Q 1-6 Alkyl, C 6-14 aryl, heteroaryl or heterocyclyl; or (ii) -NR a C(N(CN))Rd or –NR a C(N(CN))NR b R c ; where each R a 、R b 、R c and R d As defined herein. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is C independently substituted by one or more substituents Q 1-6 Alkyl, C 6-14 In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is C substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (VI) to (IX), R 5a Is -NR a S(O)2R d Substituted C 1-6 Alkyl, where R a and R d In certain embodiments, in any one of Formulas (VI) to (IX), R 5a It is 2-methylsulfonylaminoethyl or 3-methylsulfonylaminopropyl.

[0094] In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is C substituted with one or more substituents Q 6-14 In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is a C substituted with one or two substituents 6-14 Aryl, each of said substituents is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is phenyl substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is phenyl substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (VI) to (IX), R 5ais phenyl substituted with one or two substituents, each of which is independently -OR a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is phenyl substituted with one or two substituents, each of which is independently –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is phenyl substituted with one or two substituents, each of which is independently hydroxy or methylsulfonyl. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is a phenyl group substituted with one or two methylsulfonyl groups. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a It is 3-hydroxyphenyl, 3,5-dihydroxyphenyl, 3-methylsulfonylphenyl or 3,5-dimethylsulfonylphenyl.

[0095] In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is a heteroaryl group substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is a monocyclic heteroaryl substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is a 5- or 6-membered heteroaryl group independently substituted by one or more substituents Q. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is a 5- or 6-membered heteroaryl group independently substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is a 5- or 6-membered heteroaryl group independently substituted with one or two substituents, each of which is independently -S(O)2R a ; where R a As defined herein. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is pyrrolyl, pyrazolyl, or pyridinyl, each independently substituted with one or two substituents, each of which is independently -S(O)2R a ; where R aAs defined herein. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is pyrrolyl, pyrazolyl or pyridinyl, each of which is independently substituted by one or two methylsulfonyl groups. In certain embodiments, in any one of formulas (VI) to (IX), R 5a It is 1-(methylsulfonyl)pyrrol-3-yl, 1-(methylsulfonyl)pyrazol-3-yl, 1-(methylsulfonyl)pyrazol-4-yl or 5-(methylsulfonyl)pyridin-3-yl.

[0096] In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is a heterocyclyl group optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is a monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is a 3-, 4-, 5-, 6- or 7-membered heterocyclyl group optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is a 5- or 6-membered heterocyclic group substituted by one or more substituents Q. In certain embodiments, in any one of formulas (VI) to (IX), R 5a is a 5- or 6-membered heterocyclic group independently substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is a 5- or 6-membered heterocyclic group independently substituted by one or two substituents, each of which is independently -S(O)2R a ; where R a As defined herein. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a is a 5- or 6-membered heterocyclic group, each of which is independently substituted by one or two methylsulfonyl groups. In certain embodiments, in any one of Formulas (VI) to (IX), R 5a It is 1-(methylsulfonyl)pyrrolidin-3-yl or 1-(methylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl.

[0097] In certain embodiments, in any one of Formulas (VI) to (IX), R 5a Yes – NRa C(N(CN))R d , where R a and R d In certain embodiments, in any one of Formulas (VI) to (IX), R 5a Yes – NR a C(N(CN))NR b R c , where R a 、R b and R c In certain embodiments, in any one of Formulas (VI) to (IX), R 5a It is thiophen-2-yl-carboxamido, (S)-3-hydroxypyrrolidine-1-carboxamido, (E)-N'-cyano-3-hydroxy-pyrrolidine-1-carboxamido, (E)-N'-cyano-3,4-dihydroxypyrrolidine-1-carboxamido or 2-cyano-3,3-bis(2-hydroxyethyl)guanidino.

[0098] In certain embodiments, in any one of Formulas (VI) to (IX), R 5a 2-methylsulfonylaminoethyl, 3-methylsulfonylaminopropyl, 3-hydroxyphenyl, 3,5-dihydroxyphenyl, 3-methylsulfonylphenyl, 3,5-dimethylsulfonylphenyl, 1-(methylsulfonyl)pyrrol-3-yl, 1-(methylsulfonyl)pyrazol-3-yl, 1-(methylsulfonyl)pyrazol-4-yl, 5-(methylsulfonyl)pyridin-3-yl, 1-(methylsulfonyl)pyridin-4-yl, In certain embodiments, in any one of Formulas (VI) to (IX), R 5a It is 3-methylsulfonylphenyl.

[0099] In certain embodiments, in any one of Formulas (I) to (IX), R 1 (i) 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 aralkyl, heteroaryl or heterocyclyl; or (ii) –OR 1a , where R1a As defined herein. In certain embodiments, in any one of Formulas (I) to (IX), R 1 (i) C optionally substituted with one or more substituents Q 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14 Aryl or C 1-6 or (ii) hydroxy. In certain embodiments, in any one of Formulas (I) to (IX), R 1 is methyl, ethyl, isopropyl, n-butyl, cyclopropyl, 3-hydroxyphenyl, hydroxy, methoxy or ethoxy. In certain embodiments, in any one of formulas (I) to (IX), R 1 It's methyl.

[0100] In certain embodiments, in Formula (I), (II) or (VI), each R 3 C is independently halogenated or optionally substituted with one or more substituents Q 1-6 In certain embodiments, in Formula (I), (II) or (VI), each R 3 In certain embodiments, in Formula (I), (II) or (VI), each R 3 It is chlorinated.

[0101] In certain embodiments, in any one of Formulas (I) to (IX), R 4 is (i) hydrogen; or (ii) C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (IX), R 4 In certain embodiments, in any one of Formulas (I) to (IX), R 4 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (IX), R 4 It's methyl.

[0102] In certain embodiments, in any one of Formulas (I) to (IX), R 6 is (i) hydrogen; or (ii) C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (IX), R 6 In certain embodiments, in any one of Formulas (I) to (IX), R 6 is C optionally substituted with one or more substituents Q 1-6In certain embodiments, in any one of Formulas (I) to (IX), R 6 It's methyl.

[0103] In certain embodiments, in any one of Formulas (I) to (IX), X is (i) a bond or -O-; or (ii) C optionally substituted with one or more substituents Q. 1-6 In certain embodiments, in any one of formulas (I) to (IX), X is a bond. In certain embodiments, in any one of formulas (I) to (IX), X is -O-. In certain embodiments, X is C optionally substituted with one or more substituents Q. 1-6 In certain embodiments, X is methanediyl optionally substituted with one or more substituents Q. In certain embodiments, in any one of formulas (I) to (IX), X is a bond or -O-.

[0104] In certain embodiments, in any one of Formulas (I) to (IX), Z is (i) -O- or -S-; or (ii) C optionally substituted with one or more substituents Q. 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 In certain embodiments, in any one of Formulas (I) to (IX), Z is C optionally substituted with one or more substituents Q. 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene. In certain embodiments, in any one of formulas (I) to (IX), Z is (i) methanediyl, ethanediyl, or ethylenediyl, each optionally substituted with one or more substituents Q; or (ii) acetylenediyl. In certain embodiments, in any one of formulas (I) to (IX), Z is (i) methanediyl, ethane-1,2-diyl, or ethylene-1,2-diyl, each optionally substituted with one or more substituents Q; or (ii) acetylene-1,2-diyl. In certain embodiments, in any one of formulas (I) to (IX), Z is methanediyl, ethane-1,2-diyl, 1-hydroxyethane-1,2-diyl, ethylene-1,2-diyl, or acetylene-1,2-diyl.

[0105] In certain embodiments, in any one of formulae (I) to (IX), the moiety "-X-Y-" is -O-C- 1-6 Alkylene, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6In certain embodiments, in any one of Formulas (I) to (IX), the moiety "-X-Y-" is -O-C optionally substituted with one or more substituents Q. 1-6 In certain embodiments, in any one of formulae (I) to (IX), the moiety "-X-Y-" is -O-CH2-. In certain embodiments, in any one of formulae (I) to (IX), the moiety "-X-Y-" is C optionally substituted with one or more substituents Q. 1-6 In certain embodiments, in any one of formulae (I) to (IX), the moiety “–X–Y–” is ethanediyl optionally substituted with one or more substituents Q. In certain embodiments, in any one of formulae (I) to (IX), the moiety “–X–Y–” is ethane-1,2-diyl optionally substituted with one or more substituents Q. In certain embodiments, in any one of formulae (I) to (IX), the moiety “–X–Y–” is ethane-1,2-diyl or 1-hydroxyethane-1,2-diyl. In certain embodiments, in any one of formulae (I) to (IX), the moiety “–X–Y–” is C 2-6 In certain embodiments, in any one of formulae (I) to (IX), the moiety “–X–Y–” is an ethylene diyl group optionally substituted with one or more substituents Q. In certain embodiments, in any one of formulae (I) to (IX), the moiety “–X–Y–” is an ethylene-1,2-diyl group optionally substituted with one or more substituents Q. In certain embodiments, in any one of formulae (I) to (IX), the moiety “–X–Y–” is an ethylene-1,2-diyl group optionally substituted with one or more substituents Q. 2-6 In certain embodiments, in any one of Formulas (I) to (IX), the moiety "-X-Y-" is ethynyl-1,2-diyl.

[0106] In certain embodiments, in formula (I), (II) or (VI), m is an integer of 0, 1 or 2. In certain embodiments, in formula (I), (II) or (VI), m is an integer of 0. In certain embodiments, in formula (I), (II) or (VI), m is an integer of 1. In certain embodiments, in formula (I), (II) or (VI), m is an integer of 2.

[0107] In certain embodiments, in any one of formulae (II) to (IX), n is an integer of 0 or 1. In certain embodiments, in any one of formulae (II) to (IX), n is an integer of 0. In certain embodiments, in any one of formulae (II) to (IX), n is an integer of 1.

[0108] In one embodiment, in any one of formulae (VII) to (IX), R 1 (i) C optionally substituted with one or more substituents Q 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl; or (ii) –OR a ; R 2a is hydrogen, halogen, or –OR a ; Each R 2b are independently halo or –OR a ; R 3a and R 3b are independently (i) halo; or (ii) C optionally substituted with one or more substituents Q 1-6 alkyl; R 4 and R 6 They are hydrogen; R 5a (i) C optionally substituted with one or more substituents Q 1-6 Alkyl, C 6-14 aryl, heteroaryl or heterocyclyl; or (ii) -NR a C(N(CN))R d or –NR a C(N(CN))NR b R c ; X is a bond or –O–; Z is C optionally substituted with one or more substituents Q 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene; m is an integer 0, 1, or 2; and n is an integer 0 or 1; Each R a 、R b 、R c and R d As defined herein.

[0109] In another embodiment, in any one of Formulas (VII) to (IX), R 1 is (i) hydroxy; or (ii) C optionally substituted with one or more substituents Q 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14Aryl or C 1-6 alkoxy; R 2a is (i) hydrogen, halo or hydroxy; or (ii) C optionally substituted with one or two substituents Q 1-6 alkoxy; Each R 2b is independently (i) halo or hydroxy; or (ii) C optionally substituted with one or two substituents Q 1-6 alkoxy; R 3a and R 3b are each independently halogenated; R 4 and R 6 They are hydrogen; R 5a Yes (i) C 1-6 Alkyl, C 6-14 Aryl, heteroaryl, or heterocyclyl, each independently substituted with one or two substituents, each of which is independently -OR a ,–NR a S(O)2R d or –S(O)2R a or (ii) –NR a C(N(CN))R d or –NR a C(N(CN))NR b R c ; X is a bond or –O–; Z is C optionally substituted with one or more substituents Q 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene; m is the integer 2; and n is an integer 0 or 1; Each R a 、R b 、R c and R d As defined herein.

[0110] In another embodiment, in any one of formulae (VII) to (IX), R 1 is methyl, ethyl, isopropyl, n-butyl, cyclopropyl, 3-hydroxyphenyl, hydroxy, methoxy or ethoxy; R 2a is hydrogen, chloro, hydroxy or methoxy; Each R 2b are independently chloro, hydroxy or methoxy; R 3aand R 3b They are chlorinated; R 4 and R 6 They are hydrogen; R 5a 2-methyl-sulfonylaminoethyl, 3-methylsulfonylaminopropyl, 3-hydroxyphenyl, 3,5-dihydroxyphenyl, 3-methylsulfonylphenyl, 3,5-dimethylsulfonylphenyl, 1-(methylsulfonyl)-pyrrol-3-yl, 1-(methylsulfonyl)pyrazol-3-yl, 1-(methylsulfonyl)pyrazol-4-yl, 5-(methylsulfonyl)-pyridin-3-yl, 1-(methylsulfonyl)pyrazol-5-yl, Pyrrolidin-3-yl, 1-(methylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl, thiophen-2-yl-carboxamido, (S)-3-hydroxypyrrolidine-1-carboxamido, (E)-N'-cyano-3-hydroxy-pyrrolidine-1-carboxamido, (E)-N'-cyano-3,4-dihydroxypyrrolidine-1-carboxamido or 2-cyano-3,3-bis(2-hydroxyethyl)guanidinyl; X is a bond or –O–; Z is methanediyl, ethane-1,2-diyl, 1-hydroxyethane-1,2-diyl, ethylene-1,2-diyl, acetylene-1,2-diyl; m is the integer 2; and n is an integer 0 or 1.

[0111] In the embodiments described herein, the chemical formulae described herein, including the group R in formulae (I) to (IX), are further defined. 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 2a 、R 2b 、R 3a 、R 3b 、R 5a , X, Z, m, and n. All combinations of the embodiments provided herein for these groups are within the scope of the present disclosure.

[0112] In certain embodiments, R 1 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 1 is methyl, ethyl, propyl, butyl, pentyl or hexyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is methyl, ethyl, isopropyl or n-butyl. In certain embodiments, R 1 is C optionally substituted with one or more substituents Q1-6 In certain embodiments, R 1 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 1 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 1 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 1 is a monocyclic C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is cyclopropyl optionally substituted with one or more substituents Q. In certain embodiments, R 1 is a bicyclic C optionally substituted with one or more substituents Q 4-10 In certain embodiments, R 1 is a bridged, fused or spiro C optionally substituted with one or more substituents Q 4-10 In certain embodiments, R 1 is C optionally substituted with one or more substituents Q 6-14 In certain embodiments, R 1 is phenyl optionally substituted with one or more substituents Q. In certain embodiments, R 1 In certain embodiments, R 1 is C optionally substituted with one or more substituents Q 7-15 In certain embodiments, R 1 is a heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 1 is a monocyclic heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 1 is a 5- or 6-membered heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 1 is a bicyclic heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 1 is a 5,5-, 5,6- or 6,6-fused heteroaryl group, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is a heterocyclyl group optionally substituted with one or more substituents Q. In certain embodiments, R 1is a monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 1 is a 3-, 4-, 5-, 6- or 7-membered heterocyclyl group optionally substituted with one or more substituents Q. In certain embodiments, R 1 is a bicyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 1 is a bridged, fused or spiro heterocyclic group optionally substituted by one or more substituents Q, respectively.

[0113] In certain embodiments, R 1 Yes–OR 1a , where R 1a As defined herein. In certain embodiments, R 1 In certain embodiments, R 1 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 1 is hydroxy, methoxy or ethoxy. In certain embodiments, R 1 Yes – NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 1 is -NH2. In certain embodiments, R 1 Yes – SR 1a , where R 1a As defined herein. In certain embodiments, R 1 is -SH. In certain embodiments, R 1 is -SC optionally substituted with one or more substituents Q 1-6 alkyl.

[0114] In certain embodiments, R 2 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 2 is a monocyclic C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a bicyclic C optionally substituted with one or more substituents Q 4-10 In certain embodiments, R 2 is a bridged, fused or spiro C optionally substituted with one or more substituents Q 4-10In certain embodiments, R 2 is a bridged C optionally substituted with one or more substituents Q 4-10 In certain embodiments, R 2 is a fused C optionally substituted with one or more substituents Q 4-10 In certain embodiments, R 2 is a spiro C optionally substituted with one or more substituents Q 4-10 Cycloalkyl.

[0115] In certain embodiments, R 2 is C optionally substituted with one or more substituents Q 6-14 In certain embodiments, R 2 is phenyl optionally substituted with one or more substituents Q. In certain embodiments, R 2 is phenyl optionally substituted with 1, 2 or 3 substituents, each of which is independently halo or -OR 1a ; where R 1a As defined herein. In certain embodiments, R 2 is phenyl optionally substituted with one or two substituents, each of which is independently halo, hydroxy or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 2 is phenyl optionally substituted with one or two substituents, each of which is independently chloro, hydroxy or methoxy. 2 is phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl or 3-chloro-4-hydroxyphenyl. 2 is a bicyclic C optionally substituted with one or more substituents Q 8-14 Aryl.

[0116] In certain embodiments, R 2 is C optionally substituted with one or more substituents Q 7-15 In certain embodiments, R 2 is a heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a monocyclic heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5- or 6-membered heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5-membered heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 2is a 6-membered heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a bicyclic heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5,5-, 5,6- or 6,6-fused heteroaryl group, each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5,5-fused heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5,6-fused heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 2 is benzofuranyl or indolyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is benzofuran-2-yl, benzofuran-6-yl or indol-5-yl, each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 6,6-fused heteroaryl group optionally substituted with one or more Q substituents.

[0117] In certain embodiments, R 2 is a heterocyclyl group optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 3-, 4-, 5-, 6- or 7-membered heterocyclyl group optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 3-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 4-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 6-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 7-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a bicyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a bridged, fused or spiro heterocyclic group optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a bridged heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 2is a fused heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a spiroheterocyclyl group optionally substituted with one or more Q substituents.

[0118] In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 3 In certain embodiments, R 3 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 3 In certain embodiments, R 3 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 3 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 3 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 3 is C optionally substituted with one or more substituents Q 6-14 In certain embodiments, R 3 is C optionally substituted with one or more substituents Q 7-15 In certain embodiments, R 3 is a heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 3 is a heterocyclyl group optionally substituted by one or more substituents Q.

[0119] In certain embodiments, R 3 Yes – C(O)R 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – C(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – C(O)NR1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3 Yes – C(O)SR 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – C(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3 Yes – C(S)R 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – C(S)OR 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – C(S)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3 Yes–OR 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – OC(O)R 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – OC(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – OC(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3 Yes – OC(S)R 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – OC(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1cAs defined herein, respectively. In certain embodiments, R 3 Yes – OC(S)R 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – OC(S)OR 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – OC(S)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3 Yes – OS(O)R 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – OS(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – OS(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3 Yes – OS(O)2NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3 Yes – NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3 Yes – NR 1a C(O)R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3 Yes – NR 1a C(O)OR 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3 Yes – NR 1a C(O)NR 1b R 1c , where R 1a 、R 1b and R 1cAs defined herein, respectively. In certain embodiments, R 3 Yes – NR 1a C(O)SR 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3 Yes – NR 1a C(NR 1d )NR 1b R 1c , where R 1a 、R 1b 、R 1c and R 1d As defined herein, respectively. In certain embodiments, R 3 Yes – NR 1a C(S)R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3 Yes – NR 1a C(S)OR 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3 Yes – NR 1a C(S)NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3 Yes – NR 1a S(O)R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3 Yes – NR 1a S(O)2R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3 Yes – NR 1a S(O)NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3 Yes – NR 1a S(O)2NR 1b R 1c , where R1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3 Yes – SR 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – S(O)R 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes –S(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 3 Yes – S(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3 Yes – S(O)2NR 1b R 1c , where R 1b and R 1c Respectively as defined herein.

[0120] In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 4 In certain embodiments, R 4 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 4 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 4 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 4 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 4 is C optionally substituted with one or more substituents Q 6-14 In certain embodiments, R 4 is C optionally substituted with one or more substituents Q 7-15 In certain embodiments, R 4 is a heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 4is a heterocyclyl group optionally substituted by one or more substituents Q.

[0121] In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 5 is –OR a ,–NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2R d or –S(O)2R a Substituted C 1-6 Alkyl, where each R a 、R b 、R c and R d As defined herein. In certain embodiments, R 5 Is -NR a C(O)R d ,–NR a C(N(CN))R d or –NR a C(N(CN))NR b R c Substituted C 1-6 Alkyl, where each R a 、R b 、R c and R d As defined herein. In certain embodiments, R 5 Is -NR a C(O)R d Substituted C 1-6 Alkyl, where R a As defined herein. In certain embodiments, R 5 Is -NR a C(N(CN))R d Substituted C 1-6 Alkyl, where R a and R d As defined herein, respectively. In certain embodiments, R 5 Is -NR a C(N(CN))NR b R c Substituted C 1-6 Alkyl, where R a、R b and R c As defined herein, respectively. In certain embodiments, R 5 It is 3-methylsulfonylaminopropyl, 4-methylsulfonylaminobutyl, thiophen-2-ylcarboxamidomethyl, ((S)-3-hydroxypyrrolidine-1-carboxamido)methyl, (E)-N'-cyano-3-hydroxypyrrolidine-1-carboxamidomethyl, (E)-N'-cyano-3,4-dihydroxypyrrolidine-1-carboxamidomethyl or 2-cyano-3,3-bis(2-hydroxyethyl)guanidinomethyl.

[0122] In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 6-14 Aryl.

[0123] In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 7-15 In certain embodiments, R 5 is a C substituted with one or two substituents 7-15 Aralkyl, each substituent is independently –OR a ,–NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2R d or –S(O)2R a ; where each R a 、R b 、R c and R d As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 7-15 Aralkyl, each substituent is independently –ORa or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 7-15 Aralkyl, each substituent is independently hydroxy or methylsulfonyl. In certain embodiments, R 5 is benzyl optionally substituted with one or more substituents Q. In certain embodiments, R 5 is benzyl substituted with one or two substituents, each of which is independently -OR a ,–NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2R d or –S(O)2R a ; where each R a 、R b 、R c and R d As defined herein. In certain embodiments, R 5 is benzyl substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5 is benzyl substituted with one or two substituents, each of which is independently hydroxy or methylsulfonyl. 5 is a bicyclic C optionally substituted with one or more substituents Q 9-15 Aralkyl.

[0124] In certain embodiments, R 5 is a heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 5 is a heterocyclyl group optionally substituted with one or more substituents Q. In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 1-6 Alkylene-R 5a ; where R 5a As defined herein. In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 1-6 Alkylene-C 3-10Cycloalkyl.

[0125] In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-heteroaryl, each substituent is independently -OR a ,–NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2R d or –S(O)2R a ; where each R a 、R b 、R c and R d As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-heteroaryl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-heteroaryl; each substituent is independently hydroxy or methylsulfonyl.

[0126] In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-monocyclic heteroaryl; each substituent is independently -OR a ,–NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2R d or –S(O)2R a; where each R a 、R b 、R c and R d As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-monocyclic heteroaryl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-monocyclic heteroaryl, each substituent is independently hydroxy or methylsulfonyl. In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-5-membered heteroaryl; each substituent is independently -OR a ,–NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2R d or –S(O)2R a ; where each R a 、R b 、R c and R d As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-5-membered heteroaryl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-5-membered heteroaryl, each substituent is independently hydroxy or methylsulfonyl. In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 5is a C substituted with one or two substituents 1-6 Alkylene-6-membered heteroaryl; each substituent is independently -OR a ,–NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2R d or –S(O)2R a ; where each R a 、R b 、R c and R d As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-6-membered heteroaryl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-6-membered heteroaryl, each substituent is independently hydroxy or methylsulfonyl. In certain embodiments, R 5 In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 5 is C optionally substituted by one or more substituents Q 1-6 Alkylene-(5,5-, 5,6- or 6,6-fused heteroaryl).

[0127] In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-heterocyclyl; each substituent is independently -OR a ,–NR a C(O)R d ,–NRa C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2R d or –S(O)2R a ; where each R a 、R b 、R c and R d As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-heterocyclyl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene - a monocyclic heterocyclyl, each substituent is independently -OR a ,–NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2R d or –S(O)2R a ; where each R a 、R b 、R c and R d As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene - a monocyclic heterocyclyl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents1-6 Alkylene - monocyclic heterocyclyl, each substituent is independently hydroxy or methylsulfonyl. In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-5-membered heterocyclyl; each substituent is independently -OR a ,–NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2R d or –S(O)2R a ; where each R a 、R b 、R c and R d As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-5-membered heterocyclyl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-5-membered heterocyclyl, each substituent is independently hydroxy or methyl-sulfonyl. In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-6-membered heterocyclyl; each substituent is independently -OR a ,–NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2R d or –S(O)2R a ; where each Ra 、R b 、R c and R d As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-6-membered heterocyclyl, each substituent is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5 is a C substituted with one or two substituents 1-6 Alkylene-6-membered heterocyclyl, each substituent is independently hydroxy or methylsulfonyl. In certain embodiments, R 5 is (1-(methylsulfonyl)pyrrolidin-3-yl)methyl or (1-(methylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl)methyl. In certain embodiments, R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 5 is C optionally substituted by one or more substituents Q 1-6 Alkylene-(bridged, fused or spiro)heterocyclyl.

[0128] In certain embodiments, R 6 is hydrogen. In certain embodiments, R 6 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 6 In certain embodiments, R 6 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 6 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 6 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 6 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 6 is C optionally substituted with one or more substituents Q 6-14 In certain embodiments, R 6 is C optionally substituted with one or more substituents Q 7-15 In certain embodiments, R 6is a heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 6 is a heterocyclyl group optionally substituted by one or more substituents Q.

[0129] In certain embodiments, R 2a is hydrogen. In certain embodiments, R 2a In certain embodiments, R 2a In certain embodiments, R 2a In certain embodiments, R 2a In certain embodiments, R 2a In certain embodiments, R 2a In certain embodiments, R 2a is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 2a is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 2a is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 2a is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 2a is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 2a is C optionally substituted with one or more substituents Q 6-14 In certain embodiments, R 2a is C optionally substituted with one or more substituents Q 7-15 In certain embodiments, R 2a is a heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 2a is a heterocyclyl group optionally substituted by one or more substituents Q.

[0130] In certain embodiments, R 2a Yes – C(O)R 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes – C(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes – C(O)NR 1b R 1c , where R1b and R 1c As defined herein, respectively. In certain embodiments, R 2a Yes – C(O)SR 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes – C(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2a Yes – C(S)R 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes – C(S)OR 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes – C(S)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2a Yes–OR 1a , where R 1a As defined herein. In certain embodiments, R 2a In certain embodiments, R 2a is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 2a In certain embodiments, R 2a Yes – OC(O)R 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes – OC(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes – OC(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2a Yes – OC(S)R 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes – OC(NR 1a )NR1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2a Yes – OC(S)R 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes – OC(S)OR 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes – OC(S)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2a Yes – OS(O)R 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes – OS(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes – OS(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2a Yes – OS(O)2NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2a Yes – NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2a Yes – NR 1a C(O)R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 2a Yes – NR 1a C(O)OR 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 2a Yes – NR 1a C(O)NR1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2a Yes – NR 1a C(O)SR 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 2a Yes – NR 1a C(NR 1d )NR 1b R 1c , where R 1a 、R 1b 、R 1c and R 1d As defined herein, respectively. In certain embodiments, R 2a Yes – NR 1a C(S)R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 2a Yes – NR 1a C(S)OR 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 2a Yes – NR 1a C(S)NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2a Yes – NR 1a S(O)R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 2a Yes – NR 1a S(O)2R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 2a Yes – NR 1a S(O)NR 1b R 1c , where R 1a 、R 1b and R 1cAs defined herein, respectively. In certain embodiments, R 2a Yes – NR 1a S(O)2NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2a Yes – SR 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes – S(O)R 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes –S(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 2a Yes – S(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2a Yes – S(O)2NR 1b R 1c , where R 1b and R 1c Respectively as defined herein.

[0131] In certain embodiments, R 2b In certain embodiments, R 2b In certain embodiments, R 2b In certain embodiments, R 2b In certain embodiments, R 2b In certain embodiments, R 2b In certain embodiments, R 2b is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 2b is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 2b is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 2b is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 2b is C optionally substituted with one or more substituents Q3-10 In certain embodiments, R 2b is C optionally substituted with one or more substituents Q 6-14 In certain embodiments, R 2b is C optionally substituted with one or more substituents Q 7-15 In certain embodiments, R 2b is a heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 2b is a heterocyclyl group optionally substituted by one or more substituents Q.

[0132] In certain embodiments, R 2b Yes – C(O)R 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes – C(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes – C(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2b Yes – C(O)SR 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes – C(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2b Yes – C(S)R 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes – C(S)OR 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes – C(S)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2b Yes–OR 1a , where R 1a As defined herein. In certain embodiments, R 2bIn certain embodiments, R 2b is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 2b In certain embodiments, R 2b Yes – OC(O)R 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes – OC(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes – OC(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2b Yes – OC(S)R 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes – OC(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2b Yes – OC(S)R 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes – OC(S)OR 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes – OC(S)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2b Yes – OS(O)R 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes – OS(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes – OS(O)NR 1b R 1c , where R 1b and R 1cAs defined herein, respectively. In certain embodiments, R 2b Yes – OS(O)2NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2b Yes – NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2b Yes – NR 1a C(O)R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 2b Yes – NR 1a C(O)OR 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 2b Yes – NR 1a C(O)NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2b Yes – NR 1a C(O)SR 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 2b Yes – NR 1a C(NR 1d )NR 1b R 1c , where R 1a 、R 1b 、R 1c and R 1d As defined herein, respectively. In certain embodiments, R 2b Yes – NR 1a C(S)R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 2b Yes – NR 1a C(S)OR 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R2b Yes – NR 1a C(S)NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2b Yes – NR 1a S(O)R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 2b Yes – NR 1a S(O)2R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 2b Yes – NR 1a S(O)NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2b Yes – NR 1a S(O)2NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2b Yes – SR 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes – S(O)R 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes –S(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 2b Yes – S(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 2b Yes – S(O)2NR 1b R 1c , where R 1b and R 1c Respectively as defined herein.

[0133] In certain embodiments, R 3a is hydrogen. In certain embodiments, R 3a In certain embodiments, R 3a In certain embodiments, R 3a In certain embodiments, R 3a In certain embodiments, R 3a In certain embodiments, R 3a In certain embodiments, R 3a is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 3a In certain embodiments, R 3a is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 3a In certain embodiments, R 3a is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 3a is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 3a is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 3a is C optionally substituted with one or more substituents Q 6-14 In certain embodiments, R 3a is C optionally substituted with one or more substituents Q 7-15 In certain embodiments, R 3a is a heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 3a is a heterocyclyl group optionally substituted by one or more substituents Q.

[0134] In certain embodiments, R 3a Yes – C(O)R 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes – C(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes – C(O)NR 1b R 1c , where R 1b and R 1cAs defined herein, respectively. In certain embodiments, R 3a Yes – C(O)SR 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes – C(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3a Yes – C(S)R 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes – C(S)OR 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes – C(S)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3a Yes–OR 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes – OC(O)R 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes – OC(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes – OC(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3a Yes – OC(S)R 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes – OC(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3a Yes – OC(S)R 1a , where R 1aAs defined herein. In certain embodiments, R 3a Yes – OC(S)OR 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes – OC(S)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3a Yes – OS(O)R 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes – OS(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes – OS(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3a Yes – OS(O)2NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3a Yes – NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3a Yes – NR 1a C(O)R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3a Yes – NR 1a C(O)OR 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3a Yes – NR 1a C(O)NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3a Yes – NR 1a C(O)SR 1d , where R1a and R 1d As defined herein, respectively. In certain embodiments, R 3a Yes – NR 1a C(NR 1d )NR 1b R 1c , where R 1a 、R 1b 、R 1c and R 1d As defined herein, respectively. In certain embodiments, R 3a Yes – NR 1a C(S)R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3a Yes – NR 1a C(S)OR 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3a Yes – NR 1a C(S)NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3a Yes – NR 1a S(O)R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3a Yes – NR 1a S(O)2R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3a Yes – NR 1a S(O)NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3a Yes – NR 1a S(O)2NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3aYes – SR 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes – S(O)R 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes –S(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 3a Yes – S(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3a Yes – S(O)2NR 1b R 1c , where R 1b and R 1c Respectively as defined herein.

[0135] In certain embodiments, R 3b is hydrogen. In certain embodiments, R 3b In certain embodiments, R 3b In certain embodiments, R 3b In certain embodiments, R 3b In certain embodiments, R 3b In certain embodiments, R 3b In certain embodiments, R 3b is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 3b In certain embodiments, R 3b is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 3b In certain embodiments, R 3b is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 3b is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 3b is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 3b is C optionally substituted with one or more substituents Q 6-14 In certain embodiments, R3b is C optionally substituted with one or more substituents Q 7-15 In certain embodiments, R 3b is a heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 3b is a heterocyclyl group optionally substituted by one or more substituents Q.

[0136] In certain embodiments, R 3b Yes – C(O)R 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes – C(O)OR 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes – C(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3b Yes – C(O)SR 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes – C(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3b Yes – C(S)R 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes – C(S)OR 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes – C(S)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3b Yes–OR 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes – OC(O)R 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes – OC(O)OR 1a, where R 1a As defined herein. In certain embodiments, R 3b Yes – OC(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3b Yes – OC(S)R 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes – OC(NR 1a )NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3b Yes – OC(S)R 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes – OC(S)OR 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes – OC(S)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3b Yes – OS(O)R 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes – OS(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes – OS(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3b Yes – OS(O)2NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3b Yes – NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R3b Yes – NR 1a C(O)R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3b Yes – NR 1a C(O)OR 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3b Yes – NR 1a C(O)NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3b Yes – NR 1a C(O)SR 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3b Yes – NR 1a C(NR 1d )NR 1b R 1c , where R 1a 、R 1b 、R 1c and R 1d As defined herein, respectively. In certain embodiments, R 3b Yes – NR 1a C(S)R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3b Yes – NR 1a C(S)OR 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3b Yes – NR 1a C(S)NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3b Yes – NR 1a S(O)R 1d , where R 1a and R 1dAs defined herein, respectively. In certain embodiments, R 3b Yes – NR 1a S(O)2R 1d , where R 1a and R 1d As defined herein, respectively. In certain embodiments, R 3b Yes – NR 1a S(O)NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3b Yes – NR 1a S(O)2NR 1b R 1c , where R 1a 、R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3b Yes – SR 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes – S(O)R 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes –S(O)2R 1a , where R 1a As defined herein. In certain embodiments, R 3b Yes – S(O)NR 1b R 1c , where R 1b and R 1c As defined herein, respectively. In certain embodiments, R 3b Yes – S(O)2NR 1b R 1c , where R 1b and R 1c Respectively as defined herein.

[0137] In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, R 5a Is -NR a S(O)2R d Substituted C 1-6 Alkyl, where R a and R d As defined herein, respectively. In certain embodiments, R 5aIn certain embodiments, R 5a is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 5a is a monocyclic C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 5a is a bicyclic C optionally substituted with one or more substituents Q 4-10 In certain embodiments, R 5a is a bridged, fused or spiro C optionally substituted with one or more substituents Q 4-10 Cycloalkyl.

[0138] In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 6-14 In certain embodiments, R 5a is a C substituted with one or two substituents 6-14 Aryl, each of said substituents is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5a is phenyl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is phenyl substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5a is phenyl substituted with one or two substituents, each of which is independently -OR a ; where each R a As defined herein. In certain embodiments, R 5a is phenyl substituted with one or two substituents, each of which is independently –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5a is phenyl substituted with one or two substituents, each of which is independently hydroxy or methylsulfonyl.5a is phenyl substituted with one or two methylsulfonyl groups. 5a is 3-hydroxyphenyl, 3,5-dihydroxyphenyl, 3-methylsulfonylphenyl or 3,5-dimethylsulfonylphenyl. In certain embodiments, R 5a is a bicyclic C optionally substituted with one or more substituents Q 8-14 In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 7-15 Aralkyl.

[0139] In certain embodiments, R 5a is a heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a monocyclic heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a 5- or 6-membered heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a 5-membered heteroaryl substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5a is a 5-membered heteroaryl substituted with one or two substituents, each of which is independently -S(O)2R a ; where R a As defined herein. In certain embodiments, R 5a is a 6-membered heteroaryl substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5a is a 6-membered heteroaryl substituted with one or two substituents, each of which is independently -S(O)2R a ; where R a As defined herein. In certain embodiments, R 5a is pyrrolyl, pyrazolyl, or pyridinyl, each independently substituted with one or two substituents, each of which is independently -S(O)2R a ; where R a As defined herein. In certain embodiments, R 5a is pyrrolyl, pyrazolyl or pyridinyl, each of which is independently substituted with one or two methylsulfonyl groups. 5ais 1-(methylsulfonyl)pyrrol-3-yl, 1-(methylsulfonyl)pyrazol-3-yl, 1-(methylsulfonyl)pyrazol-4-yl or 5-(methylsulfonyl)pyridin-3-yl. In certain embodiments, R 5a is a bicyclic heteroaryl group optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a 5,5-, 5,6- or 6,6-fused heteroaryl group optionally substituted with one or more substituents Q.

[0140] In certain embodiments, R 5a is a heterocyclyl group optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a 3-, 4-, 5-, 6- or 7-membered heterocyclyl group optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a 5- or 6-membered heterocyclyl group substituted with one or more substituents Q. In certain embodiments, R 5a is a 5- or 6-membered heterocyclic group independently substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a ; where each R a As defined herein. In certain embodiments, R 5a is a 5- or 6-membered heterocyclic group independently substituted by one or two substituents, each of which is independently -S(O)2R a ; where R a As defined herein. In certain embodiments, R 5a is a 5- or 6-membered heterocyclyl, each of which is independently substituted with one or two methylsulfonyl groups. 5a is 1-(methylsulfonyl)pyrrolidin-3-yl or 1-(methylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl. In certain embodiments, R 5a is a bicyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a bridged, fused or spiro heterocyclic group optionally substituted by one or more substituents Q, respectively.

[0141] In certain embodiments, R 5a Yes – NR a C(N(CN))R d , where R a and R d As defined herein, respectively. In certain embodiments, R 5aYes – NR a C(N(CN))NR b R c , where R a 、R b and R c As defined herein, respectively. In certain embodiments, R 5a It is thiophen-2-ylcarboxamido, (S)-3-hydroxy-pyrrolidine-1-carboxamido, (E)-N'-cyano-3-hydroxy-pyrrolidine-1-carboxamido, (E)-N'-cyano-3,4-dihydroxypyrrolidine-1-carboxamido or 2-cyano-3,3-bis(2-hydroxyethyl)-guanidino.

[0142] In certain embodiments, X is a bond. In certain embodiments, X is -O-. In certain embodiments, X is -S-. In certain embodiments, X is -N(R 1b )–, where R 1b As defined herein, in certain embodiments, X is -N(H)-. In certain embodiments, X is -N(CH3)-. In certain embodiments, X is C optionally substituted with one or more substituents Q. 1-6 In certain embodiments, X is methanediyl optionally substituted with one or more substituents Q.

[0143] In certain embodiments, Z is -O-. In certain embodiments, Z is -S-. In certain embodiments, Z is -N(R 1b )–, where R 1b As defined herein, in certain embodiments, Z is -N(H)-. In certain embodiments, Z is -N(CH3)-. In certain embodiments, Z is C optionally substituted with one or more substituents Q. 1-6 In certain embodiments, Z is methanediyl or ethanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, Z is methanediyl or ethane-1,2-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, Z is methanediyl, ethane-1,2-diyl, or 1-hydroxyethane-1,2-diyl. In certain embodiments, Z is C 2-6 In certain embodiments, Z is ethylenediyl optionally substituted with one or more substituents Q. In certain embodiments, Z is ethylene-1,2-diyl optionally substituted with one or more substituents Q. In certain embodiments, Z is C 2-6 In certain embodiments, Z is ethynyl-1,2-diyl. In certain embodiments, Z is C optionally substituted with one or more substituents Q.3-10 In certain embodiments, Z is a monocyclic C optionally substituted with one or more substituents Q. 3-10 In certain embodiments, Z is a bicyclic C optionally substituted with one or more substituents Q. 4-10 In certain embodiments, Z is a bridged, fused, or spiro C optionally substituted with one or more substituents Q. 4-10 In some embodiments, Z is a heterocyclic radical optionally substituted with one or more substituents Q. In some embodiments, Z is a monocyclic heterocyclic radical optionally substituted with one or more substituents Q. In some embodiments, Z is a 3-, 4-, 5-, 6-, or 7-membered heterocyclic radical optionally substituted with one or more substituents Q. In some embodiments, Z is a bicyclic heterocyclic radical optionally substituted with one or more substituents Q. In some embodiments, Z is a bridged, fused, or spiro heterocyclic radical optionally substituted with one or more substituents Q.

[0144] In some embodiments, m is the integer 0. In some embodiments, m is the integer 1. In some embodiments, m is the integer 2. In some embodiments, m is the integer 3. In some embodiments, m is the integer 4.

[0145] In some embodiments, n is the integer 0. In some embodiments, n is the integer 1. In some embodiments, n is the integer 2. In some embodiments, n is the integer 3. In some embodiments, n is the integer 4.

[0146] In one embodiment, the following compounds are described herein: (2S)-2-(2,6-dichloro-4-(2-(hydroxy(phenyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A1; (2S)-2-(2,6-dichloro-4-((hydroxy(3-hydroxyphenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A2; (2S)-2-(2,6-dichloro-4-(2-(hydroxy(m-hydroxyphenyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A3; (2S)-2-(2,6-dichloro-4-(2-(methoxy(phenyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A4; (2S)-2-(2,6-dichloro-4-((methoxy(phenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A5; (2S)-2-(2,6-dichloro-4-(2-(ethoxy(m-hydroxyphenyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A6; (2S)-2-(2,6-dichloro-4-((methoxy(3-hydroxyphenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A7; (2S)-2-(2,6-dichloro-4-(2-(methoxy(3-hydroxyphenyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A8; (2S)-2-(2,6-dichloro-4-((methyl(phenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A9; (2S)-2-(2,6-dichloro-4-(2-(methyl(phenyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A10; (2S)-2-(2,6-dichloro-4-((methyl(3-hydroxyphenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A11; (2S)-2-(2,6-dichloro-4-((methoxy(3-methoxyphenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A12; (2S)-2-(2,6-dichloro-4-((hydroxy(3-methoxyphenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A13; (2S)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzylamino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A14; (2S)-2-(2,6-dichloro-4-((methyl(4-hydroxyphenyl)phosphoryl)ethynyl)benzylamino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A15; (2S)-2-(2,6-dichloro-4-((hydroxy(phenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A16; (2S)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(thiophen-2-ylcarboxamido)propanoic acid A17; (2S)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(1-(methylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl)propanoic acid A18; (2S)-3-((R,E)-N′-cyano-3-hydroxypyrrolidin-1-carbamimidoyl)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)propanoic acid A19; (2S)-2-(2,6-dichloro-4-((ethyl(3-hydroxyphenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A20; (2S)-2-(2,6-dichloro-4-(2-(ethyl(3-hydroxyphenyl)phosphinoyl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A21; (2S)-2-(2,6-dichloro-4-(2-(cyclopropyl(3-hydroxyphenyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A22; (2S)-2-(2,6-dichloro-4-(butyl(3-hydroxyphenyl)phosphinoethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A23; (2S)-2-(2,6-dichloro-4-((methyl(benzofuran-6-yl)phosphoryl)ethynyl)benzyl-amino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A24; (2S)-2-(2,6-dichloro-4-((methyl(benzofuran-6-yl)phosphoryl)ethyl)benzylamino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A25; (2S)-2-(4-(2-(Benzofuran-2-yl(methyl)phosphoryl)ethyl)-2,6-dichlorobenzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A26; (2S)-2-(2,6-dichloro-4-((methyl(1H-indol-5-yl)phosphoryl)ethyl)benzylamino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A27; (2S)-2-(2,6-dichloro-4-((((phenyl)(methyl)phosphoryl)oxy)methyl)-benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A28; (2S)-2-(2,6-dichloro-4-((((3-hydroxyphenyl)(methyl)phosphoryl)methyl)amino)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A29; (S)-2-(2,6-dichloro-4-(2-((S)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A30; (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A31; (2S)-2-(2,6-dichloro-4-((E)-2-(ethoxy(3-hydroxyphenyl)phosphoryl)vinyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A32; (2S)-2-(2,6-dichloro-4-(2-(methyl(4-hydroxyphenyl)phosphinoyl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A33; (2S)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzamido)-3-(3-hydroxybenzamido)propanoic acid A34; 2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzylamino)-3-(3,5-(dimethylsulfonyl)phenyl)propanoic acid A35; 2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzylamino)-3-(3,5-(dimethylsulfonyl)phenyl)propanoic acid A36; N 2 -(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzoyl)-N 6 -(Methylsulfonyl)-L-lysine A37; (2S)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzyl-amino)-3-(5-(methylsulfonyl)pyridin-3-yl)propanoic acid A38; (2S)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzyl-amino)-3-(1-(methylsulfonyl)-1H-pyrrol-3-yl)propanoic acid A39; (2S)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzyl-amino)-3-(1-(methylsulfonyl)-1H-pyrazol-3-yl)propanoic acid A40; (2S)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzyl-amino)-3-(1-(methylsulfonyl)-1H-pyrazol-4-yl)propanoic acid A41; (2S)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzyl-amino)-3-(1-(methylsulfonyl)pyrrolidin-3-yl)propanoic acid A42; (2S)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-((S)-3-hydroxypyrrolidine-1-carboxamido)propanoic acid A43; (2S)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-5-(methylsulfonylamino)pentanoic acid A44; (2S)-3-((3R,4R,E)-N′-cyano-3,4-dihydroxypyrrolidine-1-carbamimidoyl)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)propanoic acid A45; (2S)-3-(2-cyano-3,3-bis(2-hydroxyethyl)guanidino)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzamido)propanoic acid A46; (2S)-2-(2,6-dichloro-4-((methoxy(3-hydroxyphenyl)phosphoryl)ethynyl)-benzylamino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A47; (2S)-2-(2,6-dichloro-4-((methyl(4-hydroxy-3-chlorophenyl)phosphoryl)ethynyl)benzylamino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A48; (2S)-2-(2,6-dichloro-4-((hydroxy(benzofuran-6-yl)phosphoryl)ethynyl)benzyl-amino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A49; (2S)-2-(2,6-dichloro-4-(1-hydroxy-2-(hydroxy(3-hydroxyphenyl)phosphoryl)-ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A50; (2S)-2-(2,6-dichloro-4-(2-(hydroxy(m-hydroxyphenyl)phosphoryl)vinyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A51; (S,E)-2-(4-(2-(bis(3-hydroxyphenyl)phosphoryl)vinyl)-2,6-dichlorobenzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A52; (S)-2-(4-(2-(bis(3-hydroxyphenyl)phosphoryl)ethyl)-2,6-dichlorobenzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A53; (2S)-2-(2,6-dichloro-4-((E)-2-(ethoxy(4-hydroxyphenyl)phosphoryl)vinyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A54; (2S)-2-(2,6-dichloro-4-(1-hydroxy-2-(methyl(benzofuran-6-yl)phosphoryl)ethyl)-benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A55; (2S)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(isopropyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A56; (2S)-2-(2,6-dichloro-4-(2-(cyclopropyl(3-hydroxyphenyl)phosphoryl)vinyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A57; or (2S)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)vinyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A58; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0147] In one embodiment, Compound A1 is described herein, or a pharmaceutically acceptable salt thereof. In another embodiment, Compound A2 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A3 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A4 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A5 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A6 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A7 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A8 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A9 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A10 is described herein, or a pharmaceutically acceptable salt thereof.

[0148] In one embodiment, Compound A11 is described herein, or a pharmaceutically acceptable salt thereof. In another embodiment, Compound A12 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A13 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A14 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A15 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A16 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A17 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A18 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A19 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A20 is described herein, or a pharmaceutically acceptable salt thereof.

[0149] In one embodiment, Compound A21 is described herein, or a pharmaceutically acceptable salt thereof. In another embodiment, Compound A22 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A23 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A24 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A25 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A26 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A27 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A28 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A29 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A30 is described herein, or a pharmaceutically acceptable salt thereof.

[0150] In one embodiment, Compound A31 is described herein, or a pharmaceutically acceptable salt thereof. In another embodiment, Compound A32 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A33 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A34 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A35 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A36 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A37 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A38 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A39 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A40 is described herein, or a pharmaceutically acceptable salt thereof.

[0151] In one embodiment, Compound A51 is described herein, or a pharmaceutically acceptable salt thereof. In another embodiment, Compound A52 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A53 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A54 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A55 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A56 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A57 is described herein, or a pharmaceutically acceptable salt thereof. In yet another embodiment, Compound A58 is described herein, or a pharmaceutically acceptable salt thereof.

[0152] In certain embodiments, the compounds described herein are isolated or purified. In certain embodiments, the purity of the compounds described herein is at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight. In certain embodiments, the purity of the compounds described herein is at least about 90% by weight. In certain embodiments, the purity of the compounds described herein is at least about 95% by weight. In certain embodiments, the purity of the compounds described herein is at least about 98% by weight. In certain embodiments, the purity of the compounds described herein is at least about 99% by weight. In certain embodiments, the purity of the compounds described herein is at least about 99.5% by weight.

[0153] Unless specific stereochemistry is indicated, compounds described herein are intended to encompass all possible stereoisomers. When compounds described herein contain alkenyl groups, the compounds may exist as one or a mixture of geometric cis / trans (or Z / E) isomers. When structural isomers are independently interconvertible, the compounds may exist as a single tautomer or a mixture of tautomers. In compounds containing, for example, imino, keto or oxime groups, this may take the form of proton tautomerism; or in compounds containing aromatic moieties, so-called valence tautomerism may be employed. Thus, a single compound may exhibit more than one isomeric type.

[0154] The compounds described herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or may be stereoisomeric mixtures, such as a mixture of enantiomers, for example, a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one skilled in the art will recognize that for compounds that undergo epimerization in vivo, administration of a compound in its (R) form is equivalent to administration of a compound in its (S) form. Conventional techniques for preparing / isolating individual enantiomers include synthesis from suitable optically pure precursors, asymmetric synthesis from non-chiral starting materials, or resolution of enantiomeric mixtures, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization to diastereomeric adducts followed by separation.

[0155] When a compound described herein contains an acidic or basic moiety, it can also be provided as a pharmaceutically acceptable salt. See Berge et al., J. Pharm. Sci. 1977, 66, 1-19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth, eds.; John Wiley & Sons, 2011. In certain embodiments, a pharmaceutically acceptable salt of a compound described herein is a solvate. In certain embodiments, a pharmaceutically acceptable salt of a compound described herein is a hydrate.

[0156] Suitable acids for preparing pharmaceutically acceptable salts of the compounds described herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexylaminosulfonic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L -Glutamic acid, α-ketoglutaric 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-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0157] Suitable bases for preparing pharmaceutically acceptable salts of the compounds described herein include, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases such as primary, secondary, tertiary, and quaternary aliphatic and aromatic amines, including, but not limited to, L-arginine, phenethylbenzylamine, benzathine, choline, diarnol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethyl Alcoholamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydramine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, tetrahydropyrrole, 1-(2-hydroxyethyl)-tetrahydropyrrole, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

[0158] The compounds described herein can also be provided as prodrugs, which are functional derivatives of the compounds and are easily convertible into the parent compound in vivo. Prodrugs are generally useful because, in some cases, they can be easier to administer than the parent compound. For example, they can be orally bioavailable, whereas the parent compound is not. Prodrugs can also have a solubility that is improved over the parent compound in pharmaceutical compositions. Prodrugs can be converted into the parent drug by a variety of mechanisms, including enzymatic processes and metabolic hydrolysis.

[0159] The compounds described herein can be prepared, isolated or obtained by any method known to those skilled in the art, for example, by following the procedures described in US 11,325,929 B2 (the disclosure of which is incorporated herein by reference in its entirety). Pharmaceutical composition

[0160] In one embodiment, described herein are pharmaceutical compositions comprising a compound described herein, e.g., a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.

[0161] The pharmaceutical compositions described herein can be formulated in a variety of dosage forms, including, but not limited to, dosage forms for oral, parenteral, and topical administration. The pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed release, extended release, prolonged release, sustained release, pulsatile release, controlled release, accelerated release, rapid release, targeted release, programmed release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al., eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.

[0162] In one embodiment, the pharmaceutical compositions described herein are formulated in a dosage form for oral administration. In another embodiment, the pharmaceutical compositions described herein are formulated in a dosage form for parenteral administration. In yet another embodiment, the pharmaceutical compositions described herein are formulated in a dosage form for intravenous administration. In yet another embodiment, the pharmaceutical compositions described herein are formulated in a dosage form for intramuscular administration. In yet another embodiment, the pharmaceutical compositions described herein are formulated in a dosage form for subcutaneous administration. In yet another embodiment, the pharmaceutical compositions described herein are formulated in a dosage form for topical administration.

[0163] The pharmaceutical compositions described herein can be provided in unit dose form or multiple dose form. As used herein, a unit dose form refers to a physically separate unit suitable for administration to a subject and as known in the art, packaged individually. Each unit dose is combined with the required pharmaceutical excipients and contains a predetermined amount of active ingredient (e.g., a compound described herein) sufficient to produce the desired therapeutic effect. Examples of unit dose forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. The unit dose form can be administered in portions or multiple times. A multiple dose form is a plurality of identical unit dose forms packaged in a single container to be administered in separate unit dose forms. Examples of multiple dose forms include, but are not limited to, vials, tablet or capsule bottles, or pint or gallon bottles.

[0164] The pharmaceutical compositions described herein can be administered once or multiple times at regular intervals. It will be understood that the exact dosage and duration of treatment can vary with the age, weight, and condition of the subject being treated, and can be determined empirically using known testing procedures or by extrapolation from in vivo or in vitro tests or diagnostic data. It will be further understood that for any particular individual, the specific dosage regimen will be adjusted over time based on the needs of the subject and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition. A. Oral administration

[0165] The pharmaceutical compositions for oral administration described herein can be provided in solid, semisolid or liquid dosage forms for oral administration. As used herein, oral administration also includes oral, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, orally disintegrating tablets (fastmelts), chewable tablets, capsules, pills, strips, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprays, elixirs and syrups. In addition to the active ingredient, the pharmaceutical composition can contain one or more pharmaceutically useful carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye migration inhibitors, sweeteners, flavorings, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids and carbon dioxide sources.

[0166] Binders or granulating agents impart cohesiveness to the tablet to ensure that it remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH ); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, carrageenan extract, Panwar gum, ghatti gum, isabgolhusk mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), larch arabinogalactan, tragacanth gum powder, and guar gum; celluloses, such as ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); and microcrystalline cellulose, such as PH-101, PH-103, PH-105 and RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextran, kaolin, mannitol, silicic acid, sorbitol, starch, and pregelatinized starch. The amount of binder and filler in the pharmaceutical compositions described herein varies with 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 described herein at about 50 to about 99% by weight.

[0167] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. When present in sufficient amounts, certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, can impart properties that allow disintegration in the oral cavity by chewing to some compressed tablets. These compressed tablets can be used as chewable tablets. The amount of the diluent in the pharmaceutical composition described herein varies with the type of formulation and is readily distinguishable by those skilled in the art.

[0168] Suitable disintegrating agents include, but are not limited to, agar-agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and

[0014] Examples of the present invention include HV; citrus pulp; cross-linked cellulose, such as cross-linked carboxymethyl cellulose; cross-linked polymers, such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; and alginate. The amount of disintegrant in the pharmaceutical compositions described herein varies depending on the type of formulation and is readily discernible to one skilled in the art. The pharmaceutical compositions described herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.

[0169] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; and silicon dioxide or silica gel, such as 200 and The amount of lubricant in the pharmaceutical compositions described herein varies with the type of formulation and is readily discernible to one skilled in the art.The pharmaceutical compositions described herein may contain from about 0.1 to about 5% by weight of a lubricant.

[0170] Suitable glidants include, but are not limited to, colloidal silicon dioxide, and asbestos-free talc. Suitable colorants include, but are not limited to, any approved, certified water-soluble FD&C dyes and water-insoluble FD&C dyes suspended on alumina hydrate, as well as lakes. Lakes are combinations of water-soluble dyes adsorbed onto hydrated oxides of heavy metals, which results in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of pleasant-tasting compounds, such as peppermint and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifiers include, but are not limited to, gelatin, gum arabic, gum tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate ( 20), polyoxyethylene monooleate sorbitan 80 ( 80) and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Gum arabic, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinyl pyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propyl parabens, benzoic acid and sodium benzoate, and ethanol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethanol, and syrup. Suitable non-aqueous liquids used in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

[0171] It will be appreciated that many carriers and excipients may serve several functions, even within the same formulation.

[0172] The pharmaceutical compositions described herein for oral administration can be provided as compressed tablets, triturated tablets, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestines, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets covered with a sugar coating that can be helpful in masking unpleasant tastes or odors and protecting the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets made by more than one compression cycle and include layered tablets and press-coated or dry-coated tablets.

[0173] Tablet dosage forms can be prepared from the active ingredient in powder, crystalline or particulate form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and / or colorants. Flavorings and sweeteners are particularly useful in the formation of chewable tablets and lozenges.

[0174] The pharmaceutical compositions described herein for oral administration can be provided as soft or hard capsules, which can be made of gelatin, methylcellulose, starch, or calcium alginate. Hard capsules, also known as dry-fill capsules (DFCs), consist of two parts, one part sliding over the other, thereby completely enclosing the active ingredient. Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, that are plasticized by adding glycerol, sorbitol, or similar polyols. The soft gelatin shells can contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl parabens and sorbic acid. Liquid, semisolid, and solid dosage forms described herein can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing these solutions can be prepared as described in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient.

[0175] The pharmaceutical compositions for oral administration described herein can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is dispersed throughout another liquid in the form of small globules, and the emulsion can be oil-in-water or water-in-oil. Emulsions can include a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions can include a pharmaceutically acceptable suspending agent and a preservative. Aqueous alcoholic solutions can include pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes, for example, acetaldehyde diethyl acetal; and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and can also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, to facilitate measurement for administration.

[0176] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient and a dialkylated monoalkylene glycol or polyalkylene glycol, including 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These dosage forms may also contain one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0177] The pharmaceutical compositions described herein for oral administration may also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms may be prepared as described in US Patent No. 6,350,458.

[0178] The pharmaceutical compositions for oral administration described herein can be provided as non-effervescent or effervescent microparticles and powders to be reconstituted into liquid dosage forms. The pharmaceutically acceptable carriers and excipients used in the non-effervescent microparticles or powders can include diluents, sweeteners, and wetting agents. The pharmaceutically acceptable carriers and excipients used in the effervescent microparticles or powders can include organic acids and carbon dioxide sources.

[0179] Coloring and flavoring agents can be used in all dosage forms described herein.

[0180] The pharmaceutical compositions described herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms. B. Parenteral Administration

[0181] For local or systemic administration, the pharmaceutical compositions described herein can be administered parenterally by injection, infusion, or implantation. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.

[0182] The pharmaceutical compositions described herein for parenteral administration can be formulated in any dosage form suitable for parenteral administration, including, but not limited to, solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for dissolution or suspension in a liquid prior to injection. These dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science. See, for example, Remington: The Science and Practice of Pharmacy, supra.

[0183] The pharmaceutical compositions described herein for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including but not limited to aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to prevent the growth of microorganisms, stabilizers, solubilizers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusters, and inert gases.

[0184] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, medium-chain triglycerides of coconut oil, and palm kernel oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butylene glycol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0185] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and dextrose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants include those described herein, such as bisulfites and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, such as sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestrants or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin.

[0186] When the pharmaceutical compositions described herein are formulated for multiple dose administration, the multiple dose parenteral formulations must contain bacteriostatic or fungistatic concentrations of the antimicrobial agent.As known and practiced in the art, all parenteral formulations must be sterile.

[0187] In one embodiment, the pharmaceutical composition for parenteral administration is provided as a sterile solution ready for use. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, including a lyophilized powder and a subcutaneous tablet to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a sterile suspension ready for use. In yet another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a sterile emulsion ready for use.

[0188] The pharmaceutical compositions described herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0189] The pharmaceutical compositions described herein for parenteral administration can be formulated as suspensions, solids, semisolids, or thixotropic liquids for administration as implanted depots. In one embodiment, the pharmaceutical compositions described herein are dispersed in a solid inner matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse through.

[0190] Suitable inner matrices include, but are not limited to, polymethyl methacrylate, polybutyl methacrylate, plasticized or non-plasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers (such as hydrogels of esters of acrylic acid and methacrylic acid), collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0191] Suitable polymeric outer films include, but are not limited to, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers. C. Topical application

[0192] The pharmaceutical compositions described herein can be administered topically to the skin, orifices, or mucous membranes. As used herein, topical administration includes dermal (intra), conjunctival, intracorneal, intraocular, ocular, aural, transdermal, nasal, vaginal, urethral, ​​respiratory, and rectal administration.

[0193] The pharmaceutical compositions described herein can be formulated in any dosage form suitable for topical administration for local or systemic effect, including but not limited to emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, sprinkles, dressings, elixirs, lotions, suspensions, infusions, pastes, foams, films, aerosols, douches, sprays, suppositories, bandages, and dermal patches. Topical formulations of the pharmaceutical compositions described herein can also include liposomes, micelles, microspheres, and nanosystems.

[0194] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to prevent the growth of microorganisms, stabilizers, solubilizers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

[0195] Alternatively, the drug may be delivered via electroporation, iontophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT TM and BIOJECT TM The pharmaceutical composition is administered topically.

[0196] The pharmaceutical compositions described herein can be provided in the form of ointments, creams, and gels. Suitable ointment vehicles include oily or hydrocarbon vehicles, including lard, benzoated lard, olive oil, cottonseed oil and other oils, white petrolatum; emulsifiable or adsorbable vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointments; water-soluble ointment vehicles, including polyethylene glycols with different molecular weights; emulsion vehicles, i.e., any one of water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. See, for example, Remington: The Science and Practice of Pharmacy, as above. These vehicles are emollients, but usually require the addition of antioxidants and preservatives.

[0197] Suitable cream bases can be oil-in-water or water-in-oil. Suitable cream vehicles can be water-washable and contain an oil phase, an emulsifier and an aqueous phase. The oil phase is also referred to as the "inner" phase, which is typically composed of vaseline and a fatty alcohol, such as cetyl alcohol or stearyl alcohol. In terms of volume, the aqueous phase typically (although not necessarily) exceeds the oil phase and typically contains a wetting agent. The emulsifier in the cream formulation can be a nonionic, anionic, cationic or amphoteric surfactant.

[0198] Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules substantially uniformly distributed in a liquid carrier. Suitable gelling agents include, but are not limited to, cross-linked acrylic acid polymers such as carbomers, carboxypolyalkylenes, and Hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel, a dispersant such as alcohol or glycerin may be added, or the gelling agent may be dispersed by trituration, mechanical mixing, and / or stirring.

[0199] The pharmaceutical compositions described herein can be administered rectally, urethrally, vaginally, or perivably in the form of suppositories, pessaries, bougies, poultices or poultices, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional methods as described in Remington: The Science and Practice of Pharmacy, supra.

[0200] Rectal, urethral, ​​and vaginal suppositories are solids for insertion into body orifices that are solid at room temperature but melt or soften at body temperature to release the active ingredient into the orifice. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include bases or vehicles, such as hardeners, which, when formulated with the active ingredient, produce a melting point near body temperature; and antioxidants as described herein, including bisulfites and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (cocoa bean oil), glycerol-gelatin, polyethylene glycols (polyoxyethylene glycol), spermaceti, paraffin hydrocarbons, white and yellow waxes, and suitable mixtures of mono-, di-, and triglycerides of fatty acids, and hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of various vehicles may also be used. Rectal and vaginal suppositories can be prepared by compression or molding. Typical weights of rectal and vaginal suppositories are independently about 2 to about 3 g.

[0201] The pharmaceutical compositions described herein can be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.

[0202] The pharmaceutical compositions described herein can be administered intranasally or by inhalation into the respiratory tract. The pharmaceutical compositions can be provided as aerosols or solutions delivered using a pressurized container, a pump, a sprayer, a nebulizer, such as an nebulizer that uses electrohydrodynamics to generate a fine mist, or a nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions can also be provided as dry powders for insufflation, alone or in combination with an inert carrier, such as lactose or a phospholipid; and as nasal drops. For intranasal use, the powder can contain a bioadhesive, including chitosan or cyclodextrin.

[0203] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or an alternative agent suitable for dispersing, solubilizing, or prolonging the release of the active ingredient; a propellant as a solvent; and / or a surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0204] The pharmaceutical compositions described herein can be micronized to a size suitable for delivery by inhalation, such as about 50 microns or less, or about 10 microns or less. Particles of these sizes can be prepared using comminution methods known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0205] Capsules, blisters, and kits for use in an inhaler or insufflator can be formulated to contain a powder mixture of the following: a pharmaceutical composition described herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as l-leucine, mannitol, or magnesium stearate. Lactose can be anhydrous or in the form of a monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions described herein for inhaled / intranasal administration may also contain suitable flavoring agents, such as menthol and levomenthol; and / or sweeteners, such as saccharin and saccharin sodium.

[0206] The pharmaceutical compositions described herein for topical administration can be formulated to be immediate release or modified release, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. D. Regulated release

[0207] The pharmaceutical compositions described herein can be formulated as a modified release dosage form. As used herein, the term "modified release" refers to a dosage form in which the rate or location of release of the active ingredient is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed release, extended release, prolonged release, sustained release, pulsatile release, controlled release, accelerated release, and rapid release, targeted release, programmed release, and gastric retention dosage forms. Pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multi-particulate controlled release devices, ion exchange resins, enteric coatings, multi-layer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be adjusted by changing the particle size and the polymorphic form of the active ingredient. 1. Matrix controlled release device

[0208] The pharmaceutical compositions described herein can be manufactured in a modified release dosage form using matrix controlled release devices known to those skilled in the art. See, for example, Takada et al. in Encyclopedia of Controlled Drug Delivery, Mathiowitz ed.; Wiley, 1999; Vol. 2.

[0209] In certain embodiments, the pharmaceutical compositions described herein are formulated in a modified release dosage form using an erodible matrix device, which is a water-swellable, erodible, or dissolvable polymer, including but not limited to synthetic polymers and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

[0210] Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenan, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phospholipids such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics such as ethylcellulose (EC), methylethylcellulose (MEC), carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose, and (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT), and hydroxyethylcellulose ethyl ether (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid Poly(2-hydroxyethyl-methacrylate); polylactide; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymer; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate and (trimethylaminoethyl) methacrylate chloride.

[0211] In certain embodiments, the pharmaceutical compositions described herein are formulated with a non-erodible matrix device.The active ingredient is dissolved or dispersed in an inert matrix and, upon administration, is released primarily by diffusion through the inert matrix. Suitable materials for use as non-erodible matrix devices include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, ethylene / vinyloxyethanol copolymers, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, and silicone carbonate copolymers; hydrophilic polymers such as ethylcellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and aliphatic compounds such as palm wax, microcrystalline wax, and triglycerides.

[0212] In matrix controlled-release systems, the desired release kinetics can be controlled, for example, via the type of polymer used, the polymer viscosity, the particle size of the polymer and / or active ingredient, the ratio of active ingredient to polymer, and other excipients or carriers in the composition.

[0213] The pharmaceutical compositions described herein can be prepared in modified release dosage form by methods known to those skilled in the art, including direct extrusion, dry or wet granulation followed by extrusion, and melt granulation followed by extrusion. 2. Osmotic controlled-release device

[0214] The pharmaceutical compositions described herein can be manufactured in a modified release dosage form using osmotic controlled release devices, including but not limited to single-chamber systems, dual-chamber systems, asymmetric membrane technology (AMT), and extruded core systems (ECS). Typically, such devices have at least two components: (a) a core containing the active ingredient; and (b) a semipermeable membrane having at least one delivery port that encapsulates the core. The semipermeable membrane controls the flow of water from the aqueous environment used into the core to cause drug release by extrusion through the delivery port.

[0215] In addition to the active ingredient, the core of the osmotic device optionally includes an osmotic agent that creates a driving force for transporting water from the environment of use into the core of the device. One class of osmotic agents are water-swellable hydrophilic polymers, which are also known as "osmopolymers" and "hydrogels." Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic acid), poly(methacrylic acid), polyvinyl pyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, copolymers of PVA / PVP with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0216] Another class of osmotic agents is an osmogen, which is capable of absorbing water to achieve an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as glucose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

[0217] Osmotic agents with different dissolution rates can be used to affect the rate at which the active ingredient is initially delivered from the dosage form. For example, amorphous sugars such as MANNOGEM TM An EZ can be used to provide faster delivery during the first few hours to immediately produce the desired therapeutic effect, and gradually and continuously release the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient is released at such a rate to replace the amount of active ingredient that is metabolized and excreted.

[0218] The core may also include various other excipients and carriers as described herein to enhance the performance of the dosage form or to facilitate stability or processing.

[0219] Materials useful in forming the semipermeable membrane include various grades of acrylic, vinyl, ether, polyamide, polyester, and cellulose derivatives that are water permeable and water insoluble at physiologically relevant pH, or that are susceptible to being rendered water insoluble by chemical alteration, such as cross-linking. Examples of suitable polymers useful in forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA urethane, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methylsulfonate, CA butylsulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan ethyl Acid esters, beta glucan triacetate, dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene vinyl acetate, EC, PEG, PPG, PEG / PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and copolymers thereof, starch, dextrose, dextrin, chitosan, collagen, gelatin, polyolefins, polyethers, polysulfones, polyethersulfones, polystyrene, polyethylene halides, polyethylene esters and ethers, natural and synthetic waxes.

[0220] The semipermeable membrane may also be a hydrophobic microporous membrane in which the pores are substantially filled with a gas and are not wetted by aqueous media, but are permeable to water vapor, as disclosed in U.S. Patent No. 5,798, 119. Such hydrophobic but water vapor permeable membranes are typically composed of hydrophobic polymers such as polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyethylene halides, polyvinylidene fluoride, polyethylene esters and ethers, natural waxes, and synthetic waxes.

[0221] Delivery ports on the semipermeable membrane can be formed after coating by mechanical or laser drilling. Delivery ports can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over a depression in the core. Alternatively, delivery ports can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220.

[0222] The total amount of active ingredient released and the rate of release can generally be modulated by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[0223] Pharmaceutical compositions in osmotic controlled-release dosage forms may also contain other conventional excipients or carriers as described herein to facilitate performance or processing of the formulation.

[0224] Osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release, 1995, 35, 1-21; Verma et al., Drug Dev. Ind. Pharm., 2000, 26, 695-708; Verma et al., J. Controlled Release, 2002, 79, 7-27.

[0225] In certain embodiments, the pharmaceutical compositions described herein are formulated as AMT controlled-release dosage forms comprising an asymmetric osmotic membrane coated with a core comprising the active ingredient and other pharmaceutically acceptable excipients or carriers. See, for example, U.S. Patent No. 5,612,059 and WO 2002 / 17918. AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct extrusion, dry granulation, wet granulation, and dip coating.

[0226] In certain embodiments, the pharmaceutical compositions described herein are formulated as an ESC controlled-release dosage form comprising a permeable membrane coating a core comprising the active ingredient, hydroxyethylcellulose, and other pharmaceutically acceptable excipients or carriers. 3. Multi-particle controlled release device

[0227] The pharmaceutical compositions described herein can be manufactured as multiparticulate controlled release devices in a modified release dosage form comprising a plurality of particles, microparticles, or pellets having diameters independently ranging from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm. These multiparticulates can be prepared by methods known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compaction, melt-condensation, and by spraying seed cores. See, for example, Multiparticulate Oral Drug Delivery; Ghebre-Sellassie, ed.; Drugs and the Pharmaceutical Sciences 65; CRC Press: 1994; and Pharmaceutical Palletization Technology; Ghebre-Sellassie, ed.; Drugs and the Pharmaceutical Sciences 37; CRC Press: 1989.

[0228] Other excipients or carriers as described herein can be blended with the pharmaceutical composition to aid in processing and forming multiparticulates. The resulting particles can themselves constitute the multiparticulate device, or can be coated with various film-forming materials such as enteric polymers, water-swellable and water-soluble polymers. The multiparticulates can be further processed into capsules or tablets. 4. Targeted delivery

[0229] The pharmaceutical compositions described herein can also be formulated to target specific tissues, receptors, or other areas of the body of the subject to be treated, including liposomes, re-encapsulated red blood cells, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Patent Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874. How to use

[0230] In one embodiment, provided herein are methods for treating, preventing, or ameliorating one or more symptoms of inflammatory bowel disease (IBD) in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0231] In certain embodiments, the IBD is Behcet's disease, Crohn's disease, collagenous colitis, diversion colitis, lymphocytic colitis, microscopic colitis, or ulcerative colitis. In certain embodiments, the IBD is Crohn's disease or ulcerative colitis. In certain embodiments, the IBD is Crohn's disease. In certain embodiments, the IBD is ulcerative colitis.

[0232] In certain embodiments, the IBD is mild Crohn's disease. In certain embodiments, the IBD is moderate Crohn's disease. In certain embodiments, the IBD is severe Crohn's disease.

[0233] In certain embodiments, the IBD is mild ulcerative colitis. In certain embodiments, the IBD is moderate ulcerative colitis. In certain embodiments, the IBD is severe ulcerative colitis.

[0234] Symptoms of IBD include, but are not limited to, abdominal cramping, abdominal pain, bloody stools, diarrhea, fatigue, fever, bloating and gas, loss of appetite, nausea and vomiting, rectal bleeding, stomach discomfort, and weight loss.

[0235] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0236] In certain embodiments, the therapeutically effective amount of the compounds described herein is in the range of about 0.1 to about 100 mg / kg / day, about 0.1 to about 50 mg / kg / day, about 0.1 to about 25 mg / kg / day, about 0.1 to about 20 mg / kg / day, about 0.1 to about 15 mg / kg / day, about 0.1 to about 10 mg / kg / day, or about 0.1 to about 5 mg / kg / day. In one embodiment, the therapeutically effective amount of the compounds described herein is in the range of about 0.1 to about 100 mg / kg / day. In another embodiment, the therapeutically effective amount of the compounds described herein is in the range of about 0.1 to about 50 mg / kg / day. In yet another embodiment, the therapeutically effective amount of the compounds described herein is in the range of about 0.1 to about 25 mg / kg / day. In yet another embodiment, the therapeutically effective amount of the compounds described herein is in the range of about 0.1 to about 20 mg / kg / day. In yet another embodiment, the therapeutically effective amount of the compounds described herein is in the range of about 0.1 to about 15 mg / kg / day. In yet another embodiment, the therapeutically effective amount of the compounds described herein is in the range of about 0.1 to about 10 mg / kg / day. In yet another embodiment, the therapeutically effective amount of the compounds described herein is in the range of about 0.1 to about 5 mg / kg / day.

[0237] In certain embodiments, the therapeutically effective amount of the compounds described herein is in the range of about 1 to about 1,000 mg / day, about 1 to about 500 mg / day, about 1 to about 200 mg / day, or about 1 to about 100 mg / day. In one embodiment, the therapeutically effective amount of the compounds described herein is in the range of about 1 to about 1,000 mg / day. In another embodiment, the therapeutically effective amount of the compounds described herein is in the range of about 1 to about 500 mg / day. In yet another embodiment, the therapeutically effective amount of the compounds described herein is in the range of about 1 to about 200 mg / day. In yet another embodiment, the therapeutically effective amount of the compounds described herein is in the range of about 1 to about 100 mg / day.

[0238] Based on the disorder, disease or condition to be treated and the condition of the subject, the compounds described herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual or topical (e.g., transdermal or topical) routes of administration. The compounds described herein can be formulated in suitable dosage units with pharmaceutically acceptable excipients, carriers, adjuvants or vehicles suitable for each route of administration.

[0239] In one embodiment, the compounds described herein are administered orally. In another embodiment, the compounds described herein are administered parenterally. In yet another embodiment, the compounds described herein are administered intravenously. In yet another embodiment, the compounds described herein are administered intramuscularly. In yet another embodiment, the compounds described herein are administered subcutaneously. In yet another embodiment, the compounds described herein are administered topically. In yet another embodiment, the compounds described herein are administered by topical instillation.

[0240] The compounds described herein can be delivered as a single dose, such as, for example, a single bolus injection or oral tablet or pill, or over time, such as, for example, a continuous infusion over time or in divided bolus doses over time. If necessary, the compounds described herein can be administered repeatedly, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity.

[0241] The compounds described herein can be administered once a day (QD), or they can be divided into multiple daily doses, such as twice a day (BID) and three times a day (TID). In addition, administration can be continuous, i.e., daily, or intermittent. As used herein, the terms "intermittent" or "intermittently" are intended to mean stopping and starting at fixed or irregular intervals. For example, intermittent administration of the compounds described herein is administration for 1 to 6 days per week, cyclic administration (e.g., daily administration for 2 to 8 consecutive weeks, followed by a rest period of up to one week without administration), or administration every other day.

[0242] The compounds described herein may also be used in conjunction or combination with other therapeutic agents useful in the treatment and / or prevention of the conditions, disorders, or diseases described herein.

[0243] Therefore, in one embodiment, provided herein is a method for treating, preventing, or ameliorating one or more symptoms of inflammatory bowel disease (IBD) in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a therapeutically effective amount of a second therapeutic agent.

[0244] In certain embodiments, the second therapeutic agent is an NSAID, 5-amino-salicylic acid, a corticosteroid, an immunomodulator (e.g., azathioprine), an antibiotic, an anti-dysentery drug, a JAK inhibitor (e.g., tofacitinib or upadacitinib), an anti-TNF biologic (e.g., adalimumab, infliximab, etanercept, or golimumab), an anti-integrin antibody (e.g., vedolizumab), or an anti-interleukin antibody (e.g., ustekinumab, risankizumab, or guselkumab).

[0245] As used herein, the term "combination" includes the use of more than one therapy (for example, one or more preventive and / or therapeutic agents). However, the use of the term "combination" does not limit the order in which the subject with the patient's condition, illness or disease is administered therapy (for example, preventive and / or therapeutic agents). The subject can be administered a second therapy (for example, preventive or therapeutic agents) before (for example, before 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks), while or afterwards (for example, afterwards 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks) administering the first therapy (for example, preventive or therapeutic agents, compounds as described herein). Triple therapy is also contemplated herein.

[0246] The route of administration of the compounds described herein is independent of the route of administration of the second therapy. In one embodiment, the compounds described herein are administered orally. In another embodiment, the compounds described herein are administered intravenously. In another embodiment, the compounds described herein are administered topically. Therefore, according to these embodiments, the compounds described herein are administered orally, intravenously or topically, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, orally, intranasally, liposomes, by inhalation, vaginally, intraocularly, by local delivery via a catheter or stent, subcutaneously, intrafatally, intraarticularly, intrathecally, topically or in a slow release dosage form. In one embodiment, the compounds described herein and the second therapy are administered topically by the same administration form. In another embodiment, by a form of administration, for example, a compound described herein is administered topically, whereas by another form of administration, for example, a second agent (anticancer agent) is administered orally.

[0247] The compounds described herein can also be provided as articles of manufacture using packaging materials well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,525,907; 5,052,558; and 5,055,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for the selected formulation and intended form of administration and treatment.

[0248] In certain embodiments, provided herein are kits that, when used by a medical practitioner, can simplify the administration of an appropriate amount of a compound described herein as an active ingredient to a subject. In certain embodiments, provided herein are kits comprising a container and a dosage form of a compound described herein.

[0249] The kits provided herein may also include a device for administering the active ingredient. Examples of these devices include, but are not limited to, syringes, needleless syringe drip bags, patches, and inhalers. The kits provided herein may also include a condom for administering the active ingredient.

[0250] The kits provided herein may also include a pharmaceutically acceptable vehicle that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may contain a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particle-free sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0251] The present disclosure will be further understood by way of the following non-limiting examples. Example

[0252] As used herein, regardless of whether a particular abbreviation is specifically defined, the symbols and conventions used herein are consistent with those used in contemporary scientific literature, for example, the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry. Specifically, but not limiting, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimoles / liter); μM (micromoles / liter); mmol (millimole); min (minute); h (hour); DMSO (dimethyl sulfoxide); and mpk (mg / kilogram). Unless otherwise indicated, all temperatures are expressed in ° C (degrees Celsius). Example 1 Oxazolone-induced acute colitis in mice for ulcerative colitis

[0253] Compound A30 was evaluated against tofacitinib in an oxazolone-induced colitis mouse model. Boirivant et al., J. Exp. Med. 1998, 188, 1929-39. According to Table 1, Balb / c mice were randomly divided into 6 groups: 4 treatment groups (treatment groups), 1 vehicle control group (vehicle control group), and 1 sham operation group (sham operation group). Mice in the treatment and vehicle control groups were sensitized with 200 μL of 2% oxazolone in acetone and olive oil (1:4), and then 100 μL of 1.5% oxazolone was injected into the rectum of each mouse on the 5th day after sensitization. Mice in the sham operation group were sensitized with 200 μL of a mixture of acetone and olive oil (1:4) without oxazolone, and then 100 μL of 50% ethanol / water was injected into the rectum of each mouse on the 5th day after sensitization. Each mouse was anesthetized intraperitoneally with tribromoethanol (0.3 mL, 1.25%) before rectal injection. From day 4 to day 8 after sensitization, mice in the sham group and vehicle control group were administered 0.5% CMC-Na by gavage according to the dosing schedule shown in Table 1, while mice in the treatment group were administered tofacitinib or compound A30 in 0.5% CMC-Na by gavage.

[0254] The body weight of each mouse was measured every day. From the 4th day after sensitization, the fecal characteristics and occult blood determined by fecal occult blood test (FOBT) of each mouse were measured every day to calculate the disease activity index (DAI) according to Table 2. Figure 1 and 2 As shown, both compound A30 and tofacitinib slowed down weight loss and improved DAI scores. Table 1. Grouping and Dosage Administration Table 2. DAI scores score Weight loss (%) Nature of stool occult blood 0 0 normal Negative 1 1～5 soft weak positive 2 6～10 loose Positive 3 11～20 fluffy Bleeding 4 >20 water sample Large amounts of blood

[0255] On day 9 after sensitization, each mouse was euthanized and blood was collected from the heart. Serum was prepared and frozen for determination of inflammatory factors.

[0256] The colon of each mouse was collected and photographed, and the colon length was measured and weighed after removing the colon contents. As described in Bialkowska et al., J.Vis.Exp.2016, 113, e54161, a portion of each collected colon was fixed in neutral paraformaldehyde using Swiss roll technology for pathological scoring (Table 3). The rest of the colonic mucosa of each mouse was scraped and frozen for determining inflammatory factors. Table 3. Colon pathology scores

[0257] As expected, the colon of mice with oxazolone-induced colitis had increased length, decreased weight, and increased density due to inflammation. Figures 3 to 5 As shown in Figure 2, both compound A30 and tofacitinib were able to reverse the effects of the disease. Figure 6 shown.

[0258] Using BD TM IFN-γ and TNFα levels were analyzed using a flow cytometric bead array (CBA) kit. Figures 7 to 10 As shown, compound A30 and tofacitinib reduced the levels of TNFα and IFN-γ in the intestinal mucosa and serum of mice with oxazolone-induced colitis. Example 2 TNBS-induced acute colitis in mice for Crohn's disease

[0259] Compound A30 was evaluated together with mesalamine and filgotinib in a TNBS-induced colitis mouse model. Antoniou et al., Ann.Med.Surg.(Lond.)2016,11,9-15. Female Balb / c mice (approximately 20 g, 8-10 weeks old) were randomly divided into 6 groups according to Table 4: 4 treatment groups (treatment groups), 1 vehicle control group (vehicle control group) and 1 sham operation group (sham operation group). On day 0, mice were anesthetized with 0.25 mL of 1.25% avodine anesthetic. In the treatment group and the vehicle control group, 100 μL of 2% TNBS solution dissolved in 50% ethanol was injected into the rectum of each mouse. In the sham operation group, 100 μL of 50% ethanol was injected. Table 4. Grouping and Dosage Administration

[0260] The body weight of each mouse was measured daily. From day 4 after sensitization, the fecal characteristics and occult blood determined by fecal occult blood test (FOBT) of each mouse were measured daily to calculate the disease activity index (DAI). Figure 11 and 12 The relevant results are shown. *****

[0261] The above-described examples are provided so as to provide those skilled in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of the present disclosure. Modifications that are obvious to those skilled in the art are intended to be within the scope of the following claims. All patent publications, patents, and patent applications cited in this specification are hereby incorporated by reference to the same extent as if each such patent publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. A method for treating, preventing or ameliorating one or more symptoms of inflammatory bowel disease in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by chemical formula (I): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: R 1 Yes (i) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclyl; or (ii) –OR 1a ,–NR 1b R 1c or –SR 1a ; R 2 It is C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group; Each R 3 are independently (i) deuterium, cyano, halo or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, 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) –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)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)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 1c 、 –SR 1a 、 –S(O)R 1a 、 –S(O)2R 1a 、 –S(O)NR 1b R 1c or –S(O)2NR 1b R 1c ; R 4 and R 6 are each independently (i) hydrogen; or (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic group; R 5 Yes (i) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl or heterocyclic; or (ii) C 1-6 Alkylene-R 5a , where R 5a It is C 3-10 cycloalkyl, heteroaryl or heterocyclyl; X is a bond, –O–, –S–, –N(R 1b )–or C 1-6 alkylene; Z is –O–, –S–, or –N(R 1b )–、C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-10 cycloalkylene or heterocyclylene; Each R 1a 、R 1b 、R 1c and R 1d are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic; or R 1b and R 1c together with the nitrogen atom to which they are attached, form a heterocyclyl; and m is an integer 0, 1, 2, 3, or 4; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment, 1, 2, 3, or 4, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted by one or more, in one embodiment, 1, 2, 3 or 4 substituents Q a substitution; 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 、–OP(O)(OR b )OR 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)NR b R c ,–NR a C(O)SR d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–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)2NR 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 , where each R a 、R b 、R c and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclic, each of which is optionally substituted by one or more, in one embodiment, 1, 2, 3 or 4 substituents Q a or (iii) R b and R c Together with the nitrogen atom to which they are attached, they form a heterocyclic group, which is optionally substituted by one or more, in one embodiment, 1, 2, 3 or 4 substituents Q a replace; Each Q a are independently selected from: (a) deuterium, cyano, halo, nitro and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 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 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 、–OP(O)(OR f )OR 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(N(CN))R h ,–NR e C(N(CN))NR f R g ,–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 g ; where each R e 、R f 、R g and R 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 nitrogen atom to which they are attached they form a heterocyclyl.

2. The method according to claim 1, wherein R 2 is C optionally substituted by one or more substituents Q 6-14 Aryl or heteroaryl.

3. The method according to claim 1 or 2, wherein R 2 is C optionally substituted with one or more substituents Q 6-14 Aryl.

4. The method according to claim 1 or 2, wherein R 2 is heteroaryl optionally substituted with one or more Q substituents.

5. The method according to any one of claims 1, 2 and 4, wherein R 2 is a bicyclic heteroaryl group optionally substituted with one or more Q substituents.

6. The method according to any one of claims 1, 2, 4 and 5, wherein R 2 is a 5,6-fused heteroaryl group optionally substituted with one or more Q substituents.

7. The method according to claim 1 or 2, wherein R 2 It is phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 3-chloro-4-hydroxyphenyl, benzofuran-2-yl, benzofuran-6-yl or indol-5-yl.

8. The method according to any one of claims 1 to 3, which has a structure shown in chemical formula (II): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: R 2a is hydrogen or R 2b ; Each R 2b are independently (i) hydrogen, deuterium, cyano, halo or nitro; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclyl, each of which is optionally substituted by one or more, in one embodiment, 1, 2, 3 or 4 substituents Q a substitution; 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 、–OP(O)(OR b )OR 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)NR b R c , –NR a C(O)SR d , –NR a C(NR d )NR b R c , –NR a C(N(CN))R d , –NR a C(N(CN))NR b R c , –NR a C(S)R d , –NR a C(S)OR[[ID=2,9]] 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)2NR 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 ; and n is an integer 0, 1, 2, 3, or 4.

9. The method according to any one of claims 1 to 8, wherein m is the integer 2.

10. The method according to any one of claims 1 to 9, wherein each R 3 are independently halo.

11. The method according to any one of claims 1 to 10, wherein each R 3 It is chlorinated.

12. The method according to any one of claims 8 to 11, which has a structure shown in chemical formula (III): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 3a and R 3b are independently hydrogen or R 3 .

13. The method according to any one of claims 1 to 12, wherein R 5 is C optionally substituted by one or more substituents Q 1-6 Alkyl, C 7-15 Aralkyl, C 1-6 Alkylene-heteroaryl or C 1-6 Alkylene-heterocyclyl.

14. The method according to any one of claims 1 to 13, wherein R 5 is C optionally substituted with one or more substituents Q 7-15 Aralkyl.

15. The method according to any one of claims 1 to 13, wherein R 5 It is C 1-6 Alkyl, C 7-15 Aralkyl, C 1-6 Alkylene-heteroaryl or C 1-6 Alkylene-heterocyclyl, each group independently substituted with one or two substituents; wherein each substituent is independently -OR a ,–NR a C(O)R d ,–NR a C(N(CN))R d ,–NR a C(N(CN))NR b R c ,–NR a S(O)2R d or –S(O)2R a .

16. The method according to any one of claims 1 to 13 and 15, wherein R 5 is a C substituted with one or two substituents 7-15 Aralkyl; wherein each substituent is independently -OR a or –S(O)2R a .

17. The method according to any one of claims 1 to 13, wherein R 5 3-Methylsulfonylamino-propyl, 4-methylsulfonylaminobutyl, thiophen-2-ylcarboxamidomethyl, ((S)-3-hydroxypyrrolidine-1-carboxamido)methyl, (E)-N'-cyano-3-hydroxypyrrolidine-1-carboxamidomethyl, (E)-N'-cyano-3,4-dihydroxypyrrolidine-1-carboxamidomethyl, 2-cyano-3,3-bis(2-hydroxyethyl)-guanidinomethyl, 3-hydroxybenzyl, 3,5-dihydroxybenzyl, 3- methylsulfonylbenzyl, 3,5-dimethylsulfonylbenzyl, (1-(methylsulfonyl)pyrrol-3-yl)methyl, (1-(methylsulfonyl)pyrazol-3-yl)methyl, (1-(methylsulfonyl)pyrazol-4-yl)-methyl, (5-(methylsulfonyl)pyridin-3-yl)methyl, (1-(methylsulfonyl)pyrrolidin-3-yl)methyl or (1-(methylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl)methyl.

18. The method according to claim 12, wherein the compound has a structure shown in chemical formula (VII): or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 5a (i) 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 arylalkyl, heteroaryl or heterocyclyl; or (ii) -NR a C(N(CN))R d or –NR a C(N(CN))NR b R c .

19. The method according to claim 12 or 18, wherein the compound has a structure shown in chemical formula (VIII): or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

20. The method according to claim 12 or 18, wherein the compound has a structure shown in chemical formula (IX): or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

21. The method according to any one of claims 18 to 20, wherein R 5a (i) each independently substituted with one or more substituents Q 1-6 Alkyl, C 6-14 aryl, heteroaryl or heterocyclyl; or (ii) -NR a C(N(CN))R d or –NR a C(N(CN))NR b R c .

22. The method according to any one of claims 18 to 21, wherein R 5a Is -NR a S(O)2R d Substituted C 1-6 alkyl.

23. The method according to any one of claims 18 to 21, wherein R 5a is a C substituted with one or two substituents 6-14 Aryl, each substituent is independently -OR a or –S(O)2R a .

24. The method according to any one of claims 18 to 21 and 23, wherein R 5a is phenyl substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a .

25. The method according to any one of claims 18 to 21, 23 and 24, wherein R 5a is phenyl substituted with one or two substituents, each substituent being independently hydroxy or methylsulfonyl.

26. The method according to any one of claims 18 to 21 and 23 to 25, wherein R 5a It is a phenyl group substituted by one or two methylsulfonyl groups.

27. The method according to any one of claims 18 to 21, wherein R 5a is heteroaryl substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a .

28. The method according to any one of claims 18 to 21 and 27, wherein R 5a is a monocyclic heteroaryl substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a .

29. The method according to any one of claims 18 to 21, 27 and 28, wherein R 5a is a 5- or 6-membered heteroaryl group independently substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a .

30. The method according to any one of claims 18 to 21 and 27 to 29, wherein R 5a is pyrrolyl, pyrazolyl or pyridinyl, each of which is independently substituted with one or two methylsulfonyl groups.

31. The method according to any one of claims 18 to 21, wherein R 5a is a heterocyclic group substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a .

32. The method according to any one of claims 18 to 21 and 31, wherein R 5a is a monocyclic heterocyclyl substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a .

33. The method according to any one of claims 18 to 21, 31 and 32, wherein R 5a is a 5- or 6-membered heterocyclic group independently substituted with one or two substituents, each of which is independently -OR a or –S(O)2R a .

34. The method according to any one of claims 18 to 21 and 31 to 33, wherein R 5a is pyrrolyl, pyrazolyl or pyridinyl, each of which is independently substituted with one or two methylsulfonyl groups.

35. The method according to any one of claims 18 to 21, wherein R 5a 2-methylsulfonylamino-ethyl, 3-methylsulfonylaminopropyl, 3-hydroxyphenyl, 3,5-dihydroxyphenyl, 3-methylsulfonyl-phenyl, 3,5-dimethylsulfonylphenyl, 1-(methylsulfonyl)pyrrol-3-yl, 1-(methylsulfonyl)pyrazol-3-yl, 1-(methylsulfonyl)pyrazol-4-yl, 5-(methylsulfonyl)pyridin-3-yl, 1-(methylsulfonyl)- Pyrrolidin-3-yl, 1-(methylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl, thiophen-2-ylcarboxamido, (S)-3-hydroxypyrrolidin-1-carboxamido, (E)-N'-cyano-3-hydroxypyrrolidin-1-carboxamido, (E)-N'-cyano-3,4-dihydroxypyrrolidin-1-carboxamido or 2-cyano-3,3-bis(2-hydroxyethyl)-guanidino.

36. The method according to any one of claims 18 to 21 and 23 to 26, wherein R 5a It is 3-methyl-sulfonylphenyl.

37. The method according to any one of claims 8 to 36, wherein R 2a is hydrogen, halogen, or –OR a ; 38. The method according to any one of claims 8 to 37, wherein R 2a is (i) hydrogen, halo or hydroxy; or (ii) C optionally substituted with one or two substituents Q 1-6 Alkoxy.

39. The method according to any one of claims 8 to 38, wherein R 2a is hydrogen, chloro, hydroxy or methoxy.

40. The method according to any one of claims 8 to 39, wherein R 2a It is a hydroxyl group.

41. The method of any one of claims 8 to 40, wherein n is the integer 1.

42. The method according to any one of claims 8 to 41, wherein each R 2b are independently halo or –OR a .

43. The method according to any one of claims 8 to 42, wherein each R 2b is independently (i) halo or hydroxy; or (ii) C optionally substituted with one or two substituents Q 1-6 Alkoxy.

44. The method according to any one of claims 8 to 43, wherein each R 2b is independently chloro, hydroxy or methoxy.

45. The method of any one of claims 8 to 40, wherein n is the integer 0.

46. ​​The method according to any one of claims 12 to 45, wherein R 3a It is halogenated.

47. The method according to any one of claims 12 to 46, wherein R 3a It is chlorinated.

48. The method according to any one of claims 12 to 47, wherein R 3b It is halogenated.

49. The method according to any one of claims 12 to 48, wherein R 3b It is chlorinated.

50. The method according to any one of claims 1 to 49, wherein R 1 (i) C optionally substituted with one or more substituents Q 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl; or (ii) –OR a .

51. The method according to any one of claims 1 to 50, wherein R 1 is (i) hydroxy; or (ii) C optionally substituted with one or more substituents Q 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14 Aryl or C 1-6 Alkoxy.

52. The method according to any one of claims 1 to 51, wherein R 1 is C optionally substituted with one or more substituents Q 1-6 alkyl.

53. The method according to any one of claims 1 to 51, wherein R 1 is C optionally substituted with one or more substituents Q 3-10 Cycloalkyl.

54. The method according to any one of claims 1 to 51 and 53, wherein R 1 is a monocyclic C optionally substituted with one or more substituents Q 3-10 Cycloalkyl.

55. The method according to any one of claims 1 to 51, wherein R 1 is C optionally substituted with one or more substituents Q 6-14 Aryl.

56. The method according to any one of claims 1 to 51 and 55, wherein R 1 is phenyl optionally substituted with one or more substituents Q.

57. The method according to any one of claims 1 to 51, wherein R 1 is C optionally substituted with one or more substituents Q 1-6 Alkoxy.

58. The method according to any one of claims 1 to 51, wherein R 1 is methyl, ethyl, isopropyl, n-butyl, cyclopropyl, 3-hydroxyphenyl, hydroxy, methoxy or ethoxy.

59. The method according to any one of claims 1 to 51 and 58, wherein R 1 It's methyl.

60. The method according to any one of claims 1 to 59, wherein R 4 It's hydrogen.

61. The method according to any one of claims 1 to 60, wherein R 6 It's hydrogen.

62. The method of any one of claims 1 to 61, wherein X is a bond.

63. The method of any one of claims 1 to 61, wherein X is -O-.

64. according to the method described in any one of claim 1 to 63, wherein Z is C optionally substituted with one or more substituents Q, respectively. 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene.

65. The method according to any one of claims 1 to 64, wherein Z is C optionally substituted with one or more substituents Q. 1-6 Alkylene.

66. The method according to any one of claims 1 to 65, wherein Z is methanediyl or ethane-1,2-diyl, each optionally substituted with one or more substituents Q.

67. according to the method described in any one of claim 1 to 64, wherein Z is C optionally substituted with one or more substituents Q, respectively. 1-6 Alkylene.

68. The method of any one of claims 1 to 64 and 67, wherein Z is ethylene-1,2-diyl optionally substituted with one or more substituents Q.

69. according to the method described in any one of claim 1 to 64, wherein Z is C optionally substituted with one or more substituents Q, respectively. 1-6 Alkylene.

70. The method of any one of claims 1 to 64 and 69, wherein Z is ethyn-1,2-diyl.

71. The method of any one of claims 1 to 64, wherein Z is methanediyl, ethane-1,2-diyl, 1-hydroxyethane-1,2-diyl, ethylene-1,2-diyl, acetylene-1,2-diyl.

72. The method of any one of claims 1 to 66 and 67, wherein Z is ethane-1,2-diyl.

73. The method of any one of claims 1 to 62, wherein X is a bond and Z is ethane-1,2-diyl.

74. The method of claim 1, wherein the compound is: (2S)-2-(2,6-dichloro-4-(2-(hydroxy(phenyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A1; (2S)-2-(2,6-dichloro-4-((hydroxy(3-hydroxyphenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A2; (2S)-2-(2,6-dichloro-4-(2-(hydroxy(m-hydroxyphenyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A3; (2S)-2-(2,6-dichloro-4-(2-(methoxy(phenyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A4; (2S)-2-(2,6-dichloro-4-((methoxy(phenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A5; (2S)-2-(2,6-dichloro-4-(2-(ethoxy(m-hydroxyphenyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A6; (2S)-2-(2,6-dichloro-4-((methoxy(3-hydroxyphenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A7; (2S)-2-(2,6-dichloro-4-(2-(methoxy(3-hydroxyphenyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A8; (2S)-2-(2,6-dichloro-4-((methyl(phenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A9; (2S)-2-(2,6-dichloro-4-(2-(methyl(phenyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A10; (2S)-2-(2,6-dichloro-4-((methyl(3-hydroxyphenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A11; (2S)-2-(2,6-dichloro-4-((methoxy(3-methoxyphenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A12; (2S)-2-(2,6-dichloro-4-((hydroxy(3-methoxyphenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A13; (2S)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzylamino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A14; (2S)-2-(2,6-dichloro-4-((methyl(4-hydroxyphenyl)phosphoryl)ethynyl)benzylamino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A15; (2S)-2-(2,6-dichloro-4-((hydroxy(phenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A16; (2S)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(thiophen-2-ylcarboxamido)propanoic acid A17; (2S)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(1-(methylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl)propanoic acid A18; (2S)-3-((R,E)-N′-cyano-3-hydroxypyrrolidine-1-carbamimidoyl)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)propanoic acid A19; (2S)-2-(2,6-dichloro-4-((ethyl(3-hydroxyphenyl)phosphoryl)ethynyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A20; (2S)-2-(2,6-dichloro-4-(2-(ethyl(3-hydroxyphenyl)phosphinoyl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A21; (2S)-2-(2,6-dichloro-4-(2-(cyclopropyl(3-hydroxyphenyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A22; (2S)-2-(2,6-dichloro-4-(butyl(3-hydroxyphenyl)phosphinoethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A23; (2S)-2-(2,6-dichloro-4-((methyl(benzofuran-6-yl)phosphoryl)ethynyl)benzylamino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A24; (2S)-2-(2,6-dichloro-4-((methyl(benzofuran-6-yl)phosphoryl)ethyl)benzylamino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A25; (2S)-2-(4-(2-(Benzofuran-2-yl(methyl)phosphoryl)ethyl)-2,6-dichlorobenzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A26; (2S)-2-(2,6-dichloro-4-((methyl(1H-indol-5-yl)phosphoryl)ethyl)benzylamino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A27; (2S)-2-(2,6-dichloro-4-((((phenyl)(methyl)phosphoryl)oxy)methyl)-benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A28; (2S)-2-(2,6-dichloro-4-((((3-hydroxyphenyl)(methyl)phosphoryl)methyl)amino)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A29; (S)-2-(2,6-dichloro-4-(2-((S)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A30; (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A31; (2S)-2-(2,6-dichloro-4-((E)-2-(ethoxy(3-hydroxyphenyl)phosphoryl)vinyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A32; (2S)-2-(2,6-dichloro-4-(2-(methyl(4-hydroxyphenyl)phosphinoyl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A33; (2S)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzamido)-3-(3-hydroxybenzamido)propanoic acid A34; 2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzylamino)-3-(3,5-(dimethylsulfonyl)phenyl)propanoic acid A35; 2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzylamino)-3-(3,5-(dimethylsulfonyl)phenyl)propanoic acid A36; N 2 -(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzoyl)-N 6 -(Methylsulfonyl)-L-lysine A37; (2S)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzylamino)-3-(5-(methylsulfonyl)pyridin-3-yl)propanoic acid A38; (2S)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzylamino)-3-(1-(methylsulfonyl)-1H-pyrrol-3-yl)propanoic acid A39; (2S)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzylamino)-3-(1-(methylsulfonyl)-1H-pyrazol-3-yl)propanoic acid A40; (2S)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzylamino)-3-(1-(methylsulfonyl)-1H-pyrazol-4-yl)propanoic acid A41; (2S)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzylamino)-3-(1-(methylsulfonyl)pyrrolidin-3-yl)propanoic acid A42; (2S)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-((S)-3-hydroxypyrrolidine-1-carboxamido)propanoic acid A43; (2S)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-5-(methylsulfonylamino)pentanoic acid A44; (2S)-3-((3R,4R,E)-N′-cyano-3,4-dihydroxypyrrolidine-1-carbamimidoyl)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)propanoic acid A45; (2S)-3-(2-cyano-3,3-bis(2-hydroxyethyl)guanidino)-2-(2,6-dichloro-4-(2-(methyl(3-hydroxyphenyl)phosphoryl)ethyl)benzamido)propanoic acid A46; (2S)-2-(2,6-dichloro-4-((methoxy(3-hydroxyphenyl)phosphoryl)ethynyl)-benzylamino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A47; (2S)-2-(2,6-dichloro-4-((methyl(4-hydroxy-3-chlorophenyl)phosphoryl)ethynyl)benzylamino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A48; (2S)-2-(2,6-dichloro-4-((hydroxy(benzofuran-6-yl)phosphoryl)ethynyl)benzylamino)-3-(3-(methylsulfonyl)phenyl)propanoic acid A49; (2S)-2-(2,6-dichloro-4-(1-hydroxy-2-(hydroxy(3-hydroxyphenyl)phosphoryl)-ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A50; (2S)-2-(2,6-dichloro-4-(2-(hydroxy(m-hydroxyphenyl)phosphoryl)vinyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A51; (S,E)-2-(4-(2-(bis(3-hydroxyphenyl)phosphoryl)vinyl)-2,6-dichlorobenzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A52; (S)-2-(4-(2-(bis(3-hydroxyphenyl)phosphoryl)ethyl)-2,6-dichlorobenzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A53; (2S)-2-(2,6-dichloro-4-((E)-2-(ethoxy(4-hydroxyphenyl)phosphoryl)vinyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A54; (2S)-2-(2,6-dichloro-4-(1-hydroxy-2-(methyl(benzofuran-6-yl)phosphoryl)ethyl)-benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A55; (2S)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(isopropyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A56; (2S)-2-(2,6-dichloro-4-(2-(cyclopropyl(3-hydroxyphenyl)phosphoryl)vinyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A57; or (2S)-2-(2,6-dichloro-4-(2-((3-hydroxyphenyl)(methyl)phosphoryl)vinyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid A58; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

75. The method of any one of claims 1 to 74, wherein the inflammatory bowel disease is Crohn's disease.

76. The method of any one of claims 1 to 74, wherein the inflammatory bowel disease is ulcerative colitis.

77. The method of any one of claims 1 to 76, wherein the subject is a human.

78. The method of any one of claims 1 to 77, wherein the compound is administered orally.

79. The method of any one of claims 1 to 78, wherein the compound is administered as a tablet or capsule.

80. The method of any one of claims 1 to 79, wherein the therapeutically effective amount of the compound is in the range of about 0.01 to about 10 mg / kg / day.

81. The method of any one of claims 1 to 80, wherein the therapeutically effective amount of the compound is in the range of about 1 to about 1,000 mg / day.

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