Caspase inhibitors and methods of use thereof

Abstract

Provided herein are compounds of formula (I): [Formula 1] TIFF2022524049000063.tif25170Compositions containing the compounds, and methods of treating various diseases using the compounds and compositions.

Description

[Technical field]

[0001] (1. Related Applications) This application claims the benefit of priority to U.S. Provisional Application No. 62 / 815,270, filed March 7, 2019, the disclosure of which is incorporated herein by reference in its entirety.

[0002] (2. Field) Provided herein are compounds that are caspase inhibitors, pharmaceutical compositions containing those compounds, and methods of using such compounds and pharmaceutical compositions. [Background technology]

[0003] (3.Background) Twelve human caspases are known. Caspase-1, also known as interleukin-converting enzyme (ICE), was the first human caspase identified. Ten caspases have been classified into two groups based on their effects: proapoptotic caspases (caspases 2, 3, 6, 7, 8, 9, and 10) and proinflammatory caspases (caspases 1, 4, and 5). The functions of two additional human caspases (12 and 14) are less well characterized.

[0004] Caspases are a family of cysteine ​​protease enzymes that are key mediators in the signal transduction pathways for apoptosis and cell degradation (Thornberry, Chem. Biol., 1998, 5, R97-R103). Although these signal transduction pathways vary depending on the cell type and the stimulus, all apoptotic pathways show a convergence on a common effector pathway leading to the proteolysis of key proteins. Caspases are involved in both the effector step of the signal transduction pathway and further upstream in its initiation. Activation of upstream caspases involved in the initiation event in turn activates other caspases involved in the later steps of apoptosis.

[0005] The substrate specificity of human ICE has been characterized using peptides spanning the cleavage site of the enzyme. Two features of the peptide substrate are necessary for catalytic recognition by the enzyme. First, an aspartic acid adjacent to the cleavage site is strongly required, as substitution of this residue in either the IL-1β precursor or in the peptide substrate results in a substantial decrease in the rate of catalysis (Kostura et al., Proc. Natl. Acad. Sci., 86:5227, 1989; Sleath et al., J. Biol. Chem., 265:14526, 1990; Howard et al., J. Immunol., 147:2964, 1991).

[0006] Enzymatically active caspase-1 is generated from its inactive precursor, procaspase-1, by the action of a protein complex known as the inflammasome. The biochemical function of the inflammasome is to generate active caspase-1. Active caspase-1 converts the inactive precursor, pro-interleukin-1β (pro-IL-1β), to the active cytokine, interleukin-1β (IL-1β), as well as pro-IL-18 to the mature, active IL-1β. IL-1β is known as a proinflammatory master cytokine and is involved in a number of human diseases. IL-18 is also a proinflammatory cytokine implicated in human diseases. Caspase-1 also cleaves the protein gasdermin D, initiating a form of inflammatory cell death known as pyroptosis. Sollberger, G. et al., Innate Immunity 20, pp.115-125 (2013) and Denes, A et al., Cell Death Disease 3, e338 (2012). Caspase-1 is associated with many inflammatory disease conditions due to its role in regulating the production of proinflammatory cytokines and activating pyroptosis. Caspase-1 and IL-1β have been linked to autoinflammatory diseases, autoimmune diseases, CNS diseases, liver diseases, respiratory diseases, cardiovascular diseases, skin diseases, rheumatic diseases, renal diseases, ophthalmological diseases, and cancer.Flores, J. et al., Nature Comm. 9, 3916 (2018); McKenzie, B. et al., PNAS 115, (26), E6065-E6074 (2018); Melnikov, V. et al., J Clin Invest. 110, pp. 1083-1091 (2002); Wang, W. et al., PNAS, 113, (34) pp. 9587-9592 (2016); Morrison, M. et al., Int J Obesity Res. 40, pp. 1416-1423 (2016); Guo B. et al., Sci Rep. 6, p. 36107 (2016); Stack, J. et al., J. Immunol. 175, pp. 2630-2634 (2005); Kim, R. et al., Am. J. Resp. Care Med. 196, pp. 283-297 (2017); Rudolphi, K. et al., Osteoarthritis Cartilage 11, pp. 738-746 (2003); Audia, J. et al., Basic Res. Cardiol. 113, (5), pp. 32 (2018); Aira, L. et al., J. Invest. Derm. DOI: 10.1016 / j.jid.2018.11.031 (2018), Wooff, Y. et al., Sci. Rep. 10, p. 2263 (2020). Thus, inhibitors of the proinflammatory and pathogenic actions of caspase-1, caspase-4 and caspase-5 may be beneficial in the treatment of several human diseases.

[0007] In view of the multiple uses of caspase inhibitors, there is a constant need to develop new, more effective compounds capable of selectively inhibiting certain caspases. Summary of the Invention

[0008] (4. Overview) Provided herein are compounds, pharmaceutical compositions comprising the compounds, and methods of their use in treating diseases modulated by certain caspases, including, but not limited to, caspase-1, caspase-4, and / or caspase-5. In one embodiment, the compounds for use in the compositions and methods provided herein are of Formula I, or an enantiomer or mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X, Y, Y 1 , Y 2 and Z 3 is as defined elsewhere herein).

[0009] Also provided herein are pharmaceutical compositions comprising one or more compounds of Formula I and a pharma- ceutically acceptable carrier.

[0010] In one embodiment, provided herein is a method of treating a disease or condition associated with inflammatory caspases (i.e., caspase-1, caspase-4, and caspase-5) and / or modulation of inflammatory caspases by administering a therapeutically effective amount of a compound provided herein. Treatment can include amelioration, alleviation, and / or prevention. In some embodiments, the disease or condition associated with inflammatory caspases and / or modulation of inflammatory caspases is selected from autoimmune diseases, inflammatory diseases, CNS diseases, liver diseases, respiratory diseases, cardiovascular diseases, skin diseases, rheumatic diseases, renal diseases, and cancer. In some embodiments, the disease or condition associated with inflammatory caspases and / or modulation of inflammatory caspases is selected from autoimmune diseases, inflammatory diseases, CNS diseases, liver diseases, respiratory diseases, cardiovascular diseases, skin diseases, rheumatic diseases, renal diseases, ophthalmological diseases, and cancer.

[0011] In one embodiment, provided herein is a method of treating a disease or condition associated with caspase-1, caspase-4, and / or caspase-5, and / or modulation of caspase-1, caspase-4, and / or caspase-5, by administering a therapeutically effective amount of a compound herein. Treatment can include amelioration, alleviation, and / or prevention. In certain embodiments, the condition or disease associated with caspase-1, caspase-4, and / or caspase-5, and / or modulation of caspase-1, caspase-4, and / or caspase-5 is selected from autoinflammatory, autoimmune, inflammatory, CNS, liver, respiratory, cardiovascular, skin, rheumatic, renal, and cancer. In one embodiment, the condition or disease associated with caspase-1, caspase-4 and / or caspase-5 and / or the modulation of caspase-1, caspase-4 and / or caspase-5 is selected from autoinflammatory, autoimmune diseases, inflammatory diseases, CNS diseases, liver diseases, respiratory diseases, cardiovascular diseases, skin diseases, rheumatic diseases, renal diseases, ophthalmological diseases and cancer.

[0012] In one embodiment, the compositions described herein are useful for treating, preventing or ameliorating autoinflammatory, neuroinflammatory, autoimmune and other inflammatory conditions. In one embodiment, the compositions described herein are useful for treating liver diseases, particularly non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and viral hepatitis. In one embodiment, the compositions described herein are useful for treating gastrointestinal diseases, particularly inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease. In one embodiment, the compositions described herein are useful for treating CNS and neuroinflammatory diseases, particularly multiple sclerosis (MS), Alzheimer's disease, Huntington's disease (HD), Parkinson's disease (PD) and epilepsy. The compositions described herein are useful for treating cardiovascular and metabolic diseases, particularly myocardial infarction (MI), atherosclerosis, type 2 diabetes, and type 1 diabetes. In one embodiment, the compositions described herein are useful for treating kidney diseases, particularly acute kidney injury (AKI), glomerulonephritis, and lupus nephritis. In one embodiment, the compositions described herein are useful for treating skin diseases, particularly psoriasis and acne. In one embodiment, the compositions described herein are useful for treating rheumatic diseases, particularly rheumatoid arthritis (RA), osteoarthritis (OA), and gout. Exemplary specific autoimmune diseases to which the compounds described herein may be applied may also include systemic lupus erythematosus, polychondritis, edema sclerosis, Wegener's granulomatosis, dermatomyositis, Stevens-Johnson syndrome, endocrine ophthalmopathy, and Graves' disease.

[0013] In one embodiment, the compositions described herein are also useful for treating, preventing, or ameliorating asthma, steroid-resistant asthma, emphysema, and other obstructive or inflammatory airways diseases.

[0014] In one embodiment, the compositions described herein are also useful for treating, preventing, or ameliorating ophthalmic disorders, such as retinal degenerative disorders, such as age-related macular degeneration (AMD).

[0015] In one embodiment, the compositions described herein may be used to treat cancer.

[0016] In one embodiment, the present disclosure relates to the use of the compounds provided herein for the treatment and / or prevention of cancer. Exemplary cancers include colorectal cancer (CRC), melanoma, gastric cancer (including esophageal cancer), renal cell carcinoma (RCC), breast cancer, prostate cancer, head and neck cancer, bladder cancer, hepatocellular carcinoma (HCC), ovarian cancer, cervical cancer, endometrial cancer, pancreatic cancer, neuroendocrine cancer, hematological cancer (particularly multiple myeloma, acute myeloblastic leukemia (AML)), and biliary tract cancer.

[0017] In one embodiment, the compounds provide a therapy for improving the treatment of cancers that have at least a partial inflammatory basis. In one embodiment, the compounds are useful for the treatment and / or prevention of cancers that have at least a partial inflammatory basis. In another aspect, provided herein are specific clinical dosing regimens for the administration of the compounds for the treatment and / or prevention of cancer. In another aspect, the compounds provided herein are administered to a subject in need thereof with one or more therapeutic agents (e.g., chemotherapeutic agents) and / or the subject in some embodiments has undergone / will undergo tumor debulking surgery in addition to administration of the compounds herein.

[0018] In one embodiment, provided herein is a method of treating or preventing cancer in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein.

[0019] In one embodiment, provided herein is the use of a compound for the manufacture of a medicament for the treatment of cancer.

[0020] In some embodiments, the compounds provided herein are used to treat or prevent cryopyrin-associated periodic fever syndromes (CAPS), familial Mediterranean fever (FMF), systemic onset juvenile idiopathic arthritis (SJIA), hyperimmunoglobulin D syndrome (HIDS), and tumor necrosis factor receptor-associated periodic syndromes (TRAPS), among others, familial cold urticaria, neonatal-onset multisystem inflammatory disease, SJIA and FMF, and Muckle-Wells syndrome.

[0021] In practicing the method, an effective amount of a compound or composition, including a therapeutically effective concentration of the compound, is administered to an individual exhibiting symptoms of the disease or disorder to be treated, which amount is effective to bring about the amelioration or elimination of one or more symptoms of the disease or disorder.

[0022] Also provided is a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical composition. Optionally, such containers may be accompanied by a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, the notice reflecting approval by the agency for manufacture, use, or sale for human administration. The pack or kit may be labeled with information regarding the mode of administration, the order of drug administration (e.g., separately, sequentially, or simultaneously), etc.

[0023] These and other aspects of the subject matter described herein will become evident upon reference to the following detailed description. [Brief description of the drawings]

[0024] 5. BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 provides a dose-response study of the compound of Example 6 and the reference compound IDN-7314 for inhibition of IL-1β in THP-1 cells.

[0025] [Diagram 2]FIG. 2 provides the results of a dose-response study of the compound of Example 6 and the reference compound IDN-7314 on Fas-induced apoptosis in Jurkat cells.

[0026] [Diagram 3] FIG. 3 shows the in vivo inhibition of the proinflammatory cytokines IL-1β and IL-18 by the compound of Example 6 and the reference compound MCC950.

[0027] [Figure 4] FIG. 4 provides the effect of twice daily oral administration of the compound of Example 6 and a reference compound on preventing weight loss in an ulcerative colitis model.

[0028] [Diagram 5] FIG. 5 provides the effect of twice daily oral administration of the compound of Example 6 and a reference compound on colonic histological parameters in an ulcerative colitis model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] 6. Detailed Description of the Preferred Embodiments (6.1.Definition) Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.All patents, applications, published applications, and other publications are incorporated by reference in their entirety.In the present specification, if there are multiple definitions for a term, the definition in this section shall prevail unless otherwise stated.

[0030] As used herein, "halogen" refers to all halogens, i.e., the halogen substituent may be chloro (Cl), fluoro (F), bromo (Br) or iodo (I).

[0031] "Hydroxyl" or "hydroxy" refers to the group --OH.

[0032] "Thio" refers to the group -SH.

[0033] As used herein, "lower alkyl" refers to a group derived from an alkane containing 1 to 6 carbon atoms (unless otherwise defined), including straight-chain or branched alkyl. As used herein, the term "alkyl" refers to any straight-chain or branched C alkyl, such as methyl, ethyl, tert-butyl, iso-propyl, n-octyl, etc. 1 ~C 10 "lower alkyl" refers to a carbon chain. A straight or branched alkyl group is chemically available and may be attached at any available point to produce a stable compound. In an embodiment, lower alkyl is a straight or branched alkyl group containing 1-6, 1-4, or 1-2 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc. "Substituted lower alkyl" refers to a lower alkyl that is optionally independently substituted with one or more, e.g., 1, 2, 3, 4, or 5, as well as 1, 2, or 3, substituents, unless otherwise indicated, and may be attached at any available atom to produce a stable compound. Where the substituents are -F, -OH, -NH 2 , -NO 2 , -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH 2 , -C(S)-NH 2 , -S(O) 2 -NH 2 , -N(H)-C(O)-NH 2 , -N(H)-C(S)-NH 2 , -N(H)-S(O) 2 -NH 2 , -C(NH), -NH 2 , -OR o , -SR o , -OC(O)-R o , -OC(S)-R o , -C(O)-R o , -C(S)-R o , -C(O)-OR o , -C(S)-OR o , -S(O)-R o , -S(O) 2 -R o , -C(O)-N(H)-R o , -C(S)-N(H)-R o、-C(O)-N(R o )-R o 、-C(S)-N(R o )-R o 、-S(O) 2 -N(H)-R o 、-S(O) 2 -N(R o )-R o 、-C(NH)-N(H)-R o 、-C(NH)-N(R p )-R c 、-N(H)-C(O)-R o 、-N(H)-C(S)-R o 、-N(R o )-C(O)-R o 、-N(R o )-C(S)-R o 、-N(H)-S(O) 2 -R o 、-N(R o )-S(O) 2 -R o 、-N(H)-C(O)-N(H)-R o 、-N(H)-C(S)-N(H)-R o 、-N(R o )-C(O)-NH 2 、-N(R o )-C(S)-NH 2 、-N(R o )-C(O)-N(H)-R o 、-N(R o )-C(S)-N(H)-R o 、-N(H)-C(O)-N(R o )-R o 、-N(H)-C(S)-N(R o )-R o 、-N(R o )-C(O)-N(R o )-R o 、-N(R o )-C(S)-N(R o )-R o 、-N(H)-S(O) 2 -N(H)-R o 、-N(R o )-S(O) 2 -NH 2 、-N(Ro )-S(O) 2 -N(H)-R o , -N(H)-S(O) 2 -N(R o )-R o , -N(R o )-S(O) 2 -N(R o )-R o , -N(H)-R o , -N(R o )-R o , -R c , -R f , and -R g is selected from the group consisting of:

[0034] "Alkylene" refers to a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen without unsaturation. "Lower alkylene" refers to a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen without unsaturation having 1 to 6 carbon atoms, for example, methylene, ethylene, propylene, n-butylene, etc. In certain embodiments, alkylene and lower alkylene are substituted with one or more of the substituents described above in the definition of alkyl groups.

[0035] The term "lower alkenyl," alone or in combination, refers to a straight or branched chain hydrocarbon containing 2 to 6 carbon atoms (unless otherwise defined) and at least one, 1 to 3, 1 to 2, or only one carbon-carbon double bond. The term "alkenyl" refers to a straight or branched chain hydrocarbon containing at least one, 1 to 3, 1 to 2, or only one carbon-carbon double bond. 1 ~C 10"lower alkenyl" refers to a carbon chain. Carbon-carbon double bonds may be contained in either the straight-chain or branched portion. A straight-chain or branched lower alkenyl group is chemically available and may be attached at any possible point to produce a stable compound. Examples of lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like. "Substituted lower alkenyl" refers to a lower alkenyl that is optionally independently substituted with one or more, e.g., 1, 2, 3, 4, or 5, as well as 1, 2, or 3, substituents, unless otherwise indicated, and may be attached at any possible atom to produce a stable compound. Where the substituents are -F, -OH, -NH 2 , -NO 2 , -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH 2 , -C(S)-NH 2 , -S(O) 2 -NH 2 , -N(H)-C(O)-NH 2 , -N(H)-C(S)-NH 2 , -N(H)-S(O) 2 -NH 2 , -C(NH)-NH 2 , -OR o , -SR o , -OC(O)-R o , -OC(S)-R o , -C(O)-R o , -C(S)-R o , -C(O)-OR o , -C(S)-OR o , -S(O)-R o , -S(O) 2 -R o , -C(O)-N(H)-R o , -C(S)-N(H)-R o , -C(O)-N(R o )-R o , -C(S)-N(R o )-R o , -S(O) 2 -N(H)-R o , -S(O) 2 -N(R o )-R o , -C(NH)-N(H)-Ro 、-C(NH)-N(R p )-R c 、-N(H)-C(O)-R o 、-N(H)-C(S)-R o 、-N(R o )-C(O)-R o 、-N(R o )-C(S)-R o 、-N(H)-S(O) 2 -R o 、-N(R o )-S(O) 2 -R o 、-N(H)-C(O)-N(H)-R o 、-N(H)-C(S)-N(H)-R o 、-N(R o )-C(O)-NH 2 、-N(R o )-C(S)-NH 2 、-N(R o )-C(O)-N(H)-R o 、-N(R o )-C(S)-N(H)-R o 、-N(H)-C(O)-N(R o )-R o 、-N(H)-C(S)-N(R o )-R o 、-N(R o )-C(O)-N(R o )-R o 、-N(R o )-C(S)-N(R o )-R o 、-N(H)-S(O) 2 -N(H)-R o 、-N(R o )-S(O) 2 -NH 2 、-N(R o )-S(O) 2 -N(H)-R o 、-N(H)-S(O) 2 -N(R o )-R o 、-N(R o )-S(O) 2 -N(R o )-R o 、-N(H)-Ro , -N(R o )-R o , -R d , -R f , and -R g is selected from the group consisting of:

[0036] The term "lower alkynyl," alone or in combination, refers to a straight or branched chain hydrocarbon containing 2 to 6 carbon atoms (unless otherwise defined) and at least one, or only one, carbon-carbon triple bond. The term "alkynyl" refers to a straight or branched chain hydrocarbon containing at least one, or only one, carbon-carbon triple bond. 1 ~C 10 means a carbon chain. A straight or branched lower alkynyl group is chemically available and may be attached at any available point to produce a stable compound. Examples of alkynyl groups include ethynyl, propynyl, butynyl, and the like. "Substituted lower alkynyl" refers to a lower alkynyl group that is optionally independently substituted with one or more, e.g., 1, 2, 3, 4, or 5, as well as 1, 2, or 3, substituents, unless otherwise indicated, and may be attached at any available atom to produce a stable compound. Where the substituents are -F, -OH, -NH 2 , -NO 2 , -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH 2 , -C(S)-NH 2 , -S(O) 2 -NH 2 , -N(H)-C(O)-NH 2 , -N(H)-C(S)-NH 2 , -N(H)-S(O) 2 -NH 2 , -C(NH)-NH 2 , -OR o , -SR o , -OC(O)-R o , -OC(S)-R o , -C(O)-R o , -C(S)-R o , -C(O)-OR o , -C(S)-OR o , -S(O)-R o , -S(O)2 -R o 、-C(O)-N(H)-R o 、-C(S)-N(H)-R o 、-C(O)-N(R o )-R o 、-C(S)-N(R o )-R o 、-S(O) 2 -N(H)-R o 、-S(O) 2 -N(R o )-R o 、-C(NH)-N(H)-R o 、-C(NH)-N(R p )-R c 、-N(H)-C(O)-R o 、-N(H)-C(S)-R o 、-N(R o )-C(O)-R o 、-N(R o )-C(S)-R o 、-N(H)-S(O) 2 -R o 、-N(R o )-S(O) 2 -R o 、-N(H)-C(O)-N(H)-R o 、-N(H)-C(S)-N(H)-R o 、-N(R o )-C(O)-NH 2 、-N(R o )-C(S)-NH 2 、-N(R o )-C(O)-N(H)-R o 、-N(R o )-C(S)-N(H)-R o 、-N(H)-C(O)-N(R o )-R o 、-N(H)-C(S)-N(R o )-R o 、-N(R o )-C(O)-N(R o )-R o 、-N(R o )-C(S)-N(R o )-R o 、-N(H)-S(O) 2 -N(H)-Ro , -N(R o )-S(O) 2 -NH 2 , -N(R o )-S(O) 2 -N(H)-R o , -N(H)-S(O) 2 -N(R o )-R o , -N(R o )-S(O) 2 -N(R o )-R o , -N(H)-R o , -N(R o )-R o , -R d , -R e , and -R g is selected from the group consisting of:

[0037] "Cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic, bicyclic or tricyclic carbocyclic ring system having 3 to 10, as well as 3 to 8 or 3 to 6 ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, cis- or trans-decalin, bicyclo[2.2.1]hept-2-ene, cyclohex-1-enyl, cyclopent-1-enyl, 1,4-cyclooctadienyl, and the like. The term "(cycloalkyl)alkyl" refers to an alkyl group as defined above substituted with a cycloalkyl ring. Examples of such groups include (cyclohexyl)methyl, 3-(cyclopropyl)-n-propyl, 5-(cyclopentyl)hexyl, 6-(adamantyl)hexyl, and the like.

[0038] "Substituted cycloalkyl" means, unless otherwise indicated, cycloalkyl that is optionally independently substituted with one or more, e.g., 1, 2, 3, 4, or 5, as well as 1, 2, or 3, substituents, attached at any available atom to produce a stable compound, where the substituents are halogen, -OH, -NH 2 , -NO 2 , -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH 2 , -C(S)-NH2 、-S(O) 2 -NH 2 、-N(H)-C(O)-NH 2 、-N(H)-C(S)-NH 2 、-N(H)-S(O) 2 -NH 2 、-C(NH)-NH 2 、-O-R o 、-S-R o 、-O-C(O)-R o 、-O-C(S)-R o 、-C(O)-R o 、-C(S)-R o 、-C(O)-O-R o 、-C(S)-O-R o 、-S(O)-R o 、-S(O) 2 -R o 、-C(O)-N(H)-R o 、-C(S)-N(H)-R o 、-C(O)-N(R o )-R o 、-C(S)-N(R o )-R o 、-S(O) 2 -N(H)-R o 、-S(O) 2 -N(R o )-R o 、-C(NH)-N(H)-R o 、-C(NH)-N(R p )-R c 、-N(H)-C(O)-R o 、-N(H)-C(S)-R o 、-N(R o )-C(O)-R o 、-N(R o )-C(S)-R o 、-N(H)-S(O) 2 -R o 、-N(R o )-S(O) 2 -R o 、-N(H)-C(O)-N(H)-R o 、-N(H)-C(S)-N(H)-R o 、-N(R o )-C(O)-NH 2, -N(R o )-C(S)-NH 2 , -N(R o )-C(O)-N(H)-R o , -N(R o )-C(S)-N(H)-R o , -N(H)-C(O)-N(R o )-R o , -N(H)-C(S)-N(R o )-R o , -N(R o )-C(O)-N(R o )-R o , -N(R o )-C(S)-N(R o )-R o , -N(H)-S(O) 2 -N(H)-R o , -N(R o )-S(O) 2 -NH 2 , -N(R o )-S(O) 2 -N(H)-R o , -N(H)-S(O) 2 -N(R o )-R o , -N(R o )-S(O) 2 -N(R o )-R o , -N(H)-R o , -N(R o )-R o , -R d , -R e , -R f , and -R g For example, "C 3-6 "Cycloalkyl" refers to a cycloalkyl containing 3 to 6 carbon atoms, 3-5 "Cycloalkyl" refers to a cycloalkyl containing 3 to 5 carbon atoms.

[0039] "Heterocycloalkyl" refers to a saturated or unsaturated non-aromatic cycloalkyl group containing 5 to 10 atoms, in which 1 to 3 carbon atoms in the ring are replaced with heteroatoms O, S, or N, and is optionally fused to a 5- to 6-membered benzo or heteroaryl. Heterocycloalkyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxide of a tertiary ring nitrogen. Heterocycloalkyl is also intended to include compounds in which ring carbons may be oxo-substituted, i.e., ring carbons are carbonyl groups, lactones, lactams, and the like. The attachment point of the heterocycloalkyl ring is at a carbon or nitrogen atom such that a stable ring is maintained. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl. "Nitrogen-containing heterocycloalkyl" refers to a heterocycloalkyl in which at least one heteroatom is N. The term "(heterocycloalkyl)alkyl" refers to an alkyl group as defined above substituted with a heterocycloalkyl ring.

[0040] A "substituted heterocycloalkyl," unless otherwise indicated, is a heterocycloalkyl that is optionally independently substituted with one or more, e.g., 1, 2, 3, 4, or 5, as well as 1, 2, or 3, substituents, attached at any available atom to produce a stable compound, where the substituents are halogen, -OH, -NH 2 , -NO 2 , -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH 2 , -C(S)-NH 2 , -S(O) 2 -NH 2 , -N(H)-C(O)-NH 2 , -N(H)-C(S)-NH 2 , -N(H)-S(O) 2 -NH 2 , -C(NH)-NH 2 , -OR o , -SR o , -OC(O)-Ro 、-O-C(S)-R o 、-C(O)-R o 、-C(S)-R o 、-C(O)-O-R o 、-C(S)-O-R o 、-S(O)-R o 、-S(O) 2 -R o 、-C(O)-N(H)-R o 、-C(S)-N(H)-R o 、-C(O)-N(R o )-R o 、-C(S)-N(R o )-R o 、-S(O) 2 -N(H)-R o 、-S(O) 2 -N(R o )-R o 、-C(NH)-N(H)-R o 、-C(NH)-N(R p )-R c 、-N(H)-C(O)-R o 、-N(H)-C(S)-R o 、-N(R o )-C(O)-R o 、-N(R o )-C(S)-R o 、-N(H)-S(O) 2 -R o 、-N(R o )-S(O) 2 -R o 、-N(H)-C(O)-N(H)-R o 、-N(H)-C(S)-N(H)-R o 、-N(R o )-C(O)-NH 2 、-N(R o )-C(S)-NH 2 、-N(R o )-C(O)-N(H)-R o 、-N(R o )-C(S)-N(H)-R o 、-N(H)-C(O)-N(R o )-R o 、-N(H)-C(S)-N(R o )-Ro , -N(R o )-C(O)-N(R o )-R o , -N(R o )-C(S)-N(R o )-R o , -N(H)-S(O) 2 -N(H)-R o , -N(R o )-S(O) 2 -NH 2 , -N(R o )-S(O) 2 -N(H)-R o , -N(H)-S(O) 2 -N(R o )-R o , -N(R o )-S(O) 2 -N(R o )-R o , -N(H)-R o , -N(R o )-R o , -R d , -R e , -R f , and -R g is selected from the group consisting of:

[0041] "Aryl," alone or in combination, refers to a monocyclic or bicyclic ring system containing an aromatic hydrocarbon, such as phenyl or naphthyl, optionally fused to a cycloalkyl, e.g., 5-7 ring members, or, e.g., 5-6 ring members. "Substituted aryl," unless otherwise indicated, is an aryl that is optionally independently substituted with one or more, e.g., 1, 2, 3, 4, or 5, as well as 1, 2, or 3, substituents, attached at any available atom to produce a stable compound, where the substituents are halogen, -OH, -NH 2 , -NO 2 , -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH 2 , -C(S)-NH 2 , -S(O) 2 -NH 2 , -N(H)-C(O)-NH 2 , -N(H)-C(S)-NH2 、-N(H)-S(O) 2 -NH 2 、-C(NH)-NH 2 、-O-R o 、-S-R o 、-O-C(O)-R o 、-O-C(S)-R o 、-C(O)-R o 、-C(S)-R o 、-C(O)-O-R o 、-C(S)-O-R o 、-S(O)-R o 、-S(O) 2 -R o 、-C(O)-N(H)-R o 、-C(S)-N(H)-R o 、-C(O)-N(R o )-R o 、-C(S)-N(R o )-R o 、-S(O) 2 -N(H)-R o 、-S(O) 2 -N(R o )-R o 、-C(NH)-N(H)-R o 、-C(NH)-N(R p )-R c 、-N(H)-C(O)-R o 、-N(H)-C(S)-R o 、-N(R o )-C(O)-R o 、-N(R o )-C(S)-R o 、-N(H)-S(O) 2 -R o 、-N(R o )-S(O) 2 -R o 、-N(H)-C(O)-N(H)-R o 、-N(H)-C(S)-N(H)-R o 、-N(R o )-C(O)-NH 2 、-N(R o )-C(S)-NH 2 、-N(R o )-C(O)-N(H)-R o 、-N(Ro )-C(S)-N(H)-R o 、-N(H)-C(O)-N(R o )-R o 、-N(H)-C(S)-N(R o )-R o 、-N(R o )-C(O)-N(R o )-R o 、-N(R o )-C(S)-N(R o )-R o 、-N(H)-S(O) 2 -N(H)-R o 、-N(R o )-S(O) 2 -NH 2 、-N(R o )-S(O) 2 -N(H)-R o 、-N(H)-S(O) 2 -N(R o )-R o 、-N(R o )-S(O) 2 -N(R o )-R o 、-N(H)-R o 、-N(R o )-R o 、-R d 、-R e 、-R f 、けき-R gIn some embodiments, the substituents are selected from the group consisting of halo, trihalomethyl, amino, protected amino, amino salt, monosubstituted amino, disubstituted amino, carboxy, protected carboxy, carboxylate, hydroxy, protected hydroxy, salt of a hydroxy group, lower alkoxy, lower alkylthio, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, (cycloalkyl)alkyl, substituted (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, and substituted phenylalkyl groups. In some embodiments, the substituents are selected from trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl. In some embodiments, the substituents are one or more trifluoromethyl.

[0042] The term "substituted phenyl" refers to a phenyl group substituted with one or more substituents selected from the "aryl" substituents specified above. In an embodiment, the substituents are selected from halogen, hydroxy, protected hydroxy, cyano, nitro, trifluoromethyl, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(lower alkyl)carboxamide, protected N-(lower alkyl)carboxamide, N,N-di(lower alkyl)carboxamide, N-((lower alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino, or a substituted or unsubstituted phenyl group, the latter being selected to be a biphenyl or naphthyl group. Examples of the term "substituted phenyl" include mono-, di-, tri- or tetra(halo)phenyl groups, such as 2-, 3- or 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3,5-trichlorophenyl, 2,3,5,6-tetrachlorophenyl, 2-, 3- or 4-bromophenyl, 2,6-dibromophenyl, 2,5-dibromophenyl, 3,4-dibromophenyl, 2,3,5-tribromophenyl, 2,3,5,6-tetrabromo ... 4-fluorophenyl, 2,6-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 2,3,5-trifluorophenyl, 2,3,5,6-tetrafluorophenyl, 3-chloro-4-fluorophenyl, etc.; mono- or di(hydroxy)phenyl groups, for example 2-, 3- or 4-hydroxyphenyl, 2,4-dihydroxyphenyl, protected hydroxy derivatives thereof, etc.; nitrophenyl groups, for example 2-, 3- or 4-nitrophenyl; cyanophenyl groups, for example 2-, 3- or 4-cyanophenyl;mono- or di(alkyl)phenyl groups, such as 2-, 3- or 4-methylphenyl, 2,4-dimethylphenyl, 2-, 3- or 4-(isopropyl)phenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4-(n-propyl)phenyl, etc.; mono- or di(alkoxy)phenyl groups, such as 2,6-dimethoxyphenyl, 2-, 3- or 4-(isopropoxy)phenyl, 2-, 3- or 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl, etc.; 2-, 3- or 4-trifluoromethylphenyl; mono- or dicarboxyphenyl or (protected carboxyphenyl groups, such as 2-, 3- or 4-carboxyphenyl, etc. or 2,4-di(protected carboxy)phenyl; mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl, such as 2-, 3- or 4-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or mono- or di(N-(methylsulfonylamino))phenyl, such as 2-, 3- or 4-(N-(methylsulfonylamino))phenyl. The term "substituted phenyl" also refers to phenyl groups disubstituted with different substituents, such as 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl, etc.;

[0043] The term "arylalkyl" means an aryl group bonded to one of the alkyl groups described above, and the term "substituted arylalkyl" means either an aryl or an alkyl, or both, substituted with one or more substituents defined above. Examples of "arylalkyl" substituents include, for example, phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylisopropyl, and the like. Examples of "substituted phenyl" groups include 2-phenyl-1-chloroethyl, 2-(4'-methoxyphenyl)ethyl, 4-(2',6'-dihydroxyphenyl)n-hexyl, 2-(5'-cyano-3'-methoxyphenyl)n-pentyl, 3-(2',6'-dimethylphenyl)n-propyl, 4-chloro-3-aminobenzyl, 6-(4'-methoxyphenyl)-3-carboxy(n-hexyl), 5-(4'-aminomethylphenyl)-3-(aminomethyl)n-pentyl, 5-phenyl-3-oxo-n-pent-1-yl, (4-hydroxynaphth-2-yl)methyl, and the like.

[0044] "Heteroaryl," alone or in combination, refers to a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8-10 atoms, containing one or more, e.g., 1-4, 1-3, or 1-2 heteroatoms independently selected from the group consisting of O, S, and N, and optionally fused to a cycloalkyl, e.g., 5-7 ring members, or, e.g., 5-6 ring members. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced. Examples of heteroaryl groups (either substituted or unsubstituted) include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, pyrrolidinyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, pyridyl, oxazinyl, triazinyl, thiadiazinyltetrazolo, 1,5-[b]pyridazinyl and purinyl, as well as benzo-fused derivatives such as benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuryl and indolyl. "Nitrogen-containing heteroaryl" refers to a heteroaryl in which at least one heteroatom is N. In some cases, for example, when a nitrogen R group combines with the nitrogen to form a 5- or 7-membered nitrogen-containing heteroaryl, any heteroatom in such 5- or 7-membered heteroaryl is N. An "optionally substituted heteroaryl," unless otherwise indicated, is a heteroaryl that is optionally substituted independently with one or more, e.g., 1, 2, 3, 4, or 5, as well as 1, 2, or 3, substituents, attached at any available atom to produce a stable compound, where the substituents are halogen, -CF 3 , -OH, -NH 2 , -NO 2 , -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH2 、-C(S)-NH 2 、-S(O) 2 -NH 2 、-N(H)-C(O)-NH 2 、-N(H)-C(S)-NH 2 、-N(H)-S(O) 2 -NH 2 、-C(NH)-NH 2 、-O-R o 、-S-R o 、-O-C(O)-R o 、-O-C(S)-R o 、-C(O)-R o 、-C(S)-R o 、-C(O)-O-R o 、-C(S)-O-R o 、-S(O)-R o 、-S(O) 2 -R o 、-C(O)-N(H)-R o 、-C(S)-N(H)-R o 、-C(O)-N(R o )-R o 、-C(S)-N(R o )-R o 、-S(O) 2 -N(H)-R o 、-S(O) 2 -N(R o )-R o 、-C(NH)-N(H)-R o 、-C(NH)-N(R p )-R c 、-N(H)-C(O)-R o 、-N(H)-C(S)-R o 、-N(R o )-C(O)-R o 、-N(R o )-C(S)-R o 、-N(H)-S(O) 2 -R o 、-N(R o )-S(O) 2 -R o 、-N(H)-C(O)-N(H)-R o 、-N(H)-C(S)-N(H)-R o 、-N(R o)-C(O)-NH 2 ,-N(R o )-C(S)-NH 2 ,-N(R o )-C(O)-N(H)-R o ,-N(R o )-C(S)-N(H)-R o ,-N(H)-C(O)-N(R o )-R o ,-N(H)-C(S)-N(R o )-R o ,-N(R o )-C(O)-N(R o )-R o ,-N(R o )-C(S)-N(R o )-R o ,-N(H)-S(O) 2 -N(H)-R o ,-N(R o )-S(O) 2 -NH 2 ,-N(R o )-S(O) 2 -N(H)-R o ,-N(H)-S(O) 2 -N(R o )-R o ,-N(R o )-S(O) 2 -N(R o )-R o ,-N(H)-R o ,-N(R o )-R o ,-R d ,-R e ,-R f ,-and -R g is selected from the group consisting of.

[0045] Substituents for the optionally substituted heteroaryl rings are set forth above, for example for the "aryl" and "phenyl" groups. In certain embodiments, the substituents are selected from one to three of halo, trihalomethyl, amino, protected amino, amino salt, monosubstituted amino, disubstituted amino, carboxy, protected carboxy, carboxylate, hydroxy, protected hydroxy, salt of a hydroxy group, lower alkoxy, lower alkylthio, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, (cycloalkyl)alkyl, substituted (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, and substituted phenylalkyl groups.

[0046] As used herein, "pyridyl" refers to a 6-membered aromatic ring having one "N" atom. As used herein, "pyridazinyl" refers to a 6-membered aromatic ring having two "N" atoms at positions 1 and 2, "pyrimidyl" refers to a 6-membered aromatic ring having two "N" atoms at positions 1 and 3, and "pyrazinyl" refers to a 6-membered aromatic ring having two "N" atoms at positions 1 and 4.

[0047] Substituents for the "pyridyl", "pyridazinyl", "pyrimidyl" and "pyrazinyl" groups defined above are as set forth above for the "aryl", "phenyl," and "heteroaryl" groups, for example. In some embodiments, the substituents are selected from one to three of halo, trihalomethyl, amino, protected amino, amino salt, monosubstituted amino, disubstituted amino, carboxy, protected carboxy, carboxylate, hydroxy, protected hydroxy, salt of a hydroxy group, lower alkoxy, lower alkylthio, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, (cycloalkyl)alkyl, substituted (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, and substituted phenylalkyl groups. In some embodiments, the substituents are selected from trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl. In some embodiments, the substituents are one or more trifluoromethyl.

[0048] The variable R used in describing the optional substituents for alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, phenyl, napthyl, and heteroaryl. o , R p , R c , R d , R e , R f and R g is defined as follows: Each R o , R p and R c is independently R d , R e , R f and R g or R p and R c are combined with the nitrogen to which they are attached to form a 5- to 7-membered heterocycloalkyl or a 5- or 7-membered nitrogen-containing heteroaryl, which 5- to 7-membered heterocycloalkyl or 5- or 7-membered nitrogen-containing heteroaryl is selected from the group consisting of halogen, -NO 2, -CN, -OH, -NH 2 , -OR u , -SR u , -N(H)-R u , -N(R u )-R u , -R x , and -R y optionally substituted with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2 or 3, substituents selected from the group consisting of: Each R d is independently lower alkyl, and the lower alkyl is selected from fluoro, -OH, -NH 2 , -NO 2 , -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH 2 , -C(S)-NH 2 , -S(O) 2 -NH 2 , -N(H)-C(O)-NH 2 , -N(H)-C(S)-NH 2 , -N(H)-S(O) 2 -NH 2 , -C(NH)-NH 2 , -OR k , -SR k , -OC(O)-R k , -OC(S)-R k , -C(O)-R k , -C(S)-R k , -C(O)-OR k , -C(S)-OR k , -S(O)-R k , -S(O) 2 -R k , -C(O)-N(H)-R k , -C(S)-N(H)-R k , -C(O)-N(R k )-R k , -C(S)-N(R k )-R k , -S(O) 2 -N(H)-R k , -S(O) 2 -N(R k )-R k , -C(NH)-N(H)-Rk 、-C(NH)-N(R m )-R n 、-N(H)-C(O)-R k 、-N(H)-C(S)-R k 、-N(R k )-C(O)-R k 、-N(R k )-C(S)-R k 、-N(H)-S(O) 2 -R k 、-N(R k )-S(O) 2 -R k 、-N(H)-C(O)-N(H)-R k 、-N(H)-C(S)-N(H)-R k 、-N(R k )-C(O)-NH 2 、-N(R k )-C(S)-NH 2 、-N(R k )-C(O)-N(H)-R k 、-N(R k )-C(S)-N(H)-R k 、-N(H)-C(O)-N(R k )-R k 、-N(H)-C(S)-N(R k )-R k 、-N(R k )-C(O)-N(R k )-R k 、-N(R k )-C(S)-N(R k )-R k 、-N(H)-S(O) 2 -N(H)-R k 、-N(R k )-S(O) 2 -NH 2 、-N(R k )-S(O) 2 -N(H)-R k 、-N(H)-S(O) 2 -N(R k )-R k 、-N(R k )-S(O) 2 -N(R k )-R k 、-N(H)-Rk , -N(R k )-R k , -R i , and -R j optionally substituted with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2 or 3, substituents selected from the group consisting of: Each R e is independently lower alkenyl, and the lower alkenyl is selected from fluoro, -OH, -NH 2 , -NO 2 , -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH 2 , -C(S)-NH 2 , -S(O) 2 -NH 2 , -N(H)-C(O)-NH 2 , -N(H)-C(S)-NH 2 , -N(H)-S(O) 2 -NH 2 , -C(NH)-NH 2 , -OR k , -SR k , -OC(O)-R k , -OC(S)-R k , -C(O)-R k , -C(S)-R k , -C(O)-OR k , -C(S)-OR k , -S(O)-R k , -S(O) 2 -R k , -C(O)-N(H)-R k , -C(S)-N(H)-R k , -C(O)-N(R k )-R k , -C(S)-N(R k )-R k , -S(O) 2 -N(H)-R k , -S(O) 2 -N(R k )-R k , -C(NH)-N(H)-R k , -C(NH)-N(R m )-R n , -N(H)-C(O)-R k、-N(H)-C(S)-R k 、-N(R k )-C(O)-R k 、-N(R k )-C(S)-R k 、-N(H)-S(O) 2 -R k 、-N(R k )-S(O) 2 -R k 、-N(H)-C(O)-N(H)-R k 、-N(H)-C(S)-N(H)-R k 、-N(R k )-C(O)-NH 2 、-N(R k )-C(S)-NH 2 、-N(R k )-C(O)-N(H)-R k 、-N(R k )-C(S)-N(H)-R k 、-N(H)-C(O)-N(R k )-R k 、-N(H)-C(S)-N(R k )-R k 、-N(R k )-C(O)-N(R k )-R k 、-N(R k )-C(S)-N(R k )-R k 、-N(H)-S(O) 2 -N(H)-R k 、-N(R k )-S(O) 2 -NH 2 、-N(R k )-S(O) 2 -N(H)-R k 、-N(H)-S(O) 2 -N(R k )-R k 、-N(R k )-S(O) 2 -N(R k )-R k 、-N(H)-R k 、-N(R k )-R k 、-R h 、けき-R joptionally substituted with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2 or 3, substituents selected from the group consisting of: Each R f is independently lower alkynyl, and the lower alkynyl is selected from fluoro, -OH, -NH 2 , -NO 2 , -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH 2 , -C(S)-NH 2 , -S(O) 2 -NH 2 , -N(H)-C(O)-NH 2 , -N(H)-C(S)-NH 2 , -N(H)-S(O) 2 -NH 2 , -C(NH)-NH 2 , -OR k , -SR k , -OC(O)-R k , -OC(S)-R k , -C(O)-R k , -C(S)-R k , -C(O)-OR k , -C(S)-OR k , -S(O)-R k , -S(O) 2 -R k , -C(O)-N(H)-R k , -C(S)-N(H)-R k , -C(O)-N(R k )-R k , -C(S)-N(R k )-R k , -S(O) 2 -N(H)-R k , -S(O) 2 -N(R k )-R k , -C(NH)-N(H)-R k , -C(NH)-N(R m )-R n , -N(H)-C(O)-R k , -N(H)-C(S)-R k , -N(R k )-C(O)-R k , -N(Rk )-C(S)-R k , -N(H)-S(O) 2 -R k , -N(R k )-S(O) 2 -R k , -N(H)-C(O)-N(H)-R k , -N(H)-C(S)-N(H)-R k , -N(R k )-C(O)-NH 2 , -N(R k )-C(S)-NH 2 , -N(R k )-C(O)-N(H)-R k , -N(R k )-C(S)-N(H)-R k , -N(H)-C(O)-N(R k )-R k , -N(H)-C(S)-N(R k )-R k , -N(R k )-C(O)-N(R k )-R k , -N(R k )-C(S)-N(R k )-R k , -N(H)-S(O) 2 -N(H)-R k , -N(R k )-S(O) 2 -NH 2 , -N(R k )-S(O) 2 -N(H)-R k , -N(H)-S(O) 2 -N(R k )-R k , -N(R k )-S(O) 2 -N(R k )-R k , -N(H)-R k , -N(R k )-R k , -R h , and -R j optionally substituted with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2 or 3, substituents selected from the group consisting of: Each R g is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH 2 , -C(S)-NH 2 , -S(O) 2 -NH 2 , -N(H)-C(O)-NH 2 , -N(H)-C(S)-NH 2 , -N(H)-S(O) 2 -NH 2 , -C(NH)-NH 2 , -OR k , -OC(O)-R k , -OC(S)-R k , -C(O)-R k , -C(S)-R k , -C(O)-OR k , -C(S)-OR k , -S(O)-R k , -S(O) 2 -R k , -C(O)-N(H)-R k , -C(S)-N(H)-R k , -C(O)-N(R k )-R k , -C(S)-N(R k )-R k , -S(O) 2 -N(H)-R k , -S(O) 2 -N(R k )-R k , -C(NH)-N(H)-R k , -C(NH)-N(R m )-R n , -N(H)-C(O)-R k , -N(H)-C(S)-R k , -N(R k )-C(O)-R k , -N(R k )-C(S)-R k, -N(H)-S(O) 2 -R k , -N(R k )-S(O) 2 -R k , -N(H)-C(O)-N(H)-R k , -N(H)-C(S)-N(H)-R k , -N(R k )-C(O)-NH 2 , -N(R k )-C(S)-NH 2 , -N(R k )-C(O)-N(H)-R k , -N(R k )-C(S)-N(H)-R k , -N(H)-C(O)-N(R k )-R k , -N(H)-C(S)-N(R k )-R k , -N(R k )-C(O)-N(R k )-R k , -N(R k )-C(S)-N(R k )-R k , -N(H)-S(O) 2 -N(H)-R k , -N(R k )-S(O) 2 -NH 2 , -N(R k )-S(O) 2 -N(H)-R k , -N(H)-S(O) 2 -N(R k )-R k , -N(R k )-S(O) 2 -N(R k )-R k , -N(H)-R k , -N(R k )-R k , -R h , -R i , and -R j optionally substituted with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2 or 3, substituents selected from the group consisting of: 〇Here, Rk , R m , and R n is independent in each case, R h , R i , and R j or R m and R n are combined with the nitrogen to which they are attached to form a 5- to 7-membered heterocycloalkyl or a 5- or 7-membered nitrogen-containing heteroaryl, and the 5- to 7-membered heterocycloalkyl or the 5- or 7-membered nitrogen-containing heteroaryl are each independently selected from the group consisting of halogen, -NO 2 , -CN, -OH, -NH 2 , -OR u , -SR u , -N(H)-R u , -NR u R u , -R x , and -R y optionally substituted with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2 or 3, substituents selected from the group consisting of: Here, each R h are independently lower alkyl, fluoro, -OH, -NH 2 , -NO 2 , -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH 2 , -C(S)-NH 2 , -S(O) 2 -NH 2 , -N(H)-C(O)-NH 2 , -N(H)-C(S)-NH 2 , -N(H)-S(O) 2 -NH 2 , -C(NH)-NH 2 , -OR r , -SR r , -OC(O)-R r , -OC(S)-R r , -C(O)-R r , -C(S)-R r , -C(O)-OR r , -C(S)-OR r , -S(O)-R r , -S(O)2 -R r 、-C(O)-N(H)-R r 、-C(S)-N(H)-R r 、-C(O)-N(R r )-R r 、-C(S)-N(R r )-R r 、-S(O) 2 -N(H)-R r 、-S(O) 2 -N(R r )-R r 、-C(NH)-N(H)-R r 、-C(NH)-N(R s )-R t 、-N(H)-C(O)-R r 、-N(H)-C(S)-R r 、-N(R r )-C(O)-R r 、-N(R r )-C(S)-R r 、-N(H)-S(O) 2 -R r 、-N(R r )-S(O) 2 -R r 、-N(H)-C(O)-N(H)-R r 、-N(H)-C(S)-N(H)-R r 、-N(R r )-C(O)-NH 2 、-N(R r )-C(S)-NH 2 、-N(R r )-C(O)-N(H)-R r 、-N(R r )-C(S)-N(H)-R r 、-N(H)-C(O)-N(R r )-R r 、-N(H)-C(S)-N(R r )-R r 、-N(R r )-C(O)-N(R r )-R r 、-N(R r )-C(S)-N(R r )-R r 、-N(H)-S(O) 2 -N(H)-Rr , -N(R r )-S(O) 2 -NH 2 , -N(R r )-S(O) 2 -N(H)-R r , -N(H)-S(O) 2 -N(R r )-R r , -N(R r )-S(O) 2 -N(R r )-R r , -N(H)-R r , -N(R r )-R r , -R i , and -R j optionally substituted with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2 or 3, substituents selected from the group consisting of: Here, each R i is independently selected from the group consisting of lower alkenyl and lower alkynyl, where the lower alkenyl or lower alkynyl is selected from fluoro, -OH, -NH 2 , -NO 2 , -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH 2 , -C(S)-NH 2 , -S(O) 2 -NH 2 , -N(H)-C(O)-NH 2 , -N(H)-C(S)-NH 2 , -N(H)-S(O) 2 -NH 2 , -C(NH)-NH 2 , -OR r , -SR r , -OC(O)-R r , -OC(S)-R r , -C(O)-R r , -C(S)-R r , -C(O)-OR r , -C(S)-OR r , -S(O)-R r , -S(O) 2 -R r , -C(O)-N(H)-Rr 、-C(S)-N(H)-R r 、-C(O)-N(R r )-R r 、-C(S)-N(R r )-R r 、-S(O) 2 -N(H)-R r 、-S(O) 2 -N(R r )-R r 、-C(NH)-N(H)-R r 、-C(NH)-N(R s )-R t 、-N(H)-C(O)-R r 、-N(H)-C(S)-R r 、-N(R r )-C(O)-R r 、-N(R r )-C(S)-R r 、-N(H)-S(O) 2 -R r 、-N(R r )-S(O) 2 -R r 、-N(H)-C(O)-N(H)-R r 、-N(H)-C(S)-N(H)-R r 、-N(R r )-C(O)-NH 2 、-N(R r )-C(S)-NH 2 、-N(R r )-C(O)-N(H)-R r 、-N(R r )-C(S)-N(H)-R r 、-N(H)-C(O)-N(R r )-R r 、-N(H)-C(S)-N(R r )-R r 、-N(R r )-C(O)-N(R r )-R r 、-N(R r )-C(S)-N(R r )-R r 、-N(H)-S(O) 2 -N(H)-R r 、-N(R r )-S(O)2 -NH 2 , -N(R r )-S(O) 2 -N(H)-R r , -N(H)-S(O) 2 -N(R r )-R r , -N(R r )-S(O) 2 -N(R r )-R r , -N(H)-R r , -N(R r )-R r , and -R j optionally substituted with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2 or 3, substituents selected from the group consisting of: Here, each R j is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH 2 , -C(S)-NH 2 , -S(O) 2 -NH 2 , -N(H)-C(O)-NH 2 , -N(H)-C(S)-NH 2 , -N(H)-S(O) 2 -NH 2 , -C(NH)-NH 2 , -OR r , -SR r , -OC(O)-R r , -OC(S)-R r , -C(O)-R r , -C(S)-R r , -C(O)-OR r , -C(S)-OR r , -S(O)-R r , -S(O) 2 -R r , -C(O)-N(H)-R r , -C(S)-N(H)-Rr 、-C(O)-N(R r )-R r 、-C(S)-N(R r )-R r 、-S(O) 2 -N(H)-R r 、-S(O) 2 -N(R r )-R r 、-C(NH)-N(H)-R r 、-C(NH)-N(R s )-R t 、-N(H)-C(O)-R r 、-N(H)-C(S)-R r 、-N(R r )-C(O)-R r 、-N(R r )-C(S)-R r 、-N(H)-S(O) 2 -R r 、-N(R r )-S(O) 2 -le、-N(H)-C(O)-N(H)-R r 、-N(H)-C(S)-N(H)-R r 、-N(R r )-C(O)-NH 2 、-N(R r )-C(S)-NH 2 、-N(R r )-C(O)-N(H)-R r 、-N(R r )-C(S)-N(H)-R r 、-N(H)-C(O)-N(R r )-R r 、-N(H)-C(S)-N(R r )-R r 、-N(R r )-C(O)-N(R r )-R r 、-N(R r )-C(S)-N(R r )-R r 、-N(H)-S(O) 2 -N(H)-R r 、-N(R r )-S(O) 2 -NH 2 、-N(R r)-S(O) 2 -N(H)-R r , -N(H)-S(O) 2 -N(R r )-R r , -N(R r )-S(O) 2 -N(R r )-R r , -N(R r )-R r , cycloalkylamino, and -R x optionally substituted with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2 or 3, substituents selected from the group consisting of: Here, each R r , R s , and R t is, independently in each occurrence, lower alkyl, C 3-6 Alkenyl, C 3-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the lower alkyl is selected from the group consisting of -R y , Fluoro, -OH, -NH 2 , lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino, and optionally substituted with one or more, e.g., 1, 2, 3, 4, or 5, also 1, 2, or 3, substituents selected from the group consisting of: 3-6 Alkenyl or C 3-6 Alkynyl is -R y , fluoro, lower alkyl, fluoro-substituted lower alkyl, lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, e.g., 1, 2, 3, 4, or 5, as well as 1, 2, or 3, substituents selected from the group consisting of halogen, -OH, -NH 2 , -NO 2, -CN, lower alkyl, fluoro-substituted lower alkyl, lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino, or R s and R t are combined with the nitrogen to which they are attached to form a 5- to 7-membered heterocycloalkyl or a 5- or 7-membered nitrogen-containing heteroaryl, which 5- to 7-membered heterocycloalkyl or 5- or 7-membered nitrogen-containing heteroaryl is selected from the group consisting of halogen, -NO 2 , -CN, -OH, -NH 2 , -OR u , -SR u , -N(H)-R u , -N(R u )-R u , -R x , and -R y optionally substituted with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2 or 3, substituents selected from the group consisting of: Here, each R u are independently lower alkyl, C 3-6 Alkenyl, C 3-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the lower alkyl is selected from the group consisting of -R y , Fluoro, -OH, -NH 2 , lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino, and optionally substituted with one or more, e.g., 1, 2, 3, 4, or 5, also 1, 2, or 3, substituents selected from the group consisting of: 3-6 Alkenyl or C 3-6 Alkynyl is -R y , Fluoro, -OH, -NH 2, lower alkyl, fluoro-substituted lower alkyl, lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, e.g., 1, 2, 3, 4, or 5, as well as 1, 2, or 3, substituents selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 optionally substituted with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2 or 3, substituents selected from the group consisting of -CN, lower alkyl, fluoro-substituted lower alkyl, lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino; Here, each R x is selected from the group consisting of lower alkyl, lower alkenyl, and lower alkynyl, where the lower alkyl is -R y , Fluoro, -OH, -NH 2 , lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino, and the lower alkenyl or lower alkynyl is optionally substituted by one or more, for example 1, 2, 3, 4 or 5, also 1, 2 or 3, substituents selected from the group consisting of -R y , Fluoro, -OH, -NH 2 optionally substituted with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2 or 3, substituents selected from the group consisting of lower alkyl, fluoro-substituted lower alkyl, lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino; Here, each R yis selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, lower alkyl, fluoro-substituted lower alkyl, lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino.

[0049] In some embodiments, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted C 3-6 Alkenyl, optionally substituted lower alkynyl, or optionally substituted C 3-6 In all cases of alkynyl, fluoro, -NO 2 , -CN, -OR 1a , -SR 1a , -N(R 1a )-R 1a , -OC(O)-R 1a , -OC(S)-R 1a , -C(O)-R 1a , -C(S)-R 1a , -C(O)-OR 1a , -C(S)-OR 1a , -C(O)-N(R 1a )-R 1a , -C(S)-N(R 1a )-R 1a , -S(O) 2 -N(R 1a )-R 1a , -C(NH)-N(R 1a )-R 1a , -N(R 1a )-C(O)-R 1a , -N(R 1a )-C(S)-R 1a , -N(R 1a )-S(O) 2 -R 1a , -N(R1a )-C(O)-N(R 1a )-R 1a , -N(R 1a )-C(S)-N(R 1a )-R 1a , -N(R 1a )-S(O) 2 -N(R 1a )-R 1a , -S(O)-R 1a , -S(O) 2 -R 1a , cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted with one or more, as well as one, two or three, groups or substituents selected from the group consisting of halogen, -NO 2 , -CN, -OR 1a , -SR 1a , -N(R 1a )-R 1a , -OC(O)-R 1a , -OC(S)-R 1a , -C(O)-R 1a , -C(S)-R 1a , -C(O)-OR 1a , -C(S)-OR 1a , -C(O)-N(R 1a )-R 1a , -C(S)-N(R 1a )-R 1a , -S(O) 2 -N(R 1a )-R 1a , -C(NH)-N(R 1a )-R 1a , -N(R 1a )-C(O)-R 1a , -N(R 1a )-C(S)-R 1a , -N(R 1a )-S(O) 2 -R 1a , -N(R 1a )-C(O)-N(R 1a )-R 1a , -N(R 1a )-C(S)-N(R 1a )-R 1a , -N(R1a )-S(O) 2 -N(R 1a )-R 1a , -S(O)-R 1a , -S(O) 2 -R 1a , -R 1b and optionally fluoro, -OH, -NH 2 , lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and -R 1b and optionally substituted with one or more, also 1, 2 or 3 groups or substituents, selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted 5- to 7-membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5- or 7-membered nitrogen-containing heteroaryl; and optionally substituted with one or more, also 1, 2 or 3 groups or substituents, selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted 5- to 7-membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5- or 7-membered nitrogen-containing heteroaryl. 2 , -CN, -OR 1a , -SR 1a , -N(R 1a )-R 1a , -OC(O)-R 1a , -OC(S)-R 1a , -C(O)-R 1a , -C(S)-R 1a , -C(O)-OR 1a , -C(S)-OR 1a , -C(O)-N(R 1a )-R 1a , -C(S)-N(R 1a )-R 1a , -S(O) 2 -N(R 1a )-R 1a , -C(NH)-N(R 1a )-R 1a , -N(R 1a )-C(O)-R 1a , -N(R 1a )-C(S)-R 1a , -N(R 1a )-S(O) 2-R 1a , -N(R 1a )-C(O)-N(R 1a )-R 1a , -N(R 1a )-C(S)-N(R 1a )-R 1a , -N(R 1a )-S(O) 2 -N(R 1a )-R 1a , -S(O)-R 1a , -S(O) 2 -R 1a , -R 1b and optionally fluoro, -OH, -NH 2 , lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and -R 1b and optionally substituted with one or more, also one, two or three groups or substituents selected from the group consisting of lower alkyl, which is substituted with one or more, also one, two or three groups or substituents selected from the group consisting of 1a is optionally fluoro, -OH, -NH 2 , lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and -R 1b hydrogen, -R 1b and lower alkyl, 1b are cycloalkyl, heterocycloalkyl, aryl and heteroaryl are halogen, -CN, -OH, -NH 2 , cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted with one or more, in turn with one, two or three groups or substituents selected from the group consisting of lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino.

[0050] In some embodiments, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted C 3-6 Alkenyl, optionally substituted lower alkynyl, or optionally substituted C 3-6 In all cases of alkynyl, fluoro, -CN, -OR 1a , -SR 1a , -N(R 1a )-R 1a , -C(O)-R 1a , -C(S)-R 1a , -C(O)-OR 1a , -C(O)-N(R 1a )-R 1a , -C(S)-N(R 1a )-R 1a , -S(O) 2 -N(R 1a )-R 1a , -N(R 1a )-C(O)-R 1a , -N(R 1a )-C(S)-R 1a , -N(R 1a )-S(O) 2 -R 1a , -S(O)-R 1a , -S(O) 2 -R 1a , cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted with one or more, as well as one, two or three, groups or substituents selected from the group consisting of halogen, -CN, -OR 1a , -SR 1a , -N(R 1a )-R 1a , -C(O)-R 1a , -C(S)-R 1a , -C(O)-OR 1a , -C(O)-N(R 1a )-R 1a , -C(S)-N(R 1a )-R 1a , -S(O) 2 -N(R 1a )-R 1a, -N(R 1a )-C(O)-R 1a , -N(R 1a )-C(S)-R 1a , -N(R 1a )-S(O) 2 -R 1a , -S(O)-R 1a , -S(O) 2 -R 1a , -R 1b and optionally fluoro, -OH, -NH 2 , lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and -R 1b and optionally substituted with one or more, also 1, 2 or 3 groups or substituents, selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted 5- to 7-membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5- or 7-membered nitrogen-containing heteroaryl, optionally substituted with halogen, -CN, -OR 1a , -SR 1a , -N(R 1a )-R 1a , -C(O)-R 1a , -C(S)-R 1a , -C(O)-OR 1a , -C(O)-N(R 1a )-R 1a , -C(S)-N(R 1a )-R 1a , -S(O) 2 -N(R 1a )-R 1a , -N(R 1a )-C(O)-R 1a , -N(R 1a )-C(S)-R 1a , -N(R 1a )-S(O) 2 -R 1a , -S(O)-R 1a , -S(O) 2 -R1a , -R 1b and optionally fluoro, -OH, -NH 2 , lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and -R 1b and optionally substituted with one or more, also one, two or three groups or substituents selected from the group consisting of lower alkyl, which is substituted with one or more, also one, two or three groups or substituents selected from the group consisting of 1a is hydrogen, -R 1b and optionally fluoro, -OH, -NH 2 , lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and -R 1b and wherein -R 1b is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from the group consisting of halogen, -CN, -OH, -NH 2 , optionally substituted with one or more, as well as one, two or three, groups or substituents selected from the group consisting of lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino.

[0051] As used herein, "lower alkoxy" refers to -OR z (wherein R z "Substituted lower alkoxy" refers to any of the groups listed herein in the description of compounds of formula I, including, for example, the descriptions of substituted cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which are attached at any available atom to provide a stable compound. zrefers to lower alkoxy, where is lower alkyl substituted with one or more substituents. In some embodiments, the substitution of the lower alkoxy is with 1, 2, 3, 4 or 5 substituents, likewise with 1, 2 or 3 substituents. For example, "fluoro-substituted lower alkoxy" refers to lower alkoxy, where the lower alkyl is substituted with one or more fluorine atoms, in some embodiments, the lower alkoxy is substituted with 1, 2, 3, 4 or 5 fluorine atoms, likewise with 1, 2 or 3 fluorine atoms. It is understood that the substitution on the alkoxy is chemically feasible and can be attached at any available atom to provide a stable compound.

[0052] It is understood that all possible substitutions defined above include a subset of those substitutions as shown herein, for example in the description of compounds of formula I, which are attached at any possible atom to provide a stable compound. For example, "fluoro-substituted phenyl" refers to a phenyl group substituted with one or more fluorine atoms, for example, phenyl is substituted with 1, 2, 3, 4 or 5 fluorine atoms, for example, 2,3,5,6-tetrafluorophenyl. It is also understood that any substitution made according to the above definition is chemically feasible and is attached at any possible atom to provide a stable compound.

[0053] It is understood that the compounds provided herein may contain chiral centers. Such chiral centers may be in either the (R) or (S) configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, or may be stereoisomeric or diastereoisomeric mixtures. Thus, one skilled in the art will recognize that for compounds that undergo epimerization in vivo, administration of the compound in its (R) form is equivalent to administration of the compound in its (S) form.

[0054] As used herein, "substantially pure" means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard analytical methods used by those skilled in the art to assess such purity, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), or sufficiently pure that further purification would not appreciably alter the physical and chemical properties, such as enzymatic and biological activity, of the material. Methods of purifying compounds to prepare substantially chemically pure compounds are known to those skilled in the art. However, a substantially chemically pure compound may be a mixture of stereoisomers. In such cases, further purification may increase the specific activity of the compound. The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R) and (S), or (D) and (L) isomers may be prepared using chiral synthons or chiral reagents and resolved using conventional techniques, such as reverse-phase HPLC. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as all tautomers.

[0055] In certain embodiments, the compounds used in the methods provided herein are "stereochemically pure." A stereochemically pure compound has a level of stereochemical purity that would be recognized as "pure" by one of ordinary skill in the art. In certain embodiments, "stereochemically pure" refers to a compound that is substantially free of alternative isomers. In particular embodiments, the compound is 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% free of other isomers.

[0056] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0057] As used herein, a "subject" is an animal, such as a mammal, including a human patient.

[0058] As used herein, "biological activity" refers to the in vitro or in vivo activity of a compound or the physiological response reaction that results from in vivo administration of a compound, composition, or other mixture. Thus, biological activity encompasses the therapeutic effects and pharmacokinetic behavior of such compounds, compositions, and mixtures. Biological activity can be observed in in vitro and in vitro systems designed to test for such activity.

[0059] As used herein, a "pharmaceutically acceptable derivative" of a compound includes its salts, esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates, or prodrugs. Such derivatives can be readily prepared by one of ordinary skill in the art using known methods for such derivatization. The compounds prepared can be administered to animals or humans without substantial toxic effects and are either pharmaceutically active or are prodrugs. Pharmaceutically acceptable salts include, but are not limited to, salts of amines, including, but not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, and tris(hydroxymethyl)aminomethane; and the like; including, but not limited to, lithium, potassium, and sodium. These include, but are not limited to, salts of alkali metals, salts of alkaline earth metals, including but not limited to barium, calcium, and magnesium, salts of transition metals, including but not limited to zinc, and inorganic salts, including but not limited to sodium hydrogen phosphate and disodium phosphate, as well as salts of mineral acids, including but not limited to hydrochlorides and sulfates, and salts of organic acids, including but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, mesylates, and fumarates. Pharmaceutically acceptable esters include alkyl, alkenyl, alkynyl, aryl, arylalkyl, and cycloalkyl esters of acidic groups, including but not limited to carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids, and boronic acids.Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or from 1 to about 100, or from 1 to about 10, or from 1 to about 2, 3, or 4 solvent or water molecules. Exemplary prodrugs include those published in J. Rautio, NA. Meanwell, L. di, MJ. Hageman, "The expanding role of prodrugs in contemporary drug design and development," Nat Rev Drug Discov. 2018;17(8):559-587, the entirety of which is incorporated herein by reference.

[0060] As used herein, "treatment" refers to any manner in which a disease or disorder, or one or more symptoms of a disease or disorder, is ameliorated or otherwise beneficially altered. Treatment also includes any pharmaceutical use of the compositions herein, such as use to treat cancer. References herein to "treatment" also include prevention, amelioration, or palliation.

[0061] As used herein, "prevention" refers to any manner in which the risk of acquiring a disease or disorder or experiencing one or more symptoms of a disease or disorder is reduced. Such risk can be reduced, for example, by between about 5% and 100%, such as by about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100%.

[0062] As used herein, "amelioration" or "alleviation" of symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition are used interchangeably and refer to any reduction in symptoms, either permanent or temporary, either persistent or transient, that may result from or be associated with administration of the compound or composition.

[0063] As used herein, "complication" refers to a condition that develops in association with a condition or disease. A complication may be a direct result caused by a condition or disease, or may be related to the presence of a primary condition or disease. In some embodiments, a complication of a disease may be manifested as a symptom, in which case the two terms are used interchangeably herein.

[0064] Unless otherwise specified, the terms "manage," "managing," and "management" as used herein include preventing the recurrence of a particular disease or disorder in a patient who has already had the disease or disorder and / or extending the time that a patient who has had the disease or disorder remains in remission. These terms include modulating the threshold, onset, and / or duration of the disease or disorder, or changing the way the patient responds to the disease or disorder.

[0065] As used herein, the term "in combination" refers to the use of more than one therapy (e.g., a caspase inhibitor and another agent). The use of the term "in combination" does not restrict the order in which the therapies (e.g., a caspase inhibitor and another agent) are administered to a subject with a disorder. The first therapy (e.g., caspase inhibitor and other agents) can be administered to a subject with a disorder prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of the other therapy (e.g., caspase inhibitor and other agents).

[0066] The term "parenteral" as used herein includes the administration of a compound to a subject using subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0067] As used herein, "selective inhibitors of caspase-1, caspase-4, and / or caspase-5" refers to compounds provided herein that bind more selectively to caspase-1, caspase-4, and / or caspase-5 than to caspase-3, caspase-6, and / or caspase-7. In certain embodiments, compounds provided herein have at least a 2-fold higher binding affinity to caspase-1 compared to other caspases. In certain embodiments, compounds provided herein have at least a 5-fold, 10-fold, 50-fold, 100-fold, 1000-fold, or more higher binding affinity to caspase-1, caspase-4, and / or caspase-5 compared to caspase-3, caspase-6, and / or caspase-7.

[0068] The term "about," as used herein, unless otherwise specified, refers to a value that is not more than 10% above or not more than 10% below the value that it modifies. For example, the term "about 10 mg" means a range of 9 mg to 11 mg.

[0069] Abbreviations used herein for protecting groups, amino acids and other compounds follow their common usage, accepted abbreviations, or the IUPAC IUB Biochemical Nomenclature Commission (see Biochem. 1972, 11:942-944) unless otherwise indicated.

[0070] 6.2. Caspase Inhibitor Compounds In one embodiment, provided herein is a method for treating a pulmonary circulation disorder comprising: A compound having formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof: [ka] (wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R a OR b Or -R a N(R c )(R d each of which is optionally substituted; or ii) X is -O- or -N(R c )-; Y is hydrogen, -C(O)R d , optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; R 3 , Y 1 , Y 2 And Y 3 is selected as follows: i) Y 1 is R 3 together form an optionally substituted saturated or unsaturated bicyclic ring B; Y 2 is absent, hydrogen or optionally substituted alkyl; and Y 3 is absent, hydrogen or optionally substituted alkyl; or ii) R 3 is hydrogen or optionally substituted alkyl; Y 1 and Y 2 together become =O; and Y 3 -N(Z 1 )(Z 2 ) is; X, Y, R 3 And Y 1 If X is O, then Y 1 and R 3 is selected so that it cannot form ring B; Each R a is independently alkylene or a direct bond; R bis hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted hydroxyalkyl, optionally substituted alkoxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; Each R c is independently hydrogen or optionally substituted alkyl; Each R d is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a OR b each of which is optionally substituted; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A; R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or optionally substituted alkyl; R 9 is aryl or heteroaryl, each of which is optionally substituted; R 10 is alkylene; Z 1 And Z 2 is selected as follows: i) Z 1 is hydrogen or optionally substituted alkyl; and Z 2 is aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted; or ii) Z 1 and Z2 together with the nitrogen atom on which they are substituted form an optionally substituted saturated or unsaturated ring C).

[0071] In one embodiment, provided herein is a compound of formula I, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; (wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R a OR b Or -R a N(R c )(R d ) is; or ii) X is -O- or -N(R c )-; Y is hydrogen, -C(O)R d , alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; Y is any number from 1 to 3 Qs 1 is substituted with a group; R 3 , Y 1 , Y 2 And Y 3 is selected as follows: i) Y 1 is R 3 together form an optionally substituted saturated or unsaturated bicyclic ring B, the substituents on ring B, if present, being selected from 1 to 3 Q 1 selected from the group; Y 2 is absent, hydrogen or alkyl; and Y 3 is absent, hydrogen or alkyl; or ii) R 3 is hydrogen or alkyl; Y 1 and Y 2 together become =O; and Y 3 -N(Z 1 )(Z 2 ) is; X, Y, R 3 And Y 1 If X is O, then Y 1 and R 3 is selected so that it cannot form ring B; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; Each R a is independently alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each R c is independently hydrogen or alkyl; Each R d is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 4 , R 5, R 6 , R 7 and R 8 are each independently hydrogen or alkyl; R 9 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 1 is replaced by; R 10 is alkylene; Z 1 And Z 2 is selected as follows: i) Z 1 is hydrogen or alkyl; and Z 2 is aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which optionally has 1 to 4 substituents Q 3 is substituted with; or ii) Z 1 and Z 2 together with the nitrogen atom on which they are substituted form an optionally substituted saturated or unsaturated ring C, the substituents on ring C, if present, being selected from 1 to 3 Q 3 Selected from the group; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R 11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R16 Each Q is selected from 3 is any 1 to 3 Q 4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; J is O or S; and (t is 0 to 2).

[0072] In one embodiment, provided herein is a compound of formula I, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR b is; or ii) X is -O-; Y is hydrogen, -C(O)R d , alkyl or aryl; Y is any number from 1 to 3 Qs 1 is substituted with a group; R 3 , Y 1 , Y 2 And Y 3 is selected as follows: i) Y 1 is R 3 together form an optionally substituted saturated or unsaturated ring B, the substituents on ring B, if present, being 1 to 3 Q 3 selected from the group; Y 2 is absent, hydrogen or alkyl; and Y 3 is absent, hydrogen or alkyl; or ii) R 3 is hydrogen or alkyl; Y 1 and Y 2 together become =O; and Y 3 -N(Z 1 )(Z 2 ) is; X, Y, R 3 And Y 1 If X is O, then Y 1 and R 3 is selected so that it cannot form ring B; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; R a is an alkylene or a direct bond; R b is hydrogen, alkyl or aryl; R d is aryl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; R 9 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 1 is replaced by; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15and -R 11 C(O)NH 2 Selected from; Each R 11 is independently alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; and R 15 is hydroxyl or alkyl).

[0073] In one embodiment, provided herein is a compound of formula I, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR b is; or ii) X is -O-; and Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; R 3 , Y 1 , Y 2 And Y 3 is selected as follows: i) Y 1 is R 3 together form an optionally substituted saturated or unsaturated ring B, the substituents on ring B, if present, being 1 to 3 Q 3 selected from the group; Y 2 is absent, hydrogen or alkyl; and Y 3 is absent, hydrogen or alkyl; or ii) R 3 is hydrogen or alkyl; Y 1 and Y 2 together become =O; and Y 3 -N(Z 1 )(Z2 ) is; X, Y, R 3 And Y 1 If X is O, then Y 1 and R 3 is selected so that it cannot form ring B; R a is an alkylene or a direct bond; R b is hydrogen, alkyl or aryl; R d is aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; R 9 is aryl or heteroaryl, each of which is optionally substituted with 1 to 4 substituents selected from halo, alkyl, and haloalkyl; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -C(O)NH 2 Selected from; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; and R 15 is hydroxyl or alkyl).

[0074] In one embodiment, provided herein is a compound of formula II, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R a OR b Or -R a N(R c )(R d ) is; or ii) X is -O- or -N(R c )-; Y is hydrogen, -C(O)R d , alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is any number from 1 to 3 Qs 1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; Each R a is independently alkylene or a direct bond; R bis hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each R c is independently hydrogen or alkyl; Each R d is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; R 9 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 1 is replaced by; R 10 is alkylene; Z 1 And Z 2 is selected as follows: i) Z 1 is hydrogen or alkyl; and Z 2 is aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which optionally has 1 to 4 substituents Q 3is substituted with; or ii) Z 1 and Z 2 together with the nitrogen atom on which they are substituted form an optionally substituted saturated or unsaturated ring C, the substituents on ring C, if present, being selected from 1 to 3 Q 3 Selected from the group; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R 11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; J is O or S; and (t is 0 to 2).

[0075] In one embodiment, provided herein is a compound of formula II, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; (wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R a OR b Or -R a N(R c )(R d ) is; or ii) X is -O- or -N(R c )-; Y is hydrogen, -C(O)R d , alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is any number from 1 to 3 Qs1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; Each R a is independently alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each R c is independently hydrogen or alkyl; Each R d is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; R 9 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 1 is replaced by; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z 2 is aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R 11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; J is O or S; and (t is 0 to 2).

[0076] In one embodiment, provided herein is a compound of formula II, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR b is; or ii) X is -O-; Y is hydrogen, -C(O)R d , alkyl or aryl; Y is any number from 1 to 3 Qs 1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; Each R a is independently alkylene or a direct bond; Each R b is independently hydrogen, alkyl or aryl; R d is aryl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; R 9 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 1 is replaced by; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -R 11 C(O)NH 2 Selected from; Each R 11 is independently alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; and R 15 is hydroxyl or alkyl).

[0077] In one embodiment, provided herein is a compound of formula II, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR b is; or ii) X is -O-; and Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; R a is an alkylene or a direct bond; R b is hydrogen, alkyl or aryl; R d is aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; R 9 is aryl or heteroaryl, each of which is optionally substituted with 1 to 4 substituents selected from halo, alkyl, and haloalkyl; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -C(O)NH 2 Selected from; Each R 11 is independently alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; and R 15 is hydroxyl or alkyl).

[0078] In one embodiment, provided herein is a compound of formula III, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R a OR b Or -R a N(R c )(R d ) is; or ii) X is -O- or -N(R c )-; Y is hydrogen, -C(O)R d , alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is any number from 1 to 3 Qs 1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; Each R a is independently alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each R c is independently hydrogen or alkyl; Each R d is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; R 10 is alkylene; Each Q 5 is independently alkyl, halo, or haloalkyl; Z 1 is hydrogen or alkyl; Z 2 is aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R 11 OR 11 C(J)N(R 13 )(R 14), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; J is O or S; t is between 0 and 2; and m is 0 to 4.

[0079] In one embodiment, provided herein is a compound of formula III, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR b is; or ii) X is -O-; and Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; R a is an alkylene or a direct bond; R b is hydrogen, alkyl or aryl; Each R d is independently aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; Q 1 is selected from halo, alkyl, and haloalkyl; m is 0 to 4; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -C(O)NH 2 Selected from; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; and R 15 is hydroxyl or alkyl).

[0080] In one embodiment, provided herein is a compound of formula III, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR b is; or ii) X is -O-; and Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; R a is an alkylene or a direct bond; R b is hydrogen, alkyl or aryl; R d is aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is hydrogen; Q 1 is selected from halo, alkyl, and haloalkyl; m is 0 to 4; R 10 is alkylene; R 3 , Y 1 , Y 2 And Y 3 is selected as follows: i) Y 1 is R 3 together form an optionally substituted saturated or unsaturated ring B, the substituents on ring B, if present, being 1 to 3 Q 1 Selected from the group Y 2 is absent, hydrogen or alkyl; and Y 3 is absent, hydrogen or alkyl; or ii) R 3 is hydrogen or alkyl; Y 1 and Y 2 together become =O; and Y 3 -N(Z 1 )(Z 2 ) is; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR12 , -C(O)R 15 and -C(O)NH 2 Selected from; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; and R 15 is hydroxyl or alkyl).

[0081] In one embodiment, provided herein is a compound of formula IV, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR b is; or ii) X is -O-; and Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; R a is an alkylene or a direct bond; R b is hydrogen, alkyl or aryl; R d is aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R3 , R 4 , R 5 , R 6 , R 7 and R 8 is hydrogen; Q 5 is selected from halo, alkyl, and haloalkyl; p is 0 to 3; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -C(O)NH 2 Selected from; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; and R 15 is hydroxyl or alkyl).

[0082] In one embodiment, provided herein is a compound of formula V, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R a OR b Or -R a N(R c )(R d) is; or ii) X is -O- or -N(R c )-; Y is hydrogen, -C(O)R d , alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is any number from 1 to 3 Qs 1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; Each R a is independently alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each R c is independently hydrogen or alkyl; Each R d is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; R 10 is alkylene; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R 11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each Q 5 is independently alkyl, halo, or haloalkyl; J is O or S; t is between 0 and 2; m is 0 to 4; and (n is 0 to 3).

[0083] In one embodiment, provided herein is a compound of formula V, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a ORb is; or ii) X is -O-; and Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; R a is an alkylene or a direct bond; R b is hydrogen, alkyl or aryl; R d is aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; R 10 is alkylene; Z 1 is hydrogen or alkyl; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -C(O)NH 2 Selected from; Each R 11 is independently alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; R 15is hydroxyl or alkyl; Each Q 5 is independently alkyl, halo, or haloalkyl; m is 0 to 4; and (n is 0 to 2).

[0084] In one embodiment, provided herein is a compound of formula VI, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (Wherein, Y is hydrogen, -C(O)R d , alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is any number from 1 to 3 Qs 1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; R d is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R a is an alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 1 And R 2is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl; Z 1 is hydrogen or alkyl; Z 2 is aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R 11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; R 10 Ha-CH 2 -or-CH 2 -CH 2 - and; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; J is O or S; Each Q 5 is independently alkyl, halo, or haloalkyl; t is between 0 and 2; and m is 0 to 4.

[0085] In one embodiment, provided herein is a compound of formula VI, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: wherein Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; R d is aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 or -C(O)NH 2 Selected from; Each Q 5 is independently alkyl, halo, or haloalkyl; R10 Ha-CH 2 -or-CH 2 -CH 2 - and; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; R 15 is hydroxyl or alkyl; and m is 0 to 4.

[0086] In one embodiment, provided herein is a compound of formula VI, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (Wherein, Y is hydrogen, methyl, -C(O)R d wherein the methyl is optionally substituted with phenyl, chlorophenyl or thienyl; R d is phenyl or phenyloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or methyl; or ii) R 1 and R 2 form, together with the carbon atom on which they are substituted, a cyclopentyl ring; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or methyl; R 10 Ha-CH 2 -or-CH 2 -CH 2 - and; Q 5 is fluoro, methyl or trifluoromethyl; Z 1 is hydrogen; Z2 is selected from phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl, isoquinolinyl, and benzoisothiazolyl; each optionally represents one or two Q 3 groups, and each Q 3 are independently chloro, fluoro, methyl, methoxy, trifluoromethoxy, -C(O)CH 3 , cyano, -C(O)NH 2 , benzyl, and tetrazolyl; and m is 0 to 4.

[0087] In one embodiment, provided herein is a compound of formula VII, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (In the formula, R d is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; R a is an alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 1And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl; Z 1 is hydrogen or alkyl; Z 2 is aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which optionally has 1 to 4 substituents Q 3 is substituted with; or Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R 11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from 3is any 1 to 3 Q 4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; R 10 Ha-CH 2 -or-CH 2 -CH 2 - and; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each Q 5 is independently alkyl, halo, or haloalkyl; J is O or S; t is between 0 and 2; and m is 0 to 4.

[0088] In one embodiment, provided herein is a compound of formula VII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (In the formula, R d is aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -C(O)NH 2 Selected from; R 10 Ha-CH 2 -or-CH 2 -CH 2 - and; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; R 15 is hydroxyl or alkyl; Q 5 is independently alkyl, halo, or haloalkyl; and m is 0 to 4.

[0089] In one embodiment, provided herein is a compound of formula VII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (Wherein, each R d is independently phenyl or phenyloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or methyl; or ii) R 1 and R 2 form, together with the carbon atom on which they are substituted, a cyclopentyl ring; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or methyl; R 10 Ha-CH 2 -or-CH 2 -CH 2 - and; Q 5 is fluoro, methyl or trifluoromethyl; Z 1 is hydrogen; Z 2 is selected from phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl, isoquinolinyl, and benzoisothiazolyl; each optionally represents one or two Q 3 groups, and each Q 3 are independently chloro, fluoro, methyl, methoxy, trifluoromethoxy, -C(O)CH 3, cyano, -C(O)NH 2 , benzyl, and tetrazolyl; and m is 0 to 4.

[0090] In one embodiment, provided herein is a compound of formula VIII, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (In the formula, R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R b is any 1 to 3 Q 1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 3 , R 4 , R 5 and R 6are each independently hydrogen or alkyl; Z 1 is hydrogen or alkyl; Z 2 is aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R 11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; R 10 Ha-CH 2 -or-CH 2 -CH 2 - and; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Q 5 is independently alkyl, halo, or haloalkyl; J is O or S; m is 0 to 4; (t is 0 to 2).

[0091] In one embodiment, provided herein is a compound of formula VIII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (In the formula, R b is hydrogen; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl; Z 1 is hydrogen or alkyl; Z 2 is aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14), -R 11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; R 10 Ha-CH 2 -or-CH 2 -CH 2 - and; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Q 5 is independently alkyl, halo, or haloalkyl; J is O or S; m is 0 to 4; and (t is 0 to 2).

[0092] In one embodiment, provided herein is a compound of formula VIII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (In the formula, R b is hydrogen, alkyl or aryl; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -C(O)NH 2 Selected from; R10 Ha-CH 2 -or-CH 2 -CH 2 - and; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; R 15 is hydroxyl or alkyl; Q 5 is independently alkyl, halo, or haloalkyl; and m is 0 to 4.

[0093] In one embodiment, provided herein is a compound of formula VIII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (In the formula, R b is hydrogen; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form a 3- to 5-membered cycloalkyl ring; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR12 , -C(O)R 15 and -C(O)NH 2 Selected from; R 10 Ha-CH 2 -or-CH 2 -CH 2 - and; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; R 15 is hydroxyl or alkyl; Q 5 is independently alkyl, halo, or haloalkyl; and m is 0 to 4.

[0094] In one embodiment, provided herein is a compound of formula VIII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (In the formula, R b is hydrogen; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or methyl; or ii) R 1 and R 2 form, together with the carbon atom on which they are substituted, a cyclopentyl ring; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or methyl; R 10 Ha-CH 2 -or-CH 2 -CH 2 - and; Q 5 is fluoro, methyl and trifluoromethyl; Z1 is hydrogen; Z 2 is selected from phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl, isoquinolinyl, and benzoisothiazolyl; each optionally represents one or two Q 3 groups, and each Q 3 are independently chloro, fluoro, methyl, methoxy, trifluoromethoxy, -C(O)CH 3 , cyano, -C(O)NH 2 , benzyl, and tetrazolyl; and m is 0 to 4.

[0095] In one embodiment, provided herein is a compound of formula IX, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R a OR b Or -R a N(R c )(R d ) is; or ii) X is -O- or -N(R c )-; Y is hydrogen, -C(O)R d , alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is any number from 1 to 3 Qs 1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; Each R a is independently alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each R c is independently hydrogen or alkyl; Each R d is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl; R 10 is alkylene; Q 5 is alkyl, halo, or haloalkyl; Z 1 is hydrogen or alkyl; Z 2 is aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which optionally has 1 to 4 substituents Q3 is replaced by; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R 11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; J is O or S; t is between 0 and 2; and m is 0 to 4.

[0096] In one embodiment, provided herein is a compound of formula IX, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR b is; or ii) X is -O-; and Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; R a is an alkylene or a direct bond; R b is hydrogen, alkyl or aryl; R d is aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl; Q 5 is a halo; m is 0 to 4; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -C(O)NH 2 Selected from; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; and R 15 is hydroxyl or alkyl).

[0097] In one embodiment, provided herein is a compound of formula IX, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR bis; or ii) X is -O-; and Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; R a is an alkylene or a direct bond; R b is hydrogen, alkyl or aryl; R d is aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 and R 6 are hydrogen; Q 5 is fluoro; m is 0 to 4; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -C(O)NH 2 Selected from; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; and R 15 is hydroxyl or alkyl).

[0098] In one embodiment, provided herein is a compound of formula X, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR b is; or ii) X is -O- or -N(R c )-; Y is hydrogen, -C(O)R d , alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is any number from 1 to 3 Qs 1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; R a is an alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R c is hydrogen or alkyl; R dis alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 10 is alkylene; Q 5 is alkyl, halo, or haloalkyl; Z 1 is hydrogen or alkyl; Z 2 is aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; J is O or S; t is between 0 and 2; and m is 0 to 4.

[0099] In one embodiment, provided herein is a compound of formula X, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: wherein X is C=O; and Y is -OH; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 form together with the carbon atom on which they are substituted a saturated or unsaturated ring A; R 10 is alkylene; Q 5 is alkyl, halo, or haloalkyl; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -C(O)NH 2 Selected from; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; and R 15 is hydroxyl or alkyl).

[0100] In one embodiment, provided herein is a compound of formula X, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: wherein X is C=O; and Y is -OH; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 form together with the carbon atom on which they are substituted a saturated or unsaturated ring A; R 10 is alkylene; Q 5 is a halo; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -C(O)NH 2 Selected from; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; and R 15 is hydroxyl or alkyl).

[0101] In one embodiment, provided herein is a compound of formula XI, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R a OR b Or -R a N(R c )(R d ) is; or ii) X is -O- or -N(R c )-; Y is hydrogen, -C(O)R d , alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is any number from 1 to 3 Qs 1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; Each R a is independently alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each R c is independently hydrogen or alkyl; Each R d is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R aOR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl; R 10 is alkylene; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R 11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from3 is any 1 to 3 Q 4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each Q 5 is independently alkyl, halo, or haloalkyl; J is O or S; t is between 0 and 2; and m is 0 to 4.

[0102] In one embodiment, provided herein is a compound of formula XI, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR b is; or ii) X is -O-; and Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; R a is an alkylene or a direct bond; R b is hydrogen, alkyl or aryl; R d is aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 , and R 6 are each independently hydrogen or alkyl; R 10 is alkylene; Z 1 is hydrogen or alkyl; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -C(O)NH2 Selected from; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; R 15 is hydroxyl or alkyl; Each Q 5 is independently alkyl, halo, or haloalkyl; m is 0 to 4; and (n is 0 to 2).

[0103] In one embodiment, provided herein is a compound of formula XI, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR b is; or ii) X is -O-; and Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; R a is an alkylene or a direct bond; R b is hydrogen, alkyl or aryl; R d is aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl; R 10 is alkylene; Z 1 is hydrogen or alkyl; Each Q 3 is independently alkyl or halo; Each Q 5 is independently halo or haloalkyl; m is 0 to 4; and (n is 0 to 2).

[0104] In one embodiment, provided herein is a compound of formula XII, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R a OR b Or -R a N(R c )(R d ) is; or ii) X is -O- or -N(R c )-; Y is hydrogen, -C(O)R d , alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is any number from 1 to 3 Qs 1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; Each R a is independently alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each R c is independently hydrogen or alkyl; Each R d is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl; R 10 is alkylene; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12, -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R 11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each Q 5 is independently alkyl, halo, or haloalkyl; J is O or S; (t is 0 to 2).

[0105] In one embodiment, provided herein is a compound of formula XII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR b is; or ii) X is -O-; and Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; R a is an alkylene or a direct bond; R b is hydrogen, alkyl or aryl; Each R d is aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 , and R 6 are each independently hydrogen or alkyl; R 10 is alkylene; Z 1 is hydrogen or alkyl; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -C(O)NH 2 Selected from; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; R 15 is hydroxyl or alkyl; and Each Q 5 are independently alkyl, halo, or haloalkyl.

[0106] In one embodiment, provided herein is a compound of formula XII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR b is; or ii) X is -O-; and Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; R a is an alkylene or a direct bond; R b is hydrogen, alkyl or aryl; R d is aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl; R 10 is alkylene; Z 1 is hydrogen or alkyl; Each Q 3 is independently alkyl or halo; and Each Q 5 are independently halo or haloalkyl.

[0107] In one embodiment, provided herein is a compound of formula XIII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R a OR b Or -R a N(R c )(R d ) is; or ii) X is -O- or -N(R c)-; Y is hydrogen, -C(O)R d , alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is any number from 1 to 3 Qs 1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; Each R a is independently alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each R c is independently hydrogen or alkyl; Each R d is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 3, R 4 , R 5 and R 6 are each independently hydrogen or alkyl; R 10 is alkylene; Q 5 is alkyl, halo, or haloalkyl; Z 1 is hydrogen or alkyl; Z 2 is aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R 11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; J is O or S; t is between 0 and 2; and m is 0 to 4.

[0108] In one embodiment, provided herein is a compound of formula XIII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: (wherein X and Y are selected as follows: i) X is C=O; and Y is -R a OR b is; or ii) X is -O-; and Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; R a is an alkylene or a direct bond; R b is hydrogen, alkyl or aryl; R d is aryl or aryloxy; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 form a cycloalkyl ring together with the carbon atom on which they are substituted; R 3 , R 4 , R 5 and R 6 is hydrogen; Q 5 is haloalkyl; m is 0 to 4; R 10 is alkylene; R 3 , Y 1 , Y 2 And Y 3 is selected as follows: i) Y 1 is R 3 together form an optionally substituted saturated or unsaturated ring B, the substituents on ring B, if present, being 1 to 3 Q 1 Selected from the group Y 2 is absent, hydrogen or alkyl; and Y 3 is absent, hydrogen or alkyl; or ii) R 3is hydrogen or alkyl; Y 1 and Y 2 together become =O; and Y 3 -N(Z 1 )(Z 2 ) is; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 3 is replaced by; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and -C(O)NH 2 Selected from; R 11 is an alkylene or a direct bond; R 12 is hydrogen, alkyl or haloalkyl; and R 15 is hydroxyl or alkyl).

[0109] In one embodiment, provided herein is a compound of formula XIII, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein Q is 5 is trifluoroalkyl, and the remainder of the variables are as described herein.

[0110] In one embodiment, provided herein is a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein R 10 Ha-CH 2 -or-CH 2 -CH 2- and the remaining substituents are as described herein.

[0111] In one embodiment, provided herein is a compound of Formula I, II, III, IV, V, VI, VII or VIII, IX, X, XI, XII or XIII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof. (In the formula, R 1 and R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen or methyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form a cyclopentyl ring; and the remainder of the substituents are as described herein.

[0112] In one embodiment, provided herein is a compound of Formula I or II, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein R 9 is aryl or heteroaryl, each of which is optionally substituted with 1 to 4 substituents selected from halo, alkyl, and haloalkyl; and the remaining substituents are as described herein.

[0113] In one embodiment, provided herein is a compound of Formula I or II, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein R 9 is phenyl or pyrimidinyl, each of which is optionally substituted with 1 to 4 substituents selected from halo, alkyl, and haloalkyl; and the remaining substituents are as described herein.

[0114] In one embodiment, provided herein is a compound of Formula I, II, III, IV, VI, VII, or VIII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein Z 2 is selected from 6-10 membered aryl or heteroaryl; each optionally has one or two Q 3 groups, and each Q 3 is independently selected from halo, alkyl, haloalkyl, arylalkyl, alkoxy, alkylcarbonyl, haloalkoxy, cyano, aryl, heteroaryl, and aminocarbonyl, and the remaining substituents are as described herein.

[0115] In one embodiment, provided herein is a compound of Formula I, II, III, IV or V, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof, wherein R 10 -CH 2 -or-CH 2 -CH 2 - and Z 2 is selected from 6-10 membered aryl or heteroaryl; each optionally has one or two Q 3 groups, and each Q 3 is independently selected from halo, alkyl, haloalkyl, arylalkyl, alkoxy, alkylcarbonyl, haloalkoxy, cyano, aryl, heteroaryl, and aminocarbonyl, and the remaining substituents are as described herein.

[0116] In one embodiment, provided herein is a compound of Formula I, II, III, IV or V, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof, wherein R 10 -CH 2-or-CH 2 -CH 2 - and Z 2 is selected from 6-10 membered aryl or heteroaryl; each optionally has one or two Q 3 groups, and each Q 3 is independently selected from halo, alkyl, haloalkyl, arylalkyl, alkoxy, alkylcarbonyl, haloalkoxy, cyano, aryl, heteroaryl, and aminocarbonyl, where heteroaryl contains 1 or 2 heteroatoms selected from nitrogen and sulfur, and the remaining substituents are as described herein.

[0117] In one embodiment, provided herein is a compound of Formula I, II, III, IV, VI, VII, or VIII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein Z 2 is selected from phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl, isoquinolinyl, and benzoisothiazolyl; each optionally represents one or two Q 3 groups, and each Q 3 is independently selected from halo, alkyl, haloalkyl, arylalkyl, alkoxy, alkylcarbonyl, haloalkoxy, cyano, aryl, heteroaryl, and aminocarbonyl, and the remaining substituents are as described herein.

[0118] In one embodiment, provided herein is a compound of Formula I, II, III, or VI, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein R 10 -CH 2 -or-CH 2 -CH 2 - and Z 2is selected from phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl, isoquinolinyl, and benzoisothiazolyl; each optionally represents one or two Q 3 groups, and each Q 3 is independently selected from halo, alkyl, haloalkyl, arylalkyl, alkoxy, alkylcarbonyl, haloalkoxy, cyano, aryl, heteroaryl, and aminocarbonyl, and the remaining substituents are as described herein.

[0119] In one embodiment, provided herein is a compound of Formula I, II, III, IV, VI, VII, or VIII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein Z 2 is selected from phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl, isoquinolinyl, and benzoisothiazolyl; each optionally represents one or two Q 3 groups, and each Q 3 are independently chloro, fluoro, methyl, methoxy, trifluoromethoxy, -C(O)CH 3 , cyano, -C(O)NH 2 , benzyl and tetrazolyl, and the remaining substituents are as described herein.

[0120] In one embodiment, provided herein is a compound of Formula I, II, III, or IV, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein R 10 -CH 2 -or-CH 2 -CH 2 - and Z 2 is selected from phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl, isoquinolinyl, and benzoisothiazolyl; each optionally represents one or two Q3 groups, and each Q 3 are independently chloro, fluoro, methyl, methoxy, trifluoromethoxy, -C(O)CH 3 , cyano, -C(O)NH 2 , benzyl and tetrazolyl, and the remaining substituents are as described herein.

[0121] In one embodiment, provided herein is a compound of formula XIV, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] wherein X is C=O; Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R a OR b or -R a N(R c )(R d ) each of which is optionally 1 to 3 Q 1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; Each R a is independently alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each R c is independently hydrogen or alkyl; R dis alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R 1 And R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; R 9 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 1 is replaced by; R 10 is alkylene; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; J is O or S; t is between 0 and 2; and (n is 0 to 3).

[0122] In one embodiment, provided herein is a compound of formula XIV, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; wherein X is C=O; Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R a OR b or -R a N(R c )(R d ) each of which is optionally 1 to 3 Q 1 is substituted with a group; Each Q 1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 Each Q is substituted with 2 is independently alkyl, halo, haloalkyl, aryl, or haloaryl; Each R a is independently alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Each R c is independently hydrogen or alkyl; R d is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 is substituted with a group; R 1 And R 2is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or ii) R 1 and R 2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, the substituents on ring A, if present, being selected from 1 to 3 Q 1 Selected from the group; R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; R 9 is aryl or heteroaryl, each of which optionally has 1 to 4 substituents Q 1 is replaced by; R 10 is alkylene; Each Q 3 are independently alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 11 OR 12 , -R 11 OR 11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 S.R. 12 , -R 11 OR 11 N(R 13 )(R 14 ), -R 11 C(J)N(R 13 )(R 14 ), -R 11 OR 11 C(J)N(R 13 )(R 14 ), -C(J)R 15 and R 11 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4Each Q is substituted with 4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, form a 5- or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy, or cycloalkyl; Each R 15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclyl; Each R 16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; J is O or S; t is between 0 and 2; and (n is 0 to 3).

[0123] In one embodiment, provided herein is a compound of formula XIV, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; wherein X is C=O; and Y is -R a OR b and; R a is an alkylene or a direct bond; R b is hydrogen or alkyl; R 1 and R 2 are hydrogen; R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; R 9 is aryl or heteroaryl, each of which is optionally substituted with 1 to 4 halo; R 10 is alkylene; Each Q 3 is a halo; and (n is 0 to 3).

[0124] In one embodiment, provided herein is a compound of formula XV, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] where the variables are as described herein.

[0125] In one embodiment, provided herein is a compound of formula XV, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; wherein X is C=O; and Y is -Ra OR b and; R a is an alkylene or a direct bond; R b is hydrogen or alkyl; R 9 is aryl or heteroaryl, each of which is optionally substituted with 1 to 4 halo; and Q 3 is a halo).

[0126] In one embodiment, provided herein is a compound of formula XVI, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (Wherein, each Q 7 is halo, x is 0 to 4, and the remainder of the variables are as described herein.

[0127] In one embodiment, provided herein is a compound of formula XI, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; wherein X is C=O; and Y is -R a OR b and; R a is an alkylene or a direct bond; R b is hydrogen or alkyl; R 1 and R 2 are hydrogen; R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; Each Q 7 is a halo; R 10 is alkylene; Each Q 3 is a halo; x is 0 to 4; and n is 0 to 3.

[0128] In one embodiment, provided herein is a compound of formula XVII, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (Wherein, each Q 7 is halo, x is 0 to 4, and the remainder of the variables are as described herein.

[0129] In one embodiment, provided herein is a compound of formula XVII, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; (Wherein, Y is -R a OR b and; R a is an alkylene or a direct bond; R b is hydrogen or alkyl; Each Q 7 is a halo; Each Q 3 is a halo; x is 0 to 4; and (n is 0 to 3).

[0130] In one embodiment, provided herein is a compound of formula XVIII, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (Wherein, each Q 7 is halo, and the remainder of the variables are as described herein).

[0131] In one embodiment, provided herein is a compound of formula XVIII, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; wherein X is C=O; and Y is -R a OR b and; R a is an alkylene or a direct bond; R b is hydrogen or alkyl; R 1 and R 2 are hydrogen; R 4 , R 5 and R 6 are each independently hydrogen or alkyl; Each Q 7 is a halo; R 10 is alkylene; Each Q 3 is a halo; and (n is 0 to 3).

[0132] In one embodiment, provided herein is a compound of formula XIX, or an enantiomer or a mixture of enantiomers thereof, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: [ka] (Wherein, each Q 7 is halo, and the remainder of the variables are as described herein).

[0133] In one embodiment, provided herein is a compound of formula XIX, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; (Wherein, Y is -R a OR b and; R a is an alkylene or a direct bond; R b is hydrogen or alkyl; Each Q 7 is a halo; and Each Q 3 is a halo).

[0134] In one embodiment, provided herein is a compound of formula XIX, or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; (Wherein, Y is -R a OR b and; R a is an alkylene or a direct bond; R b is hydrogen or alkyl; Each Q 7 is fluoro; and Each Q 3 is chloro).

[0135] (6.3. Treatment method) The compounds provided herein are used in methods for the treatment of conditions associated with or modulated by caspase-1, caspase-4 and / or caspase-5.

[0136] Accordingly, in one embodiment, provided herein is a method for treating or preventing a disease modulated by caspase-1, caspase-4 and / or caspase-5 in a subject, comprising administering to the subject a compound provided herein.

[0137] Disease conditions that can be treated or prevented by the compounds provided herein and / or pharmaceutical compositions thereof include, but are not limited to, inflammatory diseases, autoimmune diseases, proliferative disorders, infectious diseases, and degenerative diseases.

[0138] In one embodiment, inflammatory diseases that can be treated or prevented by the compounds provided herein and / or pharmaceutical compositions thereof include, but are not limited to, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, and adult respiratory distress syndrome.

[0139] In one embodiment, inflammatory diseases that can be treated or prevented by the compounds provided herein and / or pharmaceutical compositions thereof include chronic and acute diseases, such as, but not limited to, autoinflammatory diseases, such as cryopyrin-associated periodic fever syndrome (CAPS), and neuroinflammatory diseases, such as multiple sclerosis (MS), Parkinson's disease, and Alzheimer's disease. Treatment of acute inflammatory diseases, such as, for example, septic shock, sepsis, and adult respiratory distress syndrome, is also targeted by the methods provided herein.

[0140] In one embodiment, autoimmune diseases that can be treated or prevented by the compounds provided herein and / or pharmaceutical compositions thereof include, but are not limited to, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, and graft-versus-host disease.

[0141] In one embodiment, diseases that can be treated or prevented by the compounds provided herein and / or pharmaceutical compositions thereof include destructive bone disorders, such as, but not limited to, osteoporosis and multiple myeloma-related bone disorder.

[0142] In one embodiment, diseases that can be treated or prevented by the compounds provided herein and / or pharmaceutical compositions thereof include, but are not limited to, infectious diseases such as sepsis, septic shock, and Shigellosis.

[0143] In one embodiment, degenerative diseases that can be treated or prevented by the compounds provided herein and / or pharmaceutical compositions thereof include, but are not limited to, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, AIDS-associated encephalitis, HIV-associated encephalitis, aging, alopecia, and neurological damage due to stroke.

[0144] Other diseases that include an inflammatory or apoptotic component can also be treated or prevented by the compounds provided herein. These diseases may be systemic diseases or diseases with local effects on the liver or other organs, and may be caused by, for example, excessive dietary alcohol intake or viruses such as HBV, HCV, HGV, yellow fever virus, dengue virus, and Japanese encephalitis virus.

[0145] In one embodiment, provided herein is a method of treating or preventing a disease in a subject comprising administering to the subject a compound provided herein, the disease being inflammation or inflammatory diseases, inflammatory bowel disease, sepsis and septic shock, degenerative diseases (including Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinal-bulbar atrophy, prion diseases, dementia); cerebral hypoxia, anoxia, hyperoxia; ischemic multifocal lesions in the cortical or lenticulostriate branches of the MCA, ischemic lesions in the middle cerebral artery (MCA) or left cerebral hemisphere region caused by patent ductus arteriosus or hemodynamic abnormalities from more direct pathways including the left common carotid artery;Focal arterial infarction, retinal pericyte apoptosis, retinal neuron apoptosis, glaucoma, retinal degenerative diseases, age-related macular degeneration (AMD) retinal damage due to focal ischemia, diabetic retinopathy (retinopaty), epilepsy, apoptosis in spinal cord injury, apoptosis due to traumatic brain injury, retinal ischemia, apoptosis in pathological conditions of focal cerebral ischemia, cytotoxic T cell and natural killer cell mediated apoptosis with autoimmune diseases and transplant rejection, cardiac cell death including heart failure, cardiomyopathies, viral or bacterial infections of the heart, myocardial ischemia, myocardial infarction, and myocardial ischemia, coronary artery bypass grafting, mitochondrial drug toxicity, e.g. as a result of chemotherapy or HIV therapy, cell death during viral or bacterial infection, cell death from the follicle stage to the oocyte stage, cell death from the oocyte stage to the mature oocyte stage death, and cell death of sperm (e.g., ovarian tissue freezing and transplantation procedures, fecondation), or to preserve fertility in women and men after chemotherapy or to preserve fertility in female and male animals, macular degeneration and glaucoma, acute hepatitis, chronic active hepatitis, hepatitis B and C, hair loss, and male pattern baldness, hair loss due to radiation therapy, chemotherapy or emotional stress, skin damage (due to high levels of radiation, heat, burns, chemicals, exposure to the sun, and autoimmune diseases), cell death of bone marrow cells in myelodysplastic syndromes (MDS), pancreatitis, respiratory syndromes, or osteoarthitis, rheumatoid arthritis, psoriasis, glomerulonephritis, atheroscerosis, and graft versus host disease, disease states associated with increased inflammation;

[0146] In some embodiments, provided herein are methods of using the compounds herein for the treatment and / or prevention of cancer. Exemplary cancers include lung cancer, colorectal cancer (CRC), melanoma, gastric cancer (including esophageal cancer), renal cell carcinoma (RCC), breast cancer, prostate cancer, head and neck cancer, bladder cancer, hepatocellular carcinoma (HCC), ovarian cancer, cervical cancer, endometrial cancer, pancreatic cancer, neuroendocrine cancer, hematological cancer (particularly multiple myeloma, acute myeloblastic leukemia (AML)), and biliary tract cancer.

[0147] In one embodiment, provided herein is a therapy for improving the treatment of cancers having at least a partial inflammatory basis, such as cancers described herein, such as lung cancer. In one embodiment, provided herein is the use of the compounds herein for the treatment and / or prevention of cancers having at least a partial inflammatory basis, such as cancers described herein, such as lung cancer. In another aspect, provided herein is a specific clinical dosing regimen for the administration of the compounds herein for the treatment and / or prevention of cancer. In another aspect, a subject suffering from a cancer having at least a partial inflammatory basis, including lung cancer, is administered one or more therapeutic agents (e.g., chemotherapeutic agents) and / or has undergone / will undergo cytoreduction surgery in addition to administration of the compounds herein.

[0148] In some embodiments, a method of treating or preventing cancer in a human subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound provided herein.

[0149] Another aspect of the present invention is the use of the compounds herein for the manufacture of a medicament for the treatment of cancer.

[0150] In some embodiments, the compounds herein are used to treat or prevent cryopyrin-associated periodic fever syndromes (CAPS), familial Mediterranean fever (FMF), systemic onset juvenile idiopathic arthritis (SJIA), hyperimmunoglobulin D syndrome (HIDS), and tumor necrosis factor receptor-associated periodic syndromes (TRAPS), among others, familial cold urticaria, neonatal-onset multisystem inflammatory disease, SJIA and FMF, and Muckle-Wells syndrome.

[0151] In some embodiments, the compounds provided herein may be used in any of the methods listed above.

[0152] 6.4. Pharmaceutical Compositions Pharmaceutical compositions provided herein contain a therapeutically effective amount of one or more compounds provided herein that are useful in the prevention, treatment, or amelioration of one or more conditions associated with or modulated by caspase-1, caspase-4, and / or caspase-5, or one or more symptoms of conditions associated with or modulated by caspase-1, caspase-4, and / or caspase-5, such as those described in Section 4.4, and a pharma- ceutical acceptable carrier.

[0153] The compounds can be formulated into suitable pharmaceutical preparations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations, or elixirs for oral administration, or sterile solutions or suspensions for parenteral administration, as well as transdermal patches and dry powder inhalants. In one embodiment, the compounds provided herein are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, for example, Remington's Pharmaceutical Sciences, 20th Edition, Mack Publishing, Easton PA (2000)).

[0154] In the composition, an effective concentration of one or more compounds or pharma- ceutically acceptable derivatives are mixed with a suitable pharmaceutical carrier or vehicle. The compounds can be derivatized prior to formulation as the corresponding salts, esters, acids, bases, solvates, hydrates, or prodrugs, as described above. The concentration of the compounds in the composition is effective to deliver, upon administration, an amount that treats, prevents, or ameliorates a condition, or one or more symptoms of a condition, modulated by one or more caspases, as described in Section 4.4.

[0155] In one embodiment, the composition is formulated for single dosage administration. To formulate the composition, the weight fraction of the compound is dissolved, suspended, dispersed or mixed in the selected vehicle at a concentration effective to relieve or ameliorate the symptoms to be treated. Pharmaceutical carriers or vehicles suitable for administering the compounds provided herein include all carriers known to those skilled in the art to be suitable for the particular mode of administration.

[0156] Furthermore, the compounds may be formulated as the only pharmacoactive ingredient in the composition or may be combined with other active ingredients. Liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmacologic acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposomal formulations may be prepared as known in the art. Briefly, liposomes, such as multilamellar vesicles (MLVs), may be formed by drying down egg phosphatidylcholine and brain phosphatidylserine (7:3 molar ratio) in a flask. A compound provided herein is added in a solution of phosphate buffered saline (PBS) without divalent cations, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0157] The active compound is contained in a pharma- ceutical acceptable carrier in an amount sufficient to exert a therapeutically useful effect without causing undesirable side effects in the patient being treated. The therapeutically effective concentration can be determined empirically by testing the compound in in vitro and in vivo systems known in the art, and dosages for humans can be extrapolated from the tests.

[0158] The concentration of active compound in the pharmaceutical composition will depend on absorption, inactivation, and excretion rates of the active compound, the physicochemical properties of the compound, the dosage regimen, and the amount administered, as well as other factors known to those of skill in the art.

[0159] In one embodiment, the therapeutically effective dosage is from about 0.1 ng / ml to about 50-100 μg / ml, from about 0.5 ng / ml to about 80 μg / ml, from about 1 ng / ml to about 60 μg / ml, from about 5 ng / ml to about 50 μg / ml, from about 5 ng / ml to about 40 μg / ml, from about 10 ng / ml to about 35 μg / ml, from about 10 ng / ml to about 25 μg / ml, from about 10 ng / ml to about 10 μg / ml, from about 25 ng / ml to about 10 μg / ml, or from about 50 ng / ml to about 50 μg / ml. The dose should result in a serum concentration of the active ingredient of about 1 to about 10 μg / ml, about 50 ng / ml to about 5 μg / ml, about 100 ng / ml to about 5 μg / ml, about 200 ng / ml to about 5 μg / ml, about 250 ng / ml to about 5 μg / ml, about 500 ng / ml to about 5 μg / ml, about 1 μg / ml to about 50 μg / ml, about 0.1 ng / ml to about 5 ng / ml, about 1 ng / ml to about 10 ng / ml, or about 1 μg / ml to about 10 μg / ml. In one embodiment, the pharmaceutical composition is administered at about 0.001 mg to about 2000 mg of the compound per kg of body weight per day, about 0.002 mg to about 1000 mg of the compound per kg of body weight per day, about 0.005 mg to about 500 mg of the compound per kg of body weight per day, about 0.005 mg to about 250 mg of the compound per kg of body weight per day, about 0.005 mg to about 200 mg of the compound per kg of body weight per day, about 0.005 mg to about 100 mg of the compound per kg of body weight per day, about 0.001 mg to about 0.005 mg of the compound per kg of body weight per day, about 0.01 mg to about 100 mg of the compound per kg of body weight per day, about 0.02 ... of the compound per kg of body weight per day, about 0.005 mg of the compound per kg of body weight per day, about 0.005 mg of the compound per kg of body weight per day, about 0.005 mg of the compound per kg of body weight per day, about 0.005 mg of the compound per kg of body weight per day, about 0.005 mg of the compound per kg of body weight per day, about 0.005 mg of to about 100 mg of the compound per kg of body weight per day, about 0.05 mg to about 100 mg of the compound per kg of body weight per day, about 0.1 mg to about 100 mg of the compound per kg of body weight per day, about 0.5 mg to about 100 mg of the compound per kg of body weight per day, about 0.75 mg to about 100 mg of the compound per kg of body weight per day, about 1 mg to about 100 mg of the compound per kg of body weight per day, about 1 mg to about 10 mg of the compound per kg of body weight per day, about 0.001 mg to about 5 mg of the compound per kg of body weight per day, about 200 mg to about 2000 mg of the compound per kg of body weight per day, or about 10 mg to about 100 mg of the compound per kg of body weight per day should be provided.Pharmaceutical dosage unit forms are manufactured to provide from about 1 mg to about 1000 mg, from about 1 mg to about 800 mg, from about 5 mg to about 800 mg, from about 1 mg to about 100 mg, from about 1 mg to about 50 mg, from about 5 mg to about 100 mg, from about 10 mg to about 50 mg, from about 10 mg to about 100 mg, from about 25 mg to about 50 mg, and from about 10 mg to about 500 mg of the essential active ingredient or combination of essential ingredients per dosage unit form.

[0160] The active ingredient may be administered once or may be divided into several smaller doses and administered at intervals.It is understood that the exact dosage and duration of treatment will vary according to the effect of the disease being treated, and can be determined empirically using known test protocols or by extrapolation from in vivo or in vitro test data.It should be noted that the concentration and dosage values ​​can also vary with the severity of the symptoms to be alleviated.It should be further understood that the specific dosage regimen for any particular subject should be adjusted over time according to individual need and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges described herein are merely illustrative and are not intended to limit the scope or practice of the claimed compositions.

[0161] Pharmaceutically acceptable derivatives include acids, bases, and esters, salts, esters, hydrates, solvates, and prodrug forms. Derivatives are selected such that their pharmacokinetic properties are superior to those of the corresponding neutral compounds.

[0162] From the above, an effective concentration or amount of one or more of the compounds described herein or pharma- ceutically acceptable derivatives thereof is mixed with a pharmaceutical carrier or vehicle suitable for systemic, targeted local, or topical administration to form a pharmaceutical composition. The compound is included in an amount effective to ameliorate, treat, or prevent the recurrence of one or more symptoms associated with or modulated by caspase-1, caspase-4, and / or caspase-5, such as those described in Section 4.4. The concentration of active compound in the composition will depend on the absorption, inactivation, and excretion rates of the active compound, the dosing schedule, the dosage, the particular formulation, and other factors known to those skilled in the art.

[0163] The composition is intended to be administered by a suitable route, including orally, parenterally, by intravitreal injection, by drug-impregnated contact lens, rectally, locally targeted, topically, by inhalation spray, nasally, intraoral buccal, vaginally, by implanted reservoir, or via a nasogastric or oral gastric tube. In some embodiments, administration is by oral route. In other embodiments, administration is by parenteral route. For oral administration, capsules and tablets can be used. The composition is in liquid, semi-liquid, or solid form, and is formulated in such a way as to be suitable for each administration route. In one embodiment, the mode of administration includes parenteral and oral modes of administration. In some embodiments, oral administration is intended.

[0164] Solutions or suspensions used for parenteral, intravitreal, intradermal, subcutaneous, or targeted topical applications can contain any of the following components: sterile diluents such as water for injection, saline solution, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, dimethylacetamide, or other synthetic solvents; antibacterial agents such as benzyl alcohol and methylparaben; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, and phosphates; and isotonicity adjusters such as sodium chloride or glucose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or single- or multiple-dose vials made of glass, plastic, or other suitable materials.

[0165] In cases where a compound exhibits insufficient solubility, methods of solubilizing the compound can be used, including, but not limited to, methods known to those skilled in the art, such as using a co-solvent such as dimethylsulfoxide (DMSO), using a surfactant such as TWEEN®, or dissolving in aqueous sodium bicarbonate.

[0166] The mixture obtained by mixing or adding the compounds may be a solution, suspension, emulsion, etc. The form of the resulting mixture will depend on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to ameliorate the symptoms of the disease, disorder, or condition being treated and can be empirically determined.

[0167] Pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms (unit dose forms), such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, as well as oil / water emulsions, containing a suitable amount of the compound or its pharma- ceutically acceptable derivatives. Pharmaceutically therapeutically active compounds and their derivatives are formulated and administered in unit dosage forms or multiple dosage forms. Unit dosage forms, as used herein, refer to physically individually separated units suitable for human and animal subjects, packaged separately as known in the art. Each unit dosage contains a predetermined amount of therapeutically active compound sufficient to produce the desired therapeutic effect, together with the required pharmaceutical carrier, vehicle, or diluent. Examples of unit dosage forms include ampoules and syringes, as well as individually packaged tablets or capsules. Unit dosage forms can also be administered in fractions or multiples thereof. Multiple dosage forms are a plurality of identical unit dosage forms packaged in a single container to be administered in separate unit dosage forms. Examples of multiple-dosage forms include a vial, bottle, or pints or gallons of tablets or capsules. Thus, a multiple-dosage form is a multiple of unit doses that are not segregated in packaging.

[0168] Sustained release preparations can also be made. Suitable examples of sustained release preparations include semipermeable matrices of hydrophobic solid polymers containing the compounds provided herein, which matrices are in the form of shaped articles, e.g., films or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactic acid, copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for periods of more than 100 days, certain hydrogels release proteins for shorter periods of time. When encapsulated compounds are maintained in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37° C., resulting in loss of biological activity as well as changes in the structure of the compound. Depending on the mechanism of action involved, rational strategies for stability can be devised. For example, if the aggregation mechanism is found to be the formation of intermolecular S-S bonds via thio-disulfide exchange, stabilization can be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling the moisture content, using suitable additives, and developing specific polymer matrix compositions.

[0169] Active ingredient 0.001%~100%, Active ingredient 0.002%~100%, Active ingredient 0.005%~90%, Active ingredient 0.01%~100%, Active ingredient 0.05%~100%, Active ingredient 0.05%~90%, Activity Ingredients 0.1%~100%, Active ingredients 0.1%~1%, Active ingredients 0.1%~0.5%, Active ingredients 1%~100%, Active ingredients 1%~99%, Active ingredients 1%~98%, Active ingredients 1%~97%, Active ingredients 1%~96% Dosage forms or compositions containing the active ingredient may be prepared in the range of 1%-95% active ingredient, 5%-95% active ingredient, 10%-100% active ingredient, 10%-95% active ingredient, 15%-95% active ingredient, 20%-95% active ingredient, 25%-100% active ingredient, 50%-100% active ingredient, 50%-95% active ingredient, 60%-95% active ingredient, or 75%-100% active ingredient, with the remainder consisting of non-toxic carriers. For oral administration, pharma- ceutically acceptable non-toxic compositions may be prepared by incorporating any of the commonly employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate, or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders, and sustained release formulations, including, but not limited to, implants and microencapsulated delivery systems, as well as biodegradable, biocompatible polymers such as collagen, ethylene-vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, and others. Methods for preparing these compositions are known to those skilled in the art. Contemplated compositions may contain from 0.001% to 100% active ingredient, and in one embodiment, 75-95% active ingredient.

[0170] The active compounds or pharma- ceutically acceptable derivatives may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.

[0171] The compositions can contain other active compounds to obtain a desired combination of properties. The compounds provided herein, or their pharma- ceutically acceptable derivatives described herein, can also be advantageously administered to subjects with one or more caspase-modulated conditions for therapeutic or prophylactic purposes together with other pharmacological agents known in the general art to be of value in treating the same conditions. It should be understood that such combination therapy constitutes a further aspect of the compositions and methods of treatment provided herein.

[0172] (Composition for oral administration) Oral pharmaceutical dosage forms are either solid, gel, or liquid. Solid dosage forms are tablets, capsules, granules, and mixed powders. Types of oral tablets include compressed, chewable, lozenge, and tablets, which may be enteric-coated, sugar-coated, or film-coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with other ingredients known to those skilled in the art.

[0173] In some embodiments, the formulation is a solid dosage form such as a capsule or tablet. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients: binders, diluents, disintegrants, lubricants, flow agents, sweeteners, and flavoring agents, or compounds of a similar nature.

[0174] Examples of binders include microcrystalline cellulose, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, sucrose, and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium, and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol, and dicalcium phosphate. Flow agents include, but are not limited to, colloidal silicon dioxide. Disintegrants include, for example, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose. Coloring agents include, for example, any of the approved and certified water-soluble FD and C dyes, mixtures thereof; and water-insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol, and artificial sweeteners such as saccharin, as well as any number of spray-dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits, as well as synthetic blends of compounds that produce a pleasant sensation, such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene laural ether. Emetic coatings include fatty acids, fats, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate.

[0175] When oral administration is desired, the compound can be provided in a composition that protects the compound from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid or other such ingredient.

[0176] When the dosage unit form is a capsule, the capsule can contain liquid carriers such as fatty oils in addition to the above-mentioned types of materials.Furthermore, the dosage unit form can contain various other materials that modify the physical form of the dosage unit, such as coatings of sugar and other enteric agents.The compound can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum, etc.Syrup can contain sucrose as a sweetener, as well as certain preservatives, dyes and colorings, and flavorings in addition to the active compound.

[0177] The active materials can also be mixed with other active materials which do not impair the desired action, or materials which supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound described herein or a pharma- ceutical acceptable derivative thereof. Higher concentrations of the active ingredient, up to about 98% by weight, can also be included.

[0178] The pharma- ceutical acceptable carriers contained in the tablet are binders, lubricants, diluents, disintegrants, colorants, flavorings, and wetting agents. Enteric-coated tablets resist the action of stomach acid and dissolve or disintegrate in neutral or alkaline intestines due to the enteric coating. Sugar-coated tablets are compressed tablets to which various layers of pharma- ceutical acceptable materials are applied. Film-coated tablets are compressed tablets that are covered with a polymer or other suitable coating. Multiple compressed tablets are compressed tablets that are produced by more than one compression cycle using the pharma- ceutical acceptable materials described above. Coloring agents can also be used in the above dosage forms. Flavorings and sweetening agents are used in compressed tablets, sugar-coated tablets, multiple compressed tablets, and chewable tablets. Flavorings and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0179] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

[0180] Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, e.g., sucrose, and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents, and preservatives. Suspensions use pharma- ceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-effervescent granules for reconstitution into a liquid oral dosage form include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable substances used in effervescent granules for reconstitution into a liquid oral dosage form include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.

[0181] Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of preservatives include glycerin, methyl and propyl parabens, benzoic add, sodium benzoate, and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrup, glycerin, and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes and mixtures thereof. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation.

[0182] For solid dosage forms, the solution or suspension, for example in propylene carbonate, vegetable oils, or triglycerides, can be encapsulated in a gelatin capsule. Such solutions, and their preparation and encapsulation, are disclosed in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. For liquid dosage forms, the solution, for example in a polyethylene glycol, can be diluted with a sufficient quantity of a pharma- ceutical acceptable liquid carrier, for example, water, so that it may be easily measured for administration.

[0183] Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate), and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including but not limited to, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, 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), and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0184] Other formulations include, but are not limited to, aqueous alcohol solutions containing pharma- ceutically acceptable acetals. The alcohols used in these formulations are any pharma- ceutically acceptable water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal.

[0185] In all embodiments, the tablet and capsule formulations can be coated as known to those skilled in the art to alter or sustain dissolution of the active ingredient. Thus, for example, they can be coated with conventional enteric digestible coating agents such as phenylsalicylate, waxes, and cellulose acetate phthalate.

[0186] (Injections, solutions, and emulsions) Parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly, intravitreously, or intravenously, is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, or ethanol. In addition, if desired, the administered pharmaceutical composition can also contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffers, stabilizers, solubility enhancers, and other such agents, such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins. Implantation of a sustained-release or sustained-release system, such that a constant level of dosage is maintained, is also contemplated herein. Briefly, the compounds provided herein are dispersed in a solid inner matrix. This solid inner matrix may be, for example, a hydrophilic polymer such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone-carbonate copolymers, hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate, and is surrounded by an outer polymeric membrane. The outer polymeric membrane may be, for example, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, copolymers of ethylene and propylene with vinyl chloride, ionomeric polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers, and is insoluble in body fluids.The compound diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active compound in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.

[0187] Parenteral administration of the composition includes intravenous, intravitreal, subcutaneous and intramuscular administration.Preparations for parenteral administration include sterile liquids ready for injection, sterile dry soluble products such as freeze-dried powders that can be combined with solvents immediately before use, including tablets for subcutaneous injection, sterile suspensions ready for injection, sterile dry insoluble products that can be combined with vehicles immediately before use, and sterile emulsions.These liquids can be either aqueous or non-aqueous.

[0188] If administered intravenously, suitable carriers include saline or phosphate buffered saline (PBS), as well as solutions containing viscosity enhancing and solubilizing agents such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0189] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other pharma- ceutically acceptable substances.

[0190] Examples of aqueous vehicles include Sodium Chloride Injection, Ringer's Injection, Isotonic Dextrose Injection, Sterile Water Injection, and Lactated Ringer's Dextrose Injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multi-dose containers, and include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, the methyl and propyl esters of p-hydroxybenzoic acid, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonicity agents include sodium chloride and dextrose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Emulsifying agents include polysorbate 80 (TWEEN® 80). Sequestering or chelating agents of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol, and propylene glycol for water miscible vehicles, and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0191] The concentration of the pharma- ceutical active compound is adjusted so that injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight, and condition of the patient or animal, as is known in the art.

[0192] Unit dose parenteral preparations are packaged in ampoules, vials, or syringes with needles. All preparations for parenteral administration must be sterile, as is known and practiced in the art.

[0193] Specifically, intravenous, intravitreal, or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing the active material injected as necessary to produce the desired pharmacological effect.

[0194] Injectables are designed for local and systemic administration. In some embodiments, therapeutically effective dosages are formulated to contain at least about 0.1% w / w to as much as about 90% w / w or more, or greater than 1% w / w, of the active compound relative to the tissue(s) being treated. The active ingredient may be administered once or divided into several smaller doses and administered at intervals of time. It is understood that the precise dosage and duration of treatment will vary as a function of the tissue being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It should be noted that concentration and dosage values ​​may also vary with the age of the individual being treated. It should be further understood that the specific dosage regimen for any particular subject will be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulation, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations.

[0195] The compound may be suspended in micronized or other suitable form, and may be derivatized to make the active product more soluble, or to make a prodrug. The form of the resulting mixture depends on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to ameliorate the symptoms of the condition, and can be empirically determined.

[0196] (lyophilized powder) Also of interest herein are lyophilized powders that can be reconstituted for administration into solutions, emulsions, and other mixtures. They can also be reconstituted and formulated as solids or gels.

[0197] Sterile lyophilized powders are prepared by dissolving a compound provided herein, or a pharma- ceutically acceptable derivative thereof, in a suitable solvent. The solvent may contain excipients that improve the stability or other pharmacological components of the powder or reconstituted liquid prepared from the powder. Excipients that can be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agents. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate, or other such buffers at nearly neutral pH, known to those of skill in the art. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. Typically, the resulting solution will be dispensed into vials for lyophilization. Each vial will contain a single dose (10-1000 mg or 100-500 mg) or multiple doses of the compound. The lyophilized powder can be stored under suitable conditions, such as at about 4° C. to room temperature.

[0198] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, about 1-50 mg, 5-35 mg, or about 9-30 mg of lyophilized powder is added per mL of sterile water or other suitable carrier. The exact amount will depend on the compound selected. Such amounts can be determined empirically. (Targeted local administration) Targeted topical mixtures are prepared as described for local and systemic administration. The resulting mixture may be a solution, suspension, emulsion, etc., and is formulated as a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, irrigation, spray, suppository, dressing, transdermal patch, contact lens, or any other formulation suitable for targeted topical application.

[0199] The compound or its pharma- ceutical acceptable derivatives can be formulated as an aerosol for targeted local application, such as by inhalation (see, for example, U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for the delivery of steroids useful in the treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract may be in the form of an aerosol or liquid for nebulizers, or may be ultrafine powders for insufflation, alone or in combination with an inert carrier such as lactose. In such cases, the particles of the formulation will have a diameter of less than 50 microns or less than 10 microns.

[0200] The compounds can be formulated for topical application or targeted local application, for example, in the form of gels, creams, and lotions for targeted local application to the skin and mucous membranes, such as the ophthalmic region, and for application to the eye, or for intracisternal or intrathecal application. Targeted local administration is also intended for transdermal delivery, and also for administration to the eye or mucous membranes, or for inhalation therapy. Nasal solutions of the active compound alone or in combination with other pharma- ceutical acceptable excipients can also be administered.

[0201] These solutions, particularly those intended for ophthalmic use, can be formulated as 0.01%-10% isotonic solutions (pH about 5-7) containing appropriate salts.

[0202] Compositions for other routes of administration Other routes of administration, such as targeted topical application, transdermal patches, and rectal administration, are also contemplated herein.

[0203] For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules, and tablets for systemic action. Rectal suppositories as used herein refer to solid bodies for insertion into the rectum that melt or soften at body temperature and release one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances used in rectal suppositories are bases or vehicles, and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene glycol), and suitable mixtures of mono-, di-, and triglycerides of fatty acids. Combinations of various bases may be used. Agents to raise the melting point of the suppository include spermaceti and wax. Rectal suppositories may be prepared by either the compressed or molding method. In one embodiment, the weight of a rectal suppository is about 2 to 3 grams.

[0204] Tablets and capsules for rectal administration are manufactured using the same pharma- ceutical acceptable substance and by the same methods as those for oral administration.

[0205] Sustained Release Compositions Active ingredients, such as the compounds provided herein, can be administered by controlled release means or delivery devices known to those skilled in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,35 Nos. 6,589,548, 6,613,358, and 6,699,500, each of which is incorporated herein by reference. Such dosage forms can provide a sustained or controlled release of one or more active ingredients using, for example, hydropropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide desired release profiles at various rates. Suitable controlled release formulations known to those skilled in the art, including those described herein, can be easily selected for use with the active ingredients provided herein. Thus, the compositions provided include single unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gel caps, and caplets, that are suitable for controlled release.

[0206] All controlled release pharmaceutical products have a common goal of improving drug therapy compared to that achieved by their corresponding non-controlled counterparts. Ideally, the use of optimally designed controlled release preparations in medical treatment is characterized by the use of a minimum amount of drug substance to cure or control symptoms in a minimum amount of time. Advantages of controlled release formulations include extended drug activity effect, reduced dosing frequency, and improved subject compliance. In addition, controlled release formulations can be used to affect other characteristics, such as the time of onset of active action or blood levels of the drug, and thus affect the occurrence of side effects (e.g., adverse effects).

[0207] Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that produces a desired therapeutic effect immediately, and then slowly and continuously release another amount of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of the active ingredient can be stimulated by various conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0208] In some embodiments, the drug can be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump can be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., 1980; 88:507; Saudek et al., N. Engl. J. Med. 1989; 321: 574). In another embodiment, a polymeric material can be used. In yet another embodiment, the controlled release system can be placed in a subject at a suitable site determined by a skilled practitioner, i.e., so that only a fraction of the systemic dose is required (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, 1984, pp. 115-138). Other controlled release systems are described in the review by Langer (Science 1990; 249:1527-1533). The active ingredient can be dispersed in a solid inner matrix, such as polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized 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 and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate, surrounded by an outer polymeric membrane.The outer polymeric membrane is, for example, polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, ethylene and propylene and vinyl chloride copolymer, ionomeric polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, and is insoluble in body fluids.The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step.The percentage of active compound in such parenteral compositions is highly dependent on its specific nature and the needs of the subject.

[0209] (Targeted formulations) The compounds provided herein or their pharma- ceutical acceptable derivatives can be formulated to target specific tissues, receptors, or other sites in the body of the subject to be treated.Many such targeting methods are well known to those skilled in the art.All such targeting methods are contemplated herein for use in the present compositions. For non-limiting examples of targeting methods, see, e.g., 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.

[0210] In one embodiment, liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharma- ceutically acceptable carriers. They can be prepared according to methods known to those skilled in the art. For example, liposomal formulations can be prepared as described in U.S. Pat. No. 4,522,811. Briefly, liposomes, such as multilamellar vesicles (MLVs), can be formed by drying down egg phosphatidylcholine and brain phosphatidylserine (7:3 molar ratio) inside a flask. A solution of a compound provided herein in phosphate buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0211] Dosage and Unit Dose Form In treating humans, the physician will determine the dosage regimen that he or she considers optimal depending on the prophylactic or therapeutic treatment, as well as on the age, weight, stage of the disease, and other factors specific to the subject being treated. Typically, the dosage is about 1 to about 1000 mg per day for an adult, or about 5 to about 250 mg per day for an adult, or about 10 to 50 mg per day for an adult. In certain embodiments, the dosage is about 5 to about 400 mg per day for an adult, or 25 to 200 mg per day for an adult. Administration rates of about 50 to about 500 mg per day are also contemplated.

[0212] In some embodiments, the amount of a compound or composition that is effective in treating colon cancer or preventing one or more symptoms thereof will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered.Frequency and dosage will also vary according to factors specific to each subject, which depend on the specific therapy (e.g., therapeutic or prophylactic agent) administered, the severity of the disorder, disease, or condition, the route of administration, and the subject's age, physical condition, weight, response, and past medical history.Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0213] Exemplary dosages of the compositions include milligram or microgram amounts of chemotherapeutic agent and caspase inhibitor per kg of subject or sample animal weight (e.g., about 0.001-1000 mg / Kg, about 0.01-100 mg / Kg, about 0.01-50 mg / Kg, about 0.1-25 mg / Kg, or about 0.1-10 mg / Kg). In some embodiments, the dosage administered to a subject is between 0.20 mg / Kg and 2.00 mg / Kg, or between 0.30 mg / Kg and 1.50 mg / Kg of the subject's body weight.

[0214] In one embodiment, the recommended daily dosage range of the caspase inhibitors described herein and, optionally, if applicable, the chemotherapeutic agents co-administered for the conditions described herein ranges from about 0.1 mg to about 1000 mg of each of the chemotherapeutic agent and the caspase inhibitor per day, whether as a single, once-daily dose or as multiple doses divided over a single day. In one embodiment, the daily dosage is administered twice daily in evenly divided doses. Specifically, the daily dosage range should be between about 10 mg and about 200 mg per day, more specifically between about 10 mg and about 150 mg per day, or even more specifically between about 25 and about 100 mg per day. As will be apparent to one of skill in the art, in some cases, it may be necessary to use dosages of the active ingredients outside the ranges disclosed herein. Furthermore, it should be noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in relation to the subject's response.

[0215] As will be readily known by those skilled in the art, different therapeutically effective amounts are applicable for different diseases and symptoms.Similarly, amounts sufficient to prevent, manage, treat or alleviate such disorders, but insufficient to cause or reduce adverse effects associated with the compounds described herein, are also encompassed by the dosage and administration frequency schedules described above.Furthermore, when a subject is administered multiple dosages of the compounds described herein, not all dosages need to be the same.For example, the dosage administered to a subject can be increased to improve the preventive or therapeutic effect of the compound, and the dosage can be decreased to reduce one or more side effects suffered by a particular subject.

[0216] In one embodiment, the dosage of a compound provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof, in a subject is 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, or 15 mg / kg or more of the subject's body weight. In another embodiment, the dosage of a compound provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof, in a subject is 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 10 mg, 0.1 mg to 1 ... The unit dosage is 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

[0217] In certain embodiments, treatment or prevention begins with one or more loading doses of the caspase inhibitor and, optionally, co-administered chemotherapeutic agent, if applicable, followed by one or more maintenance doses. In such embodiments, the loading dose can be, for example, about 60 to about 400 mg per day or about 100 to about 200 mg per day for one day to five weeks. The loading dose can be followed by one or more maintenance doses. Each maintenance dose can independently be about 10 mg to about 200 mg per day, more specifically, between about 25 mg and about 150 mg per day, or even more specifically, between about 25 mg and about 80 mg per day, or between about 25 mg and about 50 mg per day. The maintenance doses can be administered daily, each as a single dose or as divided doses.

[0218] In certain embodiments, doses of the caspase inhibitors provided herein, and optionally, co-administered chemotherapeutic agents, if applicable, can be administered to achieve a steady state concentration of the active ingredient in the blood or serum of the subject. The steady state concentration can be determined by measurements according to techniques available to those of skill in the art, or can be based on the subject's physical characteristics, such as height, weight, and age. In certain embodiments, a sufficient amount of the compounds provided herein is administered to achieve a blood or serum steady state concentration of about 300 to about 4000 ng / mL, about 400 to about 1600 ng / mL, or about 600 to about 1200 ng / mL in the subject. A loading dose can be administered to achieve a blood or serum steady state concentration of about 1200 to about 8000 ng / mL, or about 2000 to about 4000 ng / mL, for 1 to 5 days. The maintenance dose can be administered to achieve a steady state concentration in the subject's blood or serum of about 300 to about 4000 ng / mL, about 400 to about 1600 ng / mL, or about 600 to about 1200 ng / mL.

[0219] In some embodiments, administration of the same compound may be repeated and each administration may be separated by at least 1, 2, 3, 5, 10, 15, 30, 45, 2, 75, 3, or 6 months. In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated and each administration may be separated by at least 1, 2, 3, 5, 10, 15, 30, 45, 2, 75, 3, or 6 months.

[0220] In certain aspects, provided herein are unit dosage forms comprising the compound or a pharma- ceutically acceptable derivative thereof in a form suitable for administration. Such forms are described in detail above. In certain embodiments, the unit dosage forms comprise 1-1000 mg, 5-250 mg, or 10-50 mg of active ingredient. In particular embodiments, the unit dosage forms comprise about 1, 5, 10, 25, 50, 100, 125, 250, 500, or 1000 mg of active ingredient. Such unit dosage forms can be prepared according to techniques well known to those skilled in the art.

[0221] (6.5.Manufactured products) The compound or pharma- ceutically acceptable derivative can be packaged as an article of manufacture comprising packaging material, a compound provided herein, or a pharma- ceutically acceptable derivative thereof, for use in the treatment, prevention, or amelioration of a condition modulated by caspase, or one or more symptoms associated with that condition, and a label indicating that the compound or a pharma- ceutically acceptable derivative thereof is used for the treatment, prevention, or amelioration of the condition, or one or more symptoms associated with that condition.

[0222] The articles of manufacture provided herein include packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those skilled in the art. For example, see U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. Various formulations of the compounds and compositions provided herein are envisioned.

[0223] (6.6. Kit) Also provided are kits for use of the compounds provided herein in therapeutic methods. The kits can include a caspase inhibitor or a composition thereof and instructions that provide a healthcare provider with information regarding use to treat or prevent one or more caspase-modulated conditions. The instructions can be provided in printed form, in the form of an electronic medium such as a CD or DVD, or in the form of a website address where such instructions can be obtained. A unit dosage of a caspase inhibitor or a composition thereof can include a dosage amount that, when administered to a subject, can maintain a therapeutically or prophylactically effective plasma level of the compound or composition in the subject for at least one day. In some embodiments, the compound or composition can be included as a sterile, aqueous pharmaceutical composition or a dry powder (e.g., lyophilized) composition.

[0224] 6.7. Overview of Compound Preparation The compounds provided herein can be prepared by the general processes outlined in the schemes below. In Schemes 1-4, Ar and Ar' are each aryl and R 1 , R 2 , R 3 , Y 1 , Y 2 and Y 3 is selected as described elsewhere herein.

[0225] Scheme 1: [ka]

[0226] Scheme 2 [ka]

[0227] Scheme 3 [ka]

[0228] Scheme 4 [ka] (wherein M is lower alkylene, OR m or NR n R o and R m is optionally substituted aryl or optionally substituted heteroaryl; R n and R o are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or R n and R o together with the nitrogen atom on which they are substituted form a heterocyclic or heteroaryl ring, each of which is optionally substituted.

[0229] The following examples set forth certain exemplary embodiments and are intended by way of illustration and not by way of limitation. EXAMPLES

[0230] 7. Working Examples The following examples are offered by way of illustration and not by way of limitation. Those skilled in the art can modify the procedures set forth in the illustrated examples to arrive at the desired products. Example 1 [ka]

[0231] Ethyl 2-((2,6-difluorophenyl)amino)-2-oxoacetate (3): Triethylamine (27.2 mL, 193.8 mmol, 1 equiv.) was added to a solution of 2,6-difluoroaniline (25.0 g, 193.8 mmol, 1 equiv.) in THF (1 L) at 0-5° C. Ethyl oxalyl chloride (21.6 mL, 193.8 mmol, 1 equiv.) was added dropwise over 60 min, maintaining the temperature below 5° C. The reaction was allowed to warm to room temperature and stirred for 24 h. The reaction was filtered through Celite, the Celite was washed with methyl t-butyl ether (500 mL), and the combined organic layers were washed with 1N HCl (2×200 mL) and water (400 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the desired product as a beige oil (44.8 g, quantitative yield).

[0232] 2-((2,6-Difluorophenyl)amino)-2-oxoacetic acid (4): 1N lithium hydroxide (233 mL, 233 mmol, 1.2 equiv.) was added to a solution of compound 3 (44.8 g, 193.8 mmol, 1 equiv.) in THF (233 mL). After stirring at room temperature for 4 h, the reaction was cooled to 0° C. and acidified to pH 2 with concentrated HCl. The aqueous mixture was saturated with sodium chloride and extracted with ethyl acetate (6×200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the desired product as a white solid (18.3 g, 47% yield).

[0233] Ethyl (2-((2,6-difluorophenyl)amino)-2-oxoacetyl)-L-alaninate (7): EDC·HCl (25.9 g, 135 mmol, 1.4 equiv.) was added to a suspension of 4 (19.4 g, 96.5 mmol, 1.0 equiv.), HOAt (18.4 g, 135 mmol, 1.4 equiv.) in acetonitrile (1.0 L). The mixture was stirred at room temperature until all solids were dissolved. L-Alanine ethyl ester hydrochloride (14.8 g, 96.5 mmol, 1.0 equiv.) and N-methylmorpholine (19.5 g, 193 mmol, 2.0 equiv.) were added and the mixture was stirred at room temperature overnight. LC-MS analysis indicated the reaction was complete. The mixture was concentrated under reduced pressure and the wet solid was diluted with ethyl acetate (300 mL) and water (100 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was dissolved in dichloromethane (200 mL) and adsorbed onto Celite (30 g). Purification on an Interchim automated system (330 g column) eluted with a 0-5% gradient of ethyl acetate to dichloromethane afforded compound 7 as a white solid (18.2 g, 62.8% yield).

[0234] (2-((2,6-difluorophenyl)amino)-2-oxoacetyl)-L-alanine (8): 1N lithium hydroxide (1.0 N, 71.5 mL, 71.5 mmol, 1.2 equiv.) was added to a solution of compound 7 (17.9 g, 59.6 mmol, 1.0 equiv.) in tetrahydrofuran (240 mL) at room temperature. After stirring for 48 h, LC-MS analysis indicated the reaction was complete. The mixture was cooled in an ice bath and adjusted to pH 2 with concentrated HCl. Saturated brine (300 mL) was added and the two layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The wet solid was mixed with 25% ethyl acetate in toluene (400 mL) at 40° C. for 30 min, concentrated under reduced pressure, and dried under vacuum at 40° C. overnight to give compound 8 as a white solid (14.1 g, 86.9% yield).

[0235] [ka] tert-Butyl 2-(7-chloro-1-oxoisoquinolin-2(1H)-yl)acetate (compound 14B): A mixture of 7-chloroisoquinolin-1-ol (18 g, 100.2 mmol, 1.0 equiv.), cesium carbonate (65.3 g, 200 mmol, 2.0 equiv.) and t-butyl bromoacetate (29.3 g, 22 mL, 150 mmol, 1.5 equiv.) in dimethylformamide (500 mL) was stirred at 80° C. for 24 hours. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (1000 mL) and washed with water (3×300 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was dissolved in dichloromethane (500 mL) and adsorbed onto silica gel (100 g). The material was divided into four equal portions. Each portion was purified on an Interchim HPLC system (silica gel column, 330 g) eluting with a 0-50% gradient of ethyl acetate in heptane to give the desired product as a white solid (25.8 g, 88% yield).

[0236] 2-(7-Chloro-1-oxoisoquinolin-2(1H)-yl)acetic acid (compound 15): A mixture of compound 14B (14.3 g, 49.1 mmol) and trifluoroacetic acid (27.9 g, 18.8 mL, 245 mmol, 5.0 equiv.) in dichloromethane (300 mL) was stirred at room temperature for 48 h. The solvent was removed under reduced pressure. The resulting solid was triturated with methyl t-butyl ether (500 mL), suction filtered, and washed with methyl t-butyl ether (3×200 mL). The solid was dried under vacuum at room temperature overnight to give the desired product as a white solid (8.1 g, 69% yield).

[0237] [ka] tert-Butyl (S)-(5-(benzyloxy)-1-bromo-2-oxopentan-3-yl)carbamate (19-3): Isobutyl chloroformate (6.59 mL, 50.8 mmol, 1.5 equiv) was added dropwise to a solution of Boc--O-benzyl-L-homoserine (19-1) (10.5 g, 33.9 mmol, 1 equiv) and N-methylmorpholine (5.96 mL, 54.2 mmol, 1.6 equiv) in THF (113 mL) at -10 °C. After stirring for 20 min at -10 °C, the reaction was filtered through Celite and concentrated under reduced pressure to give the mixed anhydride as a colorless oil (13.9 g) which was used in the next step.

[0238] Diazomethane preparation: A solution of N-methyl-N'-nitroso-p-toluenesulfonamide (Diazald®, 21.8 g, 101.6 mmol, 1 equiv.) in diethyl ether (113 mL) was added through an addition funnel to a mixture of potassium hydroxide (17.1 g, 304.8 mmol, 3 equiv.), ethanol (34 mL), and water (27 mL) in an oil bath at 65°C. A receiving flask for collecting the ethereal solution of diazomethane was cooled in an ice bath and the Diazald® solution was added at a rate that allowed dropwise distillation into the receiving flask. When all of the Diazald® solution had been added, additional diethyl ether (10 mL) was added through the addition funnel until the distillate was clear (no diazomethane remaining). After cooling to room temperature, the mixture in the distillation flask was slowly quenched with acetic acid until the yellow color disappeared.

[0239] A solution of the above freshly prepared mixed anhydrides (13.9 g, 33.9 mmol, 1 equiv) in diethyl ether (75 mL) was placed in a flask with a clear-seal joint and cooled to 0° C. in an ice bath. A freshly prepared diazomethane ethereal solution (approximately 101.6 mmol, 3 equiv) was added dropwise through an addition funnel while maintaining cooling. The resulting mixture was stirred at 0° C. for 15 min, warmed to room temperature, and stirred for 30 min. The reaction was cooled to 0° C. Meanwhile, a mixture of 48% aqueous HBr (26.8 mL, 237 mmol, 7 equiv) and acetic acid (26.8 mL) was cooled to 0° C. and slowly added to the above reaction mixture at 0° C. The mixture was stirred at 0° C. for 15 min, warmed to room temperature, and stirred for 30 min. The mixture was diluted with diethyl ether (100 mL), washed with water (3×100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an InterChim automated chromatography system (SorbTech silica gel column, 220 g) eluted with a 0-40% gradient of ethyl acetate in heptane to give compound 19-3 as a colorless oil (9.0 g, 73% yield).

[0240] tert-Butyl (S)-(5-(benzyloxy)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)carbamate (19-4): Potassium fluoride (5.46 g, 94.0 mmol, 4 equiv.) was added to a solution of compound 19-3 (9.0 g, 23.5 mmol, 1 equiv.) and 2,3,5,6-tetrafluorophenol (4.29 g, 28.8 mmol, 1.1 equiv.) in DMF (120 mL). After stirring at room temperature for 16 h, the reaction was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (100 mL) and saturated brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on an InterChim automated chromatography system (SorbTech silica gel column, 220 g) eluting with a 10-40% gradient of ethyl acetate in heptane to give compound 19-4 as a colorless oil (5.40 g, 49% yield).

[0241] (S)-3-Amino-5-(benzyloxy)-1-(2,3,5,6-tetrafluorophenoxy)pentan-2-one hydrochloride (19-5): 4M HCl in 1,4-dioxane (3.5 mL, 13.8 mmol, 1.2 equiv) was added dropwise to a solution of compound 19-4 (5.40 g, 11.5 mmol, 1 equiv) in acetonitrile (60 mL) at 5° C. The mixture was then allowed to warm to room temperature and stirred overnight. LCMS indicated the reaction was not complete. Additional 4M HCl in 1,4-dioxane (2.30 mL, 9.2 mmol, 0.8 equiv) was added and the mixture was stirred for 6 h (at which time LCMS indicated the reaction was complete). The mixture was concentrated under reduced pressure to give compound 19-5 as a light yellow solid (4.0 g, 86% yield).

[0242] N 1 -((S)-1-(((S)-5-(benzyloxy)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)-N 2-(2,6-Difluorophenyl)oxalamide (19-6, Example 1): EDC·HCl (0.907 g, 4.73 mmol, 1.1 equiv.) was added to a suspension of compound 8 (1.17 g, 4.30 mmol, 1.0 equiv.) and HOAt (0.702 g, 5.16 mmol, 1.2 equiv.) in acetonitrile (20 mL). The mixture was stirred at room temperature until all solids were dissolved. Compound 19-5 (1.75 g, 4.30 mmol, 1.0 equiv.) and triethylamine (1.20 mL, 8.6 mmol, 2.0 equiv.) were added and the mixture was stirred at room temperature overnight. LC-MS analysis showed the reaction was complete. The mixture was diluted with ethyl acetate (40 mL) and washed with saturated aqueous sodium bicarbonate (30 mL) and saturated brine (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified on an Interchim automated system (40 g column) eluting with a 10-70% gradient of ethyl acetate in heptane to give compound 19-6 (Example 1) as a bright yellow solid (1.90 g, 71% yield) (mass spectrometry m / z=626.1 (M+H)).

[0243] Example 2 N 1 -(2,6-difluorophenyl)-N 2-((S)-1-(((S)-5-hydroxy-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)oxalamide (19-7, Example 2): A mixture of compound (1.30 g, 2.08 mmol, 1.0 equiv.) and 10% palladium on activated carbon (130 mg, 50% wet) in tetrahydrofuran (18 mL) and methanol (18 mL) was hydrogenated at 45 psi (310.3 kPa) for 3 h. LC-MS analysis showed the reaction was complete. The mixture was filtered through Celite (20 g) and washed with additional methanol (25 mL). The crude product was purified twice on an Interchim automated system. Two 40 g columns were used for purification. The first purification was performed on a 40 g silica gel column eluting with dichloromethane using a 0-10% gradient of methanol. The material was then further purified on a second 40 g silica gel column eluting with heptane using a 30-90% gradient of ethyl acetate. The product was dissolved in diethyl ether (3 mL) and precipitated by the addition of heptane (5 mL). The solid was dried on the filter to give the desired product. The product was purified on an Interchim automated system (Teledyne ISCO column Gold C18 50G column) eluting with water using a 0-50% gradient of acetonitrile to give compound 19-7 (Example 2) as a white solid (325 mg, 29% yield) (mass spectrometry m / z=536 (M+H)).

[0244] Example 3 [ka] N-(tert-butoxycarbonyl)-O-(4-chlorobenzyl)-L-homoserine (42-2a): Sodium hydride (6.02 g, 150.5 mmol, 2.2 equiv.) in the form of a 60% dispersion in mineral oil was added to a solution of compound 42-1 (15.0 g, 68.4 mmol, 1 equiv.) in anhydrous N,N-dimethylacetamide (100.0 mL) at 0° C. After stirring at 0° C. for 1.5 h, 4-chlorobenzyl bromide (15.465 g, 75.3 mmol, 1.1 equiv.) was added and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with ice-cold water (200 mL) and extracted with diethyl ether (2×800 mL). The aqueous layer was acidified to pH 3.4 with 3M HCl (30 mL) and extracted with ethyl acetate (1 L). The organic layer was washed with saturated brine solution (1 L) and water (3×1 L), dried over sodium sulfate (150 g), and concentrated under reduced pressure. The crude material was adsorbed onto Celite (30 g) and purified on an Interchim automated chromatography system (Sorbtech silica gel column, 330 g) eluted with a 0-10% gradient of methanol with dichloromethane to give compound 42-2a as a viscous pale yellow oil (3.9 g, 16% yield).

[0245] Methyl N-(tert-butoxycarbonyl)-O-(4-chlorobenzyl)-L-homoserinate (42-3a): Potassium carbonate (1.369 g, 9.9 mmol, 2.0 equiv.) was added to a solution of compound 42-2a (1.7 g, 4.9 mmol, 1.0 equiv.) in DMF (10 mL). After stirring at room temperature for 10 min, methyl iodide (0.617 mL, 9.9 mmol, 2.0 equiv.) was added and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with saturated aqueous salt solution (3×500 mL) and water (500 mL). The organic layer was dried over sodium sulfate (100 g) and concentrated under reduced pressure. The crude material was adsorbed onto Celite (4 g) and purified on an Interchim automated chromatography system (Sorbtech silica gel column, 80 g) eluting with a 0-60% gradient of ethyl acetate in heptane to give compound 42-3a as a colorless oil (1.4 g, 78% yield).

[0246] tert-Butyl (S)-(1-chloro-5-((4-chlorobenzyl)oxy)-2-oxopentan-3-yl)carbamate (42-4a): 1.6 M in hexanes, n-BuLi (12.224 mL, 19.5 mmol, 5.0 equiv) was added to diisopropylamine (3.0 mL, 21.5 mmol, 5.5 equiv) in THF (20 mL) at -78°C. The reaction was warmed to 0°C for 5 min, cooled to -78°C, and slowly added to compound 42-3a (1.4 g, 3.9 mmol, 1.0 equiv) in THF (20 mL) at -78° over 45 min, maintaining the temperature below -72°C. After stirring at -78°C for 45 min, acetic acid (9 mL) was added dropwise at -78°C. The reaction was diluted with saturated brine solution (800 mL) and extracted with ethyl acetate (500 mL). The organic layer was washed with saturated bicarbonate solution (3×500 mL) and water (250 mL). The ethyl acetate layer was dried over sodium sulfate (100 g) and concentrated under reduced pressure. The crude material was adsorbed onto Celite (6 g) and purified on an Interchim automated chromatography system (Sorbtech silica gel column, 80 g) eluting with a 0-40% gradient of ethyl acetate with heptane to give compound 42-4a as a light yellow oil (1.0 g, 67% yield).

[0247] Potassium salt of 2,3,5,6-tetrafluorophenol: 2,3,5,6-tetrafluorophenol (2.0 g, 12.0 mmol, 1.0 equiv.) was added to a solution of potassium hydroxide (0.68 g, 12.0 mmol, 1.0 equiv.) in methanol. After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The residue was dried under vacuum at room temperature for 16 h to give the potassium salt of 2,3,5,6-tetrafluorophenol as a white solid (2.4 g, 97% yield).

[0248] tert-Butyl (S)-(5-((4-chlorobenzyl)oxy)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy) pentan-3-yl)carbamate (42-5a): Sodium iodide (0.6 g, 4.0 mmol, 1.5 equiv.) and the potassium salt of 2,3,5,6-tetrafluorophenol (0.813 g, 4.0 mmol, 1.5 equiv.) were added to a solution of compound 42-4a (1.0 g, 2.6 mmol, 1.0 equiv.) in acetone (12 mL). After stirring at room temperature for 20 h, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (500 mL) and washed with saturated brine (250 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was adsorbed onto Celite (4 g) and purified on an Interchim automated chromatography system (Sorbtech silica gel column, 80 g) eluting with a 0-40% gradient of ethyl acetate in heptane to give compound 42-5a as a light yellow oil (0.89 g, 66% yield).

[0249] (S)-3-amino-5-((4-chlorobenzyl)oxy)-1-(2,3,5,6-tetrafluorophenoxy)pentan-2-one hydrochloride (42-6a): 4M HCl in 1,4-dioxane (0.869 mL, 3.5 mmol, 2.0 equiv.) was added dropwise to a solution of compound 42-5a (0.885 g, 1.7 mmol, 1 equiv.) in acetonitrile (15 mL) at 5° C. The mixture was allowed to warm to room temperature and stirred for 24 h. The mixture was concentrated under reduced pressure. The residue was triturated with heptane (3×10 mL), decanted, and dried under vacuum to give compound 42-6a as an off-white solid (0.633 g, 81% yield).

[0250] N 1 -((S)-1-(((S)-5-((4-chlorobenzyl)oxy)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)-N 2 -(2,6-difluorophenyl)oxalamide (42-A, Example 3):

[0251] EDC·HCl (0.286 g, 1.5 mmol, 1.1 equiv) was added to a suspension of compound 8 (0.369 g, 1.4 mmol, 1.0 equiv) and HOAt (0.221 g, 1.6 mmol, 1.2 equiv) in acetonitrile (10 mL). The mixture was stirred at room temperature until all solids were dissolved. Compound 42-6a (0.6 g, 1.4 mmol, 1.0 equiv) and triethylamine (0.378 mL, 2.7 mmol, 2.0 equiv) were added sequentially and the mixture was stirred at room temperature for 20 h. The mixture was diluted with ethyl acetate (250 mL) and washed with saturated aqueous sodium bicarbonate (250 mL) and saturated brine (250 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was adsorbed onto Celite (4 g) and purified on an Interchim automated chromatography system (Sorbtech silica gel column, 80 g) eluting with a 0-60% gradient of ethyl acetate in heptane to give 42-A (Example 3) as a white solid (0.59 g, 65% yield), (mass spectrometry m / z=660.1 (M+H)).

[0252] N-(tert-butoxycarbonyl)-O-(thiophen-3-ylmethyl)-L-homoserine (42-2d): Sodium hydride (4.29 g, 107.3 mmol, 2.2 equiv.) in the form of a 60% dispersion in mineral oil was added to a solution of compound 42-1 (10.69 g, 48.78 mmol, 1 equiv.) in anhydrous N,N-dimethylacetamide (80.0 mL) at 0° C. After stirring at 0° C. for 1.5 h, 3-bromomethylthiophene (9.5 g, 53.6 mmol, 1.1 equiv.) was added and the reaction was stirred at room temperature for 24 h. The reaction mixture was diluted with ice-cold water (150 mL) and extracted with ethyl acetate (2×1 L). The aqueous layer was acidified to pH 3.0 with 3M HCl (16 mL) and extracted with ethyl acetate (1 L). The organic layer was washed with saturated brine solution (1 L) and water (3×1 L), dried over sodium sulfate (150 g), and concentrated under reduced pressure. The crude material was adsorbed onto Celite (30 g) and purified on an Interchim automated chromatography system (Sorbtech silica gel column, 330 g) eluted with a 0-100% gradient of ethyl acetate to heptane to give compound 42-2d as a viscous light yellow oil (2.34 g, 15% yield).

[0253] Methyl N-(tert-butoxycarbonyl)-O-(thiophen-3-ylmethyl)-L-homoserinate (42-3d): Potassium carbonate (2.05 g, 14.8 mmol, 2.0 equiv.) was added to a solution of compound 42-2d (2.34 g, 7.4 mmol, 1.0 equiv.) in DMF (12 mL). After stirring at room temperature for 10 min, methyl iodide (0.923 mL, 14.8 mmol, 2.0 equiv.) was added and the reaction was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (250 mL) and washed with saturated aqueous salt solution (3×250 mL) and water (250 mL). The organic layer was dried over sodium sulfate (100 g) and concentrated under reduced pressure. The crude material was adsorbed onto Celite (5 g) and purified on an Interchim automated chromatography system (Sorbtech silica gel column, 80 g) eluting with a 0-50% gradient of ethyl acetate in heptane to give compound 42-3d as a light yellow oil (1.9 g, 77% yield).

[0254] tert-Butyl (S)-(1-chloro-2-oxo-5-(thiophen-3-ylmethoxy)pentan-3-yl)carbamate (42-4d): 1.6 M n-BuLi in hexanes (9.5 mL, 15.2 mmol, 5.0 equiv) was added to diisopropylamine (2.34 mL, 16.7 mmol, 5.5 equiv) in THF (15 mL) at -78 °C. The reaction was warmed to 0 °C for 5 min, cooled to -78 °C, and slowly added to compound 42-3d (1.0 g, 3.0 mmol, 1.0 equiv) in THF (15 mL) at -78 °C over 30 min. After stirring at -78 °C for 25 min, acetic acid (6 mL) was added dropwise at -78 °C. The reaction was diluted with saturated brine solution (500 mL) and extracted with ethyl acetate (500 mL). The organic layer was washed with saturated bicarbonate solution (3×500 mL) and water (250 mL). The ethyl acetate layer was dried over sodium sulfate (100 g) and concentrated under reduced pressure. The crude material was adsorbed onto Celite (4 g) and purified on an Interchim automated chromatography system (Sorbtech silica gel column, 80 g) eluting with a 0-80% gradient of ethyl acetate with heptane to give compound 42-4d as a light yellow oil (0.938 g, 82% yield).

[0255] tert-Butyl (S)-(2-oxo-1-(2,3,5,6-tetrafluorophenoxy)-5-(thiophen-3-ylmethoxy)pentan-3-yl)carbamate (42-5d): Sodium iodide (0.56 g, 3.7 mmol, 1.5 equiv.) and the potassium salt of 2,3,5,6-tetrafluorophenol (0.763 g, 3.7 mmol, 1.5 equiv.) were added to a solution of compound 42-4d (0.938 g, 2.5 mmol, 1.0 equiv.) in acetone (10 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (500 mL) and washed with saturated brine (250 mL). The organic layer was dried over sodium sulfate (50 g), filtered, and concentrated under reduced pressure. The crude material was adsorbed onto Celite (4 g) and purified on an Interchim automated chromatography system (Sorbtech silica gel column, 80 g) eluting with a 0-40% gradient of ethyl acetate in heptane to give compound 42-5d as a light yellow oil (0.754 g, 63% yield).

[0256] (S)-3-Amino-1-(2,3,5,6-tetrafluorophenoxy)-5-(thiophen-3-ylmethoxy)pentan-2-one hydrochloride (42-6d): 4M HCl in 1,4-dioxane (0.78 mL, 3.1 mmol, 2.0 equiv.) was added dropwise to a solution of compound 42-5d (0.75 g, 1.6 mmol, 1 equiv.) in acetonitrile (10 mL) at 5° C. The mixture was then warmed to room temperature and stirred for 24 h. The mixture was concentrated under reduced pressure. The solid was triturated with heptane (3×10 mL), decanted, and dried under vacuum to give compound 42-6d as an off-white solid (0.514 g, 79% yield).

[0257] Example 4 N 1 -(2,6-difluorophenyl)-N 2-((S)-1-oxo-1-(((S)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)-5-(thiophen-3-ylmethoxy)pentan-3-yl)amino)propan-2-yl)oxalamide (42-D, Example 4): EDC·HCl (0.146 g, 0.8 mmol, 1.1 equiv) was added to a suspension of compound 8 (0.189 g, 0.7 mmol, 1.0 equiv) and HOAt (0.113 g, 1.0 mmol, 1.2 equiv) in acetonitrile (8 mL). The mixture was stirred at room temperature until all solids were dissolved. Compound 42-6d (0.288 g, 0.7 mmol, 1.0 equiv) and triethylamine (0.193 mL, 1.4 mmol, 2.0 equiv) were added successively and the mixture was stirred at room temperature for 20 h. The mixture was diluted with ethyl acetate (250 mL) and washed with saturated aqueous sodium bicarbonate (250 mL) and saturated brine (250 mL). The organic layer was dried over sodium sulfate (100 g), filtered, and concentrated under reduced pressure. The crude material was adsorbed onto Celite (3 g) and purified on an Interchim automated chromatography system (Sorbtech silica gel column, 25 g) eluting with a 0-90% gradient of ethyl acetate in heptane to give 42-D (Example 4) as a white solid (0.2 g, 45% yield) (mass spectrometry m / z=632.1 (M+H)).

[0258] Example 5 [ka] tert-Butyl (S)-(1-bromo-5-methoxy-2-oxopentan-3-yl)carbamate (57-3): Isobutyl chloroformate (0.84 mL, 6.43 mmol, 1.5 equiv) was added dropwise to a solution of N-(tert-butoxycarbonyl)-O-methyl-L-homoserine (57-1) (1.0 g, 4.29 mmol, 1 equiv) and N-methylmorpholine (0.75 mL, 6.86 mmol, 1.6 equiv) in THF (18 mL) at −10° C. After stirring for 20 min at −10° C., the reaction was filtered through Celite and concentrated under reduced pressure to give the mixed anhydride as a colorless oil that was used in the next step.

[0259] Diazomethane preparation: A solution of N-methyl-N'-nitroso-p-toluenesulfonamide (Diazald®, 2.76 g, 12.87 mmol, 1 equiv.) in diethyl ether (10 mL) was added through an addition funnel to a mixture of potassium hydroxide (2.54 g, 38.6 mmol, 3 equiv.), ethanol (6 mL), and water (5 mL) in an oil bath at 65°C. A receiving flask for collecting the ethereal solution of diazomethane was cooled in an ice bath and the Diazald® solution was added at a rate that allowed dropwise distillation into the receiving flask. When all of the Diazald® solution had been added, additional diethyl ether (3 mL) was added through the addition funnel until the distillate was clear (no diazomethane remaining). After cooling to room temperature, the mixture in the distillation flask was slowly quenched with acetic acid until the yellow color disappeared.

[0260] A solution of the above freshly prepared mixed anhydrides (1.37 g, 4.29 mmol, 1 equiv) in diethyl ether (25 mL) was placed in a ground joint flask and cooled to 0° C. in an ice bath. Freshly prepared diazomethane ethereal solution (approximately 12.87 mmol, 3 equiv) was added dropwise through an addition funnel while maintaining cooling. The resulting mixture was stirred at 0° C. for 15 min, warmed to room temperature, and stirred for 30 min. The reaction was cooled to 0° C. Meanwhile, a mixture of 48% aqueous HBr (4.0 mL, 30.0 mmol, 7 equiv) and acetic acid (4.0 mL) was cooled to 0° C. and slowly added to the above reaction mixture at 0° C. The mixture was stirred at 0° C. for 15 min, warmed to room temperature, and stirred for 30 min. The mixture was diluted with diethyl ether (10 mL), washed with water (3×15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an InterChim automated chromatography system (SorbTech silica gel column, 120 g) eluting with a 0-40% gradient of ethyl acetate in heptane to give compound 57-3 as a colorless oil (0.67 g, 50% yield).

[0261] tert-Butyl (S)-(5-methoxy-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)carbamate (57-4): Potassium fluoride (502 mg, 8.64 mmol, 4 equiv.) was added to a solution of compound 57-3 (0.67 g, 2.16 mmol, 1 equiv.) and 2,3,5,6-tetrafluorophenol (395 mg, 2.38 mmol, 1.1 equiv.) in DMF (10 mL). After stirring at room temperature for 16 h, the reaction was diluted with ethyl acetate (15 mL) and washed with saturated aqueous sodium bicarbonate (20 mL) and saturated brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on an InterChim automated chromatography system (SorbTech silica gel column, 120 g) eluting with a 0-40% gradient of ethyl acetate in heptane to give compound 57-4 as a colorless oil (0.53 g, 62% yield).

[0262] (S)-3-Amino-5-methoxy-1-(2,3,5,6-tetrafluorophenoxy)pentan-2-one hydrochloride (57-5): 4M HCl in 1,4-dioxane (0.34 mL, 1.34 mmol, 1.0 equiv) was added dropwise to a solution of compound 57-4 (0.53 g, 1.34 mmol, 1 equiv) in acetonitrile (10 mL) at 5° C. The mixture was allowed to warm to room temperature and stirred overnight. LCMS indicated the reaction was not complete. Additional 4M HCl in 1,4-dioxane (0.34 mL, 1.34 mmol, 1.0 equiv) was added and the mixture was stirred for 6 h (at which time LCMS indicated the reaction was complete). The mixture was concentrated under reduced pressure to give compound 57-5 as a light yellow liquid (0.48 g, 100% yield).

[0263] N 1 -(2,6-difluorophenyl)-N 2-((S)-1-(((S)-5-Methoxy-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)oxalamide (compound 57-A, example 5): EDC·HCl (0.305 g, 1.59 mmol, 1.1 equiv.) was added to a suspension of compound 8 (0.393 g, 1.446 mmol, 1.0 equiv.) and HOAt (0.237 g, 1.74 mmol, 1.2 equiv.) in acetonitrile (10 mL). The mixture was stirred at room temperature until all solids were dissolved. Compound 57-5 (0.48 g, 1.446 mmol, 1.0 equiv.) and triethylamine (0.40 mL, 2.89 mmol, 2.0 equiv.) were added sequentially and the mixture was stirred at room temperature overnight. LC-MS analysis indicated the reaction was complete. The mixture was diluted with ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL) and saturated brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified on an Interchim automated chromatography system (120 g column) eluting with a 0-60% gradient of ethyl acetate in heptane to give 57-A (Example 5) as a white solid (0.51 g, 64% yield) (mass spectrometry m / z=550.1 (M+H)).

[0264] Example 6 [ka] Benzyl (S)-6-bromo-4-((tert-butoxycarbonyl)amino)-5-oxohexanoate (58-3): Isobutyl chloroformate (5.84 mL, 45.0 mmol, 1.5 equiv) was added dropwise to a solution of (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid (58-1) (10.12 g, 30.0 mmol, 1 equiv) and N-methylmorpholine (5.28 mL, 48 mmol, 1.6 equiv) in THF (100 mL) at −10° C. After stirring for 20 min at −10° C., the reaction was filtered through Celite and concentrated under reduced pressure to give the mixed anhydride as a colorless oil that was used in the next step.

[0265] Diazomethane preparation: A solution of N-methyl-N'-nitroso-p-toluenesulfonamide (Diazald®, 19.28 g, 90.0 mmol, 1 equiv.) in diethyl ether (66 mL) was added through an addition funnel to a mixture of potassium hydroxide (15.12 g, 270 mmol, 3 equiv.), ethanol (30 mL), and water (26 mL) in an oil bath at 65°C. A receiving flask for collecting the ethereal solution of diazomethane was cooled in an ice bath and the Diazald® solution was added at a rate that allowed dropwise distillation into the receiving flask. When all of the Diazald® solution had been added, additional diethyl ether (10 mL) was added through the addition funnel until the distillate was clear (no diazomethane remaining). After cooling to room temperature, the mixture in the distillation flask was slowly quenched with acetic acid until the yellow color disappeared.

[0266] A solution of the above freshly prepared mixed anhydrides (12.70 g, 30.0 mmol, 1 equiv) in diethyl ether (110 mL) was placed in a ground joint flask and cooled to 0° C. in an ice bath. A freshly prepared diazomethane ethereal solution (approximately 90.0 mmol, 3 equiv) was added dropwise through an addition funnel while maintaining cooling. The resulting mixture was stirred at 0° C. for 15 min, warmed to room temperature, and stirred for 30 min. The reaction was cooled to 0° C. Meanwhile, a mixture of 48% aqueous HBr (24 mL, 210.0 mmol, 7 equiv) and acetic acid (24.0 mL) was cooled to 0° C. and slowly added to the above reaction mixture at 0° C. The mixture was stirred at 0° C. for 15 min, warmed to room temperature, and stirred for 30 min. The mixture was diluted with diethyl ether (80 mL), washed with water (3×100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an InterChim automated chromatography system (SorbTech silica gel column, 220 g) eluting with a 0-40% gradient of ethyl acetate in heptane to give compound 58-3 as a colorless oil (8.6 g, 69% yield).

[0267] Benzyl (S)-4-((tert-butoxycarbonyl)amino)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate (58-4): Potassium fluoride (4.83 g, 83.08 mmol, 4 equiv.) was added to a solution of compound 58-3 (8.6 g, 20.77 mmol, 1 equiv.) and 2,3,5,6-tetrafluorophenol (3.79 g, 22.85 mmol, 1.1 equiv.) in DMF (100 mL). After stirring at room temperature for 16 h, the reaction was diluted with ethyl acetate (150 mL) and washed with saturated aqueous sodium bicarbonate (200 mL) and saturated brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on an InterChim automated chromatography system (SorbTech silica gel column, 220 g) eluting with a 0-40% gradient of ethyl acetate in heptane to give compound 58-4 as a colorless oil (6.13 g, 59% yield).

[0268] (S)-3-Amino-5-methoxy-1-(2,3,5,6-tetrafluorophenoxy)pentan-2-one hydrochloride (58-5): 4M HCl in 1,4-dioxane (3.1 mL, 12.3 mmol, 1.0 equiv) was added dropwise to a solution of compound 58-4 (6.13 g, 12.28 mmol, 1 equiv) in acetonitrile (80 mL) at 5° C. The mixture was allowed to warm to room temperature and stirred overnight. LCMS indicated the reaction was not complete. Additional 4M HCl in 1,4-dioxane (3.1 mL, 12.3 mmol, 1.0 equiv) was added and the mixture was stirred for 6 h (at which time LCMS indicated the reaction was complete). The mixture was concentrated under reduced pressure to give compound 58-5 as a light yellow solid (6.2 g, 100% yield).

[0269] Benzyl (S)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido))propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate (58-6): EDC·HCl (0.483 g, 2.52 mmol, 1.1 equiv.) was added to a suspension of compound 8 (0.623 g, 2.29 mmol, 1.0 equiv.) and HOAt (0.374 g, 2.75 mmol, 1.2 equiv.) in acetonitrile (15 mL). The mixture was stirred at room temperature until all solids were dissolved. Compound 58-5 (1.0 g, 2.29 mmol, 1.0 equiv.) and triethylamine (0.638 mL, 4.58 mmol, 2.0 equiv.) were added successively and the mixture was stirred at room temperature overnight. LC-MS analysis showed the reaction was complete. The mixture was diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (30 mL) and saturated brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified on an Interchim automated chromatography system (80 g column) eluted with a 0-60% gradient of ethyl acetate in heptane to give compound 58-6 as a white solid (0.72 g, 48% yield).

[0270] (S)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido))propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid (Compound 58-A, Example 6): A suspension of compound 58-6 (0.72 g, 1.10 mmol, 1 equiv.) and 10% palladium on carbon (0.072 g, 50% wet) in THF (11 mL) and ethyl acetate (3.5 mL) was hydrogenated at 25 psi (172.4 kPa) for 2 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (120 g column) eluting with a 0-10% gradient of methanol in dichloromethane to give compound 58-A (Example 6) as a white solid (0.56 g, 90% yield) (mass spectrometry m / z=564.2 (M+H)).

[0271] Example 7 [ka] Methyl O-benzyl-N-(tert-butoxycarbonyl)-L-homoserinate (56-1): Potassium carbonate (5.53 g, 40.0 mmol, 2.0 equiv.) was added to a solution of compound 25-1 (6.18 g, 20.0 mmol, 1.0 equiv.) in DMF (25 mL). After stirring at room temperature for 15 min, methyl iodide (2.49 mL, 40.0 mmol, 2.0 equiv.) was added and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (3×50 mL) and saturated aqueous salt solution (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on an Interchim automated chromatography system (Sorbtech silica gel column, 120 g) eluting with a 0-35% gradient of ethyl acetate in heptane to give compound 56-1 as a colorless oil (5.6 g, 87% yield).

[0272] tert-Butyl (S)-(5-(benzyloxy)-1-chloro-2-oxopentan-3-yl)carbamate (56-2): Chloroiodomethane (1.16 mL, 16.0 mmol, 4.0 equiv) in tetrahydrofuran (10 mL) was added slowly to a solution of compound 56-1 (1.29 g, 4.0 mmol, 1.0 equiv) in tetrahydrofuran (20 mL) at -78 °C. Freshly prepared lithium diisopropylamide solution was added slowly over 30 min while maintaining the temperature below -70 °C. After stirring at -78 °C for 45 min, acetic acid (1.7 mL) in tetrahydrofuran (10 mL) was added slowly while maintaining the temperature at -65 °C. After stirring at -78 °C for 10 min, the reaction was diluted with saturated brine (60 mL) and extracted with ethyl acetate (60 mL). The organic layer was washed with saturated aqueous bicarbonate (3×50 mL) and water (50 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified on an Interchim automated chromatography system (Sorbtech silica gel column, 120 g) eluting with a 0-20% gradient of ethyl acetate in heptane to give compound 56-2 as a light yellow oil (0.92 g, 67% yield).

[0273] Lithium diisopropylamide solution preparation: 1.6 M n-BuLi in hexanes (12.25 mL, 20.0 mmol, 5.0 equiv) was added to diisopropylamine (3.08 mL, 22.0 mmol, 5.5 equiv) in THF (20 mL) at -78° C. The reaction was warmed to 0° C. for 30 min and cooled to -40° C.

[0274] tert-Butyl (S)-(5-(benzyloxy)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)carbamate (25-4): Sodium iodide (605 mg, 4.03 mmol, 1.5 equiv.) and potassium 2,3,5,6-tetrafluorophenolate (823 mg, 4.03 mmol, 1.5 equiv.) were added to a solution of compound 56-2 (0.92 g, 2.69 mmol, 1.0 equiv.) in acetone (15 mL). After stirring at room temperature for 20 h, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (50 mL) and washed with saturated brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on an Interchim automated chromatography system (Sorbtech silica gel column, 80 g) eluting with a 0-40% gradient of ethyl acetate in heptane to give compound 25-4 as a light yellow oil (1.10 g, 87% yield).

[0275] (S)-3-Amino-5-(benzyloxy)-1-(2,3,5,6-tetrafluorophenoxy)pentan-2-one hydrochloride (25-5): 4M HCl in 1,4-dioxane (0.80 mL, 3.20 mmol, 1.2 equiv) was added dropwise to a solution of compound 25-4 (1.25 g, 2.65 mmol, 1.0 equiv) in acetonitrile (15 mL) at 5° C. The mixture was then allowed to warm to room temperature and stirred overnight. LCMS indicated the reaction was not complete. Additional 4M HCl in 1,4-dioxane (0.53 mL, 2.12 mmol, 0.8 equiv) was added and the mixture was stirred for 6 h (at which time LCMS indicated the reaction was complete). The mixture was concentrated under reduced pressure to give compound 25-5 as a light yellow solid (1.15 g, 98% yield).

[0276] N 1 -((S)-1-(((S)-5-(benzyloxy)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)-N 2-(2,6-Difluorophenyl)oxalamide (19-6): EDC·HCl (0.559 g, 2.92 mmol, 1.1 equiv.) was added to a suspension of compound 8 (0.721 g, 2.65 mmol, 1.0 equiv.) and HOAt (0.433 g, 3.18 mmol, 1.2 equiv.) in acetonitrile (15 mL). The mixture was stirred at room temperature until all solids were dissolved. Compound 25-5 (1.08 g, 2.65 mmol, 1.0 equiv.) and triethylamine (0.74 mL, 5.3 mmol, 2.0 equiv.) were added sequentially and the mixture was stirred at room temperature overnight. LC-MS analysis showed the reaction was complete. The mixture was diluted with ethyl acetate (40 mL) and washed with saturated aqueous sodium bicarbonate (30 mL) and saturated brine (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified on an Interchim automated system (120 g column) eluting with a 0-60% gradient of ethyl acetate in heptane to give compound 19-6 as a bright yellow solid (1.02 g, 62% yield).

[0277] N 1 -(2,6-difluorophenyl)-N 2 -((S)-1-(((S)-5-hydroxy-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)oxalamide (19-7): A mixture of 19-6 (1.02 g, 1.63 mmol, 1.0 equiv) and 10% palladium on activated carbon (102 mg, 50% wet) in tetrahydrofuran (10 mL) and methanol (10 mL) was hydrogenated at 45 psi (310.3 kPa) for 3 h. LC-MS analysis indicated the reaction was complete. The mixture was filtered through Celite (15 g) and washed with additional methanol (25 mL). The crude product was purified on an Interchim automated system (120 g column) eluting with a 0-80% gradient of ethyl acetate in heptane to give compound 19-7 as a white solid (350 mg, 40% yield).

[0278] (S)-3-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido))propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentylphenylcarbonate (56-A, Example 7): Phenyl chloroformate (0.13 mL, 1.05 mmol, 1.0 equiv.) was added to a solution of compound 19-7 (565 mg, 1.05 mmol, 1.0 equiv.), pyridine (0.84 mL, 10.5 mmol, 10.0 equiv.) and 4-dimethylaminopyridine (81 mg, 0.66 mmol, 0.63 equiv.) in 12 mL dichloromethane at 0° C. The reaction mixture was stirred at room temperature for 2 hours. Additional phenyl chloroformate (0.20 mL, 1.58 mmol, 1.5 equiv.) was added to the reaction. The reaction mixture was stirred at room temperature for 2 hours (at which time LCMS analysis indicated the reaction was complete). The reaction mixture was washed with water (2×10 mL). The combined aqueous layers were extracted with dichloromethane (2×10 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (2×10 mL) and saturated brine (10 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an InterChim automated chromatography system (SorbTech silica gel column, 120 g) eluting with a 0-25% gradient of ethyl acetate with dichloromethane. The product was triturated with diethyl ether (10 mL) to give compound 56-A (Example 7) as a yellow solid (160 mg, 17% yield) (mass spectrometry m / z=656.2 (M+H)).

[0279] Example 8 (S)-3-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido))propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentylbenzoate (56-B, Example 8): Benzoyl chloride (0.34 mL, 2.97 mmol, 2.5 equiv.) was added to a solution of compound 19-7 (635 mg, 1.19 mmol, 1.0 equiv.), pyridine (0.95 mL, 11.9 mmol, 10.0 equiv.) and 4-dimethylaminopyridine (91 mg, 0.75 mmol, 0.63 equiv.) in 12 mL of dichloromethane at 0° C. After stirring at room temperature for 2 h, the reaction mixture was washed with water (2×10 mL). The combined aqueous layers were extracted with dichloromethane (2×10 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (2×10 mL) and saturated brine (10 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an InterChim automated chromatography system (SorbTech silica gel column, 120 g) eluting with a 0-25% gradient of ethyl acetate with dichloromethane. The product was triturated with diethyl ether (10 mL) to give compound 56-B (Example 8) as a yellow solid (280 mg, 37% yield) (mass spec m / z=640.2 (M+H)).

[0280] Example 9 [ka] Ethyl 2-((2,6-difluorophenyl)amino)-2-oxoacetate (3): Triethylamine (27.2 mL, 193.8 mmol, 1 equiv.) was added to a solution of 2,6-difluoroaniline (25.0 g, 193.8 mmol, 1 equiv.) in THF (1 L) at 0-5° C. Ethyl oxalyl chloride (21.6 mL, 193.8 mmol, 1 equiv.) was added dropwise over 60 min, maintaining the temperature below 5° C. The reaction was allowed to warm to room temperature and stirred for 24 h. The reaction was filtered through Celite, the Celite was washed with methyl t-butyl ether (500 mL), and the combined organic layers were washed with 1N HCl (2×200 mL) and water (400 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the desired product as a beige oil (44.8 g, quantitative yield).

[0281] 2-((2,6-Difluorophenyl)amino)-2-oxoacetic acid (4): 1N lithium hydroxide (233 mL, 233 mmol, 1.2 equiv.) was added to a solution of compound 3 (44.8 g, 193.8 mmol, 1 equiv.) in THF (233 mL). After stirring at room temperature for 4 h, the reaction was cooled to 0° C. and acidified to pH 2 with concentrated HCl. The aqueous mixture was saturated with sodium chloride and extracted with ethyl acetate (6×200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the desired product as a white solid (18.3 g, 47% yield).

[0282] Benzyl (2-((2,6-difluorophenyl)amino)-2-oxoacetyl)glycinate (60-1): N'-Ethylcarbodiimide hydrochloride (3.99 g, 20.83 mmol, 1.4 equiv.) was added to a suspension of compound 4 (2.99 g, 14.88 mmol, 1.0 equiv.), 1-hydroxy-7-azabenzotriazole (2.85 g, 20.83 mmol, 1.4 equiv.) in acetonitrile (200 mL). The mixture was stirred at room temperature until all solids were dissolved. Benzylglycinate hydrochloride (3.0 g, 14.88 mmol, 1.0 equiv.) and N-methylmorpholine (3.01 g, 29.76 mmol, 2.0 equiv.) were added and the mixture was stirred at room temperature overnight. LC-MS analysis indicated the reaction was complete. The mixture was concentrated under reduced pressure and the wet solid was diluted with ethyl acetate (60 mL) and water (20 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with saturated brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on an InterChim automated chromatography system (SorbTech silica gel column, 220 g) eluting with a 0-5% gradient of ethyl acetate with dichloromethane. The product was further purified on an InterChim automated chromatography system (SorbTech silica gel column, 220 g) eluting with a 0-50% gradient of ethyl acetate with heptane to give compound 60-1 as a white solid (1.90 g, 37% yield).

[0283] (2-((2,6-difluorophenyl)amino)-2-oxoacetyl)glycine (60-2): A mixture of compound 60-1 (1.86 g, 5.34 mmol, 1.0 equiv.) and 10% palladium on activated carbon (186 mg, 50% wet) in tetrahydrofuran (11.5 mL) and ethyl acetate (3.5 mL) was hydrogenated at 25 psi (172.4 kPa) for 2 h. LC-MS analysis showed the reaction was complete. The mixture was filtered through Celite (15 g) to give compound 60-1 as a white solid (1.31 mg, 95% yield).

[0284] Benzyl (S)-4-(2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido))acetamido))-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate (60-3): N'-Ethylcarbodiimide hydrochloride (0.388 g, 2.02 mmol, 1.1 equiv) was added to a suspension of compound 60-2 (0.474 g, 1.84 mmol, 1.0 equiv) and 1-hydroxy-7-azabenzotriazole (0.301 g, 2.21 mmol, 1.2 equiv) in acetonitrile (15 mL). The mixture was stirred at room temperature until all solids were dissolved. Compound 58-5 (0.80 g, 1.84 mmol, 1.0 equiv) and triethylamine (0.51 mL, 3.68 mmol, 2.0 equiv) were added sequentially and the mixture was stirred at room temperature overnight. LC-MS analysis showed the reaction was complete. The mixture was diluted with ethyl acetate (40 mL) and washed with saturated aqueous sodium bicarbonate (30 mL) and saturated brine (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified on an Interchim automated chromatography system (120 g column) eluting with a 0-70% gradient of ethyl acetate in heptane to give compound 60-3 as a white solid (0.42 g, 36% yield).

[0285] (S)-4-(2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido))acetamido))-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid (60-A, Example 9): A mixture of compound 60-3 (0.42 g, 0.657 mmol, 1.0 equiv.) and 10% palladium on activated carbon (42 mg, 50% wet) in tetrahydrofuran (15 mL) and ethyl acetate (5 mL) was hydrogenated at 25 psi (172.4 kPa) for 2 h. LC-MS analysis showed the reaction was complete. The mixture was filtered through Celite (15 g) and washed with additional methanol (25 mL). The crude product was purified on an Interchim automated chromatography system (80 g column) eluting with a 0-10% gradient of methanol with dichloromethane. The product was triturated with diethyl ether (10 mL) to give compound 60-A (Example 9) as a white solid (210 mg, 58% yield) (mass spec m / z=550.1 (M+H)).

[0286] Example 10 [ka] Benzyl (S)-6-bromo-4-((tert-butoxycarbonyl)amino)-5-oxohexanoate (58-3): Isobutyl chloroformate (5.84 mL, 45.0 mmol, 1.5 equiv) was added dropwise to a solution of (S)-5-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid (58-1) (10.12 g, 30.0 mmol, 1 equiv) and N-methylmorpholine (5.28 mL, 48 mmol, 1.6 equiv) in THF (100 mL) at −10° C. After stirring for 20 min at −10° C., the reaction was filtered through Celite and concentrated under reduced pressure to give the mixed anhydride as a colorless oil (12.7 g) which was used in the next step.

[0287] Diazomethane preparation: A solution of N-methyl-N'-nitroso-p-toluenesulfonamide (Diazald®, 19.28 g, 90.0 mmol, 1 equiv.) in diethyl ether (66 mL) was added through an addition funnel to a mixture of potassium hydroxide (15.12 g, 270 mmol, 3 equiv.), ethanol (30 mL), and water (26 mL) in an oil bath at 65°C. A receiving flask for collecting the ethereal solution of diazomethane was cooled in an ice bath and the Diazald® solution was added at a rate that allowed dropwise distillation into the receiving flask. When all of the Diazald® solution had been added, additional diethyl ether (10 mL) was added through the addition funnel until the distillate was clear (no diazomethane remaining). After cooling to room temperature, the mixture in the distillation flask was slowly quenched with acetic acid until the yellow color disappeared.

[0288] A solution of the above freshly prepared mixed anhydrides (12.7 g, 30.0 mmol, 1 equiv) in diethyl ether (110 mL) was placed in a ground joint flask and cooled to 0° C. in an ice bath. Freshly prepared diazomethane ethereal solution (approximately 90.0 mmol, 3 equiv) was added dropwise through an addition funnel while maintaining cooling. The resulting mixture was stirred at 0° C. for 15 min, warmed to room temperature, and stirred for 30 min. The reaction was cooled to 0° C. Meanwhile, a mixture of 48% aqueous HBr (24 mL, 210.0 mmol, 7 equiv) and acetic acid (24.0 mL) was cooled to 0° C. and slowly added to the above reaction mixture at 0° C. The mixture was stirred at 0° C. for 15 min, warmed to room temperature, and stirred for 30 min. The mixture was diluted with diethyl ether (120 mL), washed with water (3×120 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an InterChim automated chromatography system (SorbTech silica gel column, 220 g) eluting with a 0-30% gradient of ethyl acetate in heptane to give compound 58-3 as a white solid (7.26 g, 59% yield).

[0289] Benzyl (S)-6-(3,5-bis(trifluoromethyl)phenoxy)-4-((tert-butoxycarbonyl)amino)-5-oxohexanoate (59-1): Potassium fluoride (3.93 g, 67.6 mmol, 4 equiv.) was added to a solution of compound 58-3 (7.0 g, 16.9 mmol, 1 equiv.) and 3,5-bis(trifluoromethyl)phenol (2.8 mL, 18.6 mmol, 1.1 equiv.) in DMF (70 mL). After stirring at room temperature for 18 hours, the reaction was diluted with ethyl acetate (120 mL) and washed with saturated aqueous sodium bicarbonate (180 mL) and saturated brine (180 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an InterChim automated chromatography system (RediSepRf silica gel column, 220 g) eluted with a 0-25% gradient of ethyl acetate in heptane to give compound 59-1 as a white solid (6.0 g, 63% yield).

[0290] Benzyl (S)-4-amino-6-(3,5-bis(trifluoromethyl)phenoxy)-5-oxohexanoate hydrochloride (59-2): 4M HCl in 1,4-dioxane (2.9 mL, 11.7 mmol, 1.2 equiv) was added dropwise to a solution of compound 59-1 (5.5 g, 9.76 mmol, 1 equiv) in acetonitrile (100 mL) at 0-5° C. The mixture was allowed to warm to room temperature and stirred for 6.5 h. LCMS indicated the reaction was not complete. Additional 4M HCl in 1,4-dioxane (2.0 mL, 7.8 mmol, 0.8 equiv) was added and the mixture was stirred for 16 h (at which time LCMS indicated the reaction was complete). The mixture was concentrated under reduced pressure to give compound 59-2 as a white solid (4.6 g, 95% yield) which was used in the next step.

[0291] Benzyl (S)-6-(3,5-bis(trifluoromethyl)phenoxy)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido))propanamido)-5-oxohexanoate (59-3): (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.84 g, 2.2 mmol, 1.1 equiv.) was added to a solution of compound 8 (0.55 g, 2.0 mmol, 1 equiv.) in dimethylformamide (10 mL) at room temperature. After stirring at room temperature for 10 min, compound 59-2 (1.0 g, 2.0 mmol, 1 equiv.) and N,N-diisopropylethylamine (1.1 mL, 6.0 (mmol, 3 equiv.) were added sequentially. After stirring at room temperature for 18 h, the reaction mixture was diluted with ethyl acetate (50 mL). The organic layer was washed with water (2×30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on an Interchim automated chromatography system (RediSepRf silica gel column, 80 g) using a 0-60% gradient of ethyl acetate with heptane elution. After concentration of the eluted fractions under reduced pressure, the resulting solid was dried under vacuum at 45° C. for 18 h to give compound 59-3 as a slightly yellow solid (0.72 g, 50% yield).

[0292] (S)-6-(3,5-bis(trifluoromethyl)phenoxy)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido))propanamido)-5-oxohexanoic acid (59-A, Example 10): A suspension of compound 59-3 (0.53 g, 0.74 mmol, 1.0 equiv.) and 10% palladium on activated carbon (53 mg, 50% wet) in tetrahydrofuran (20 mL) was hydrogenated at 25 psi (172.4 kPa) for 2 h. LC-MS analysis showed the reaction was complete. The mixture was filtered through Celite (15 g), which was washed with tetrahydrofuran (3×50 mL). The filtrate was concentrated under reduced pressure and the crude product was dissolved in dichloromethane (12 mL) and adsorbed onto silica gel (15 g). This material was dry loaded and purified on an Interchim automated system (SorbTech silica gel column, 40 g) eluting with a 0-8% gradient of methanol in dichloromethane. After concentrating the eluted fractions under reduced pressure, the resulting solid was dried under vacuum at room temperature for 18 hours to give compound 59-A (Example 10) as an off-white solid (0.25 g, 54% yield) (mass spectrometry m / z=628.1 (M+H)).

[0293] Example 11 [ka] Benzyl (S)-4-((S)-2-(2-((2-(tert-butyl)phenyl)amino)-2-oxoacetamido))propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate (65-1): 1-Hydroxy-7-azabenzotriazole (0.21 g, 1.51 mmol, 1.2 equiv.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.29 g, 1.51 mmol, 1.2 equiv.) were added sequentially to a solution of (2-((2-(tert-butyl)phenyl)amino)-2-oxoacetyl)-L-alanine, compound A (0.37 g, 1.26 mmol, 1.0 equiv.) in acetonitrile (6 mL) and DMF (3 mL) at room temperature. After stirring at room temperature for 1 h, compound 58-5 (0.55 g, 1.26 mmol, 1.0 equiv) and triethylamine (0.35 mL, 2.52 mmol, 2 equiv) were added sequentially. After stirring at room temperature for 2 days, the reaction was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with water (10 mL) and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (SorbTech, 24 g column) eluting with a 0-30% gradient of ethyl acetate in hexane to give the desired product as a white solid (0.49 g, 58% yield).

[0294] (S)-4-((S)-2-(2-((2-(tert-butyl)phenyl)amino)-2-oxoacetamido))propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid (Compound 65-A, Example 11): A suspension of Compound 65-1 (0.49 g, 0.73 mmol, 1 equiv.) and 10% palladium on carbon (0.1 g, 50% wet) in THF (20 mL) and ethyl acetate (5 mL) was hydrogenated at 20 psi (137.9 kPa) for 2 hours. The reaction mixture was filtered through a syringe filter and concentrated under reduced pressure. The residue was purified twice on an Interchim automated chromatography system (RediSep Gold silica gel column, 12 g) eluting with a 0-5% gradient of methanol in dichloromethane to give compound 65-A (Example 11) as a white solid (140 mg, 33% yield) (mass spectrometry m / z=584.2 (M+H)).

[0295] Example 12 [ka] 2-((2,6-Difluorophenyl)amino)-2-oxoacetic acid (4) was prepared in Scheme 1.

[0296] Ethyl 2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido))-2-methylpropanoate (61-1): Compound 4 (1.5 g, 7.46 mmol, 1.0 equiv.) and 1-hydroxy-7-azabenzotriazole (1.421 g, 10.44 mmol, 1.4 equiv.) were dissolved in acetonitrile (77.3 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.002 g, 10.44 mmol, 1.4 equiv.) was added and the mixture was stirred at room temperature. After 10 min everything was dissolved. N-Methylmorpholine (1.97 mL, 17.9 mmol, 2.4 equiv.) was added followed by ethyl 2-amino-2-methylpropanoate hydrochloride (1.25 g, 7.46 mmol, 1.0 equiv.). After stirring at room temperature under nitrogen for 20 hours, the reaction was warmed to 70° C. for an additional 5 hours and then cooled to room temperature. Ethyl acetate (100 mL) and water (80 mL) were added and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×75 mL). The combined organic layers were washed with saturated brine (75 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), adsorbed onto Celite, and purified on an Interchim automated chromatography system (Sorbtech silica gel column, 80 g) eluting with a 0-50% gradient of ethyl acetate to dichloromethane to give compound 61-1 as a white solid (0.749 g, 32% yield).

[0297] 2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido))-2-methylpropanoic acid (61-2): Lithium hydroxide (68.4 mg, 2.86 mmol, 1.2 equiv) in water (2.8 mL) was added to a solution of compound 61-1 (0.748 g, 2.37 mmol, 1.0 equiv) in tetrahydrofuran (9.3 mL). The mixture was stirred at room temperature for 3 days. Additional lithium hydroxide (34.2 mg, 1.43 mmol) in water (0.7 mL) was added to the reaction mixture. After another day, additional lithium hydroxide (34.2 mg, 1.43 mmol) in water (0.4 mL) was added to the reaction mixture along with 1 mL of tetrahydrofuran. After an additional 3 hours, the reaction was cooled to 0° C. and the pH was adjusted to 2 with concentrated HCl (20 drops). The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was diluted with a 3:1 mixture of toluene and ethyl acetate, stirred at 40° C. for 30 min, and concentrated under reduced pressure. The residue was dried under vacuum at 40° C. for 4 h to give compound 61-2 as a white solid (0.629 g, 92% yield).

[0298] Benzyl (S)-4-(2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido))-2-methylpropanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate (61-3): Compound 61-2 (0.200 g, 0.698 mmol, 1.0 equiv.) and 1-hydroxybenzotriazole hydrate (0.132 g, 0.838 mmol, 1.2 equiv.) were dissolved in acetonitrile (3.9 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.161 g, 0.838 mmol, 1.2 equiv.) was added and the mixture was stirred at room temperature under nitrogen for 1 h. Diisopropylethylamine (0.243 mL, 1.4 mmol, 2.0 equiv) was added, followed by compound 58-5 (0.304 g, 0.698 mmol, 1.0 equiv) in acetonitrile (0.4 mL). The reaction was stirred at room temperature for 22 h. Ethyl acetate (10 mL) and saturated aqueous sodium bicarbonate (5 mL) were added and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on an Interchim automated chromatography system (Sorbtech silica gel column, 12 g) eluting with a 5-50% gradient of ethyl acetate in heptane to give compound 61-3 as a light yellow oil (0.117 g, 25% yield).

[0299] This procedure was repeated on a 0.362 g scale of compound 61-2 to give compound 61-3 as a light yellow oil (0.160 g, 19% yield).

[0300] (S)-4-(2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido))-2-methylpropanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid (61-A, Example 12): A mixture of compound 61-3 (0.117 g, 0.175 mmol, 1.0 equiv.) and 10% Pd / C (11.2 mg, 50% wet) in tetrahydrofuran (20 mL) was hydrogenated at 22 psi (151.7 kPa) for 2 h. The reaction mixture was filtered through Celite and washed with tetrahydrofuran (25 mL). The filtrate was concentrated under reduced pressure and purified on a Buchi automated chromatography system (Sorbtech silica gel column, 12 g) eluting with a 0-10% gradient of methanol to dichloromethane to give 63 mg of a pink solid. This solid was triturated with dichloromethane (2 mL) to give a white solid which was dried under vacuum at 40° C. overnight to give compound 61-A as a white powder (43 mg, 42% yield) (RC-3-011).

[0301] This procedure was repeated on a 0.180 g scale of compound 61-3 to give compound 61-A (65.0 mg, 42% yield). The two batches of product were combined to give 61-A, (Example 12) as a white powder (108 mg) (mass spectrometry m / z=578 (M+H)).

[0302] Example 13 [ka] (S)-2-Amino-6-(benzyloxy)-6-oxohexanoic acid (63-1B): Benzyl alcohol (125 mL, 1.21 mol, 10 eq.) was added dropwise to a suspension of L-2-aminoadipic acid (63-1A) (19.5 g, 0.12 mol, 1 eq.) in 12M HCl (10 mL, 0.12 mol, 1 eq.). The mixture was heated at 100° C. for 1 h and then cooled to room temperature. Diethyl ether (700 mL) was added to the solution. The resulting solid was filtered, washed with diethyl ether (3×100 mL), and dried under vacuum at room temperature for 18 h to give compound 63-1B as a white solid (22.5 g, 65% yield).

[0303] (S)-6-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-6-oxohexanoic acid (63-1): Sodium hydroxide (2.5 g, 62.5 mmol, 1.2 equiv.) was added to a solution of compound 63-1B (15 g, 52.1 mmol, 1 equiv.) in a mixture of acetonitrile (200 mL) and water (200 mL). The mixture was stirred at room temperature for 15 min. Di-tert-butyl dicarbonate (14.4 mL, 62.5 mmol, 1.2 equiv.) was added to the reaction mixture and stirred for 18 h. LCMS analysis indicated the reaction was not complete. Additional sodium hydroxide (1.04 g, 26.1 mmol, 0.5 equiv) and di-tert-butyl dicarbonate (6.0 mL, 26.1 mmol, 0.5 equiv) were added and the mixture was stirred for 6 h (at which time LCMS analysis indicated the reaction was complete). Acetonitrile was removed under reduced pressure. Saturated aqueous sodium bicarbonate (200 mL) was added to the aqueous solution, and the aqueous solution was extracted with diethyl ether (3×250 mL) to remove unreacted di-tert-butyl dicarbonate. The aqueous solution was cooled to 0° C. and adjusted to pH 1 with 5 M hydrochloric acid (approximately 220 mL). The mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with saturated brine (3×500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was dried under vacuum at room temperature for 18 h to give compound 63-1 as a yellow liquid (15.7 g, 86% yield).

[0304] Benzyl (S)-7-bromo-5-((tert-butoxycarbonyl)amino)-6-oxoheptanoate (63-3): Isobutyl chloroformate (5.84 mL, 45.0 mmol, 1.5 equiv) was added dropwise to a solution of compound 63-1 (10.54 g, 30.0 mmol, 1 equiv) and N-methylmorpholine (5.28 mL, 48 mmol, 1.6 equiv) in THF (100 mL) at −10° C. After stirring for 20 min at −10° C., the reaction was filtered through Celite and concentrated under reduced pressure to give the mixed anhydride as a yellow oil (12.3 g) that was used in the next step.

[0305] Diazomethane preparation: A solution of N-methyl-N'-nitroso-p-toluenesulfonamide (Diazald®, 19.28 g, 90.0 mmol, 1 equiv.) in diethyl ether (66 mL) was added through an addition funnel to a mixture of potassium hydroxide (15.12 g, 270 mmol, 3 equiv.), ethanol (30 mL), and water (26 mL) in an oil bath at 65°C. A receiving flask for collecting the ethereal solution of diazomethane was cooled in an ice bath and the Diazald® solution was added at a rate that allowed dropwise distillation into the receiving flask. When all of the Diazald® solution had been added, additional diethyl ether (10 mL) was added through the addition funnel until the distillate was clear (no diazomethane remaining). After cooling to room temperature, the mixture in the distillation flask was slowly quenched with acetic acid until the yellow color disappeared.

[0306] A solution of the above freshly prepared mixed anhydrides (12.7 g, 30.0 mmol, 1 equiv) in diethyl ether (110 mL) was placed in a ground joint flask and cooled to 0° C. Freshly prepared diazomethane ethereal solution (approximately 90.0 mmol, 3 equiv) was added dropwise through an addition funnel while maintaining cooling. The resulting mixture was stirred at 0° C. for 15 min, warmed to room temperature, and stirred for 30 min. The reaction was cooled to 0° C. Meanwhile, a mixture of 48% aqueous HBr (24 mL, 210.0 mmol, 7 equiv) and acetic acid (24.0 mL) was cooled to 0° C. and slowly added to the above reaction mixture at 0° C. The mixture was stirred at 0° C. for 15 min, warmed to room temperature, and stirred for 30 min. The mixture was diluted with diethyl ether (120 mL), washed with water (3×120 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an InterChim automated chromatography system (SorbTech silica gel column, 220 g) eluting with a 0-25% gradient of ethyl acetate in heptane to give compound 63-3 as a white solid (4.73 g, 37% yield).

[0307] Benzyl (S)-5-((tert-but...

Claims

1. N 1-((S)-1-(((S)-5-(benzyloxy)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)-N 2 -(2,6-difluorophenyl)oxalamide, N 1 -(2,6-difluorophenyl)-N 2 -((S)-1-(((S)-5-hydroxy-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)oxalamide, N 1 -((S)-1-(((S)-5-((4-chlorobenzyl)oxy)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)-N 2 -(2,6-difluorophenyl)oxalamide, N 1 -(2,6-difluorophenyl)-N 2 -((S)-1-oxo-1-(((S)-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)-5-(thiophen-3-ylmethoxy)pentan-3-yl)amino)propan-2-yl)oxalamide, N 1 -(2,6-difluorophenyl)-N 2 -((S)-1-(((S)-5-methoxy-2-oxo-1-(2,3,5,6-tetrafluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)oxalamide, (S)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-3-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentyl phenyl carbonate, (S)-3-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentyl benzoic acid ester, (S)-4-(2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)acetamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-6-(3,5-bis(trifluoromethyl)phenoxy)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-5-oxohexanoic acid, (S)-4-((S)-2-(2-((2-(tert-butyl)phenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-(2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)-2-methylpropanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-5-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-6-oxo-7-(2,3,5,6-tetrafluorophenoxy)heptanoic acid, (S)-4-(1-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)cyclopentane-1-carboxamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)hexanoic acid, (S)-4-(2-(7-chloro-1-oxoisoquinolin-2(1H)-yl)acetamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-((4-fluorophenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-((3-fluorophenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-((4-methylphenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-((3-methylphenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-((2-methylphenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-((2-methoxyphenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-((3-methoxyphenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-((4-methoxyphenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-((5-methylpyridin-2-yl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-5-oxo-4-((S)-2-(2-oxo-2-((3-(trifluoromethyl)phenyl)amino)acetamido)propanamido)-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-5-oxo-4-((S)-2-(2-oxo-2-((4-(trifluoromethyl)phenyl)amino)acetamido)propanamido)-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, benzyl (S)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate, (S)-4-((S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-((4-acetylphenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-((3-(1H-tetrazol-5-yl)phenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-((2-cyanophenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-6-((2,6-bis(trifluoromethyl)pyrimidin-4-yl)oxy)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-5-oxohexanoic acid, (S)-5-oxo-4-((S)-2-(2-oxo-2-((4-(trifluoromethoxy)phenyl)amino)acetamido)propanamido)-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-5-oxo-4-((S)-2-(2-oxo-2-(quinolin-3-ylamino)acetamido)propanamido)-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-(naphthalen-1-ylamino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-5-oxo-4-((S)-2-(2-oxo-2-(quinolin-8-ylamino)acetamido)propanamido)-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-5-oxo-4-((S)-2-(2-oxo-2-(pyridin-4-ylamino)acetamido)propanamido)-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (R)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-5-oxo-4-((S)-2-(2-oxo-2-(pyridin-2-ylamino)acetamido)propanamido)-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-5-oxo-4-((S)-2-(2-oxo-2-(pyridin-3-ylamino)acetamido)propanamido)-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-4-((S)-2-(2-((4,6-dimethylpyrimidin-2-yl)amino)-2-oxoacetamido)propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, (S)-5-oxo-4-((S)-2-(2-oxo-2-(pyrimidin-2-ylamino)acetamido)propanamido)-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid, and N 1 -(2,6-difluorophenyl)-N 2 -((S)-1-(((S)-6-(hydroxyamino)-2,6-dioxo-1-(2,3,5,6-tetrafluorophenoxy)hexan-3-yl)amino)-1-oxopropan-2-yl)oxalamide or an enantiomer or a mixture of said enantiomers, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

2. A pharmaceutical composition comprising the compound of claim 1.

3. 3. The pharmaceutical composition of claim 2 for use in treating a disease selected from a gastrointestinal disease, a respiratory disease, a cardiovascular disease, a skin disease, a rheumatic disease, a renal disease, an autoimmune disease, a CNS disease, an inflammatory disease, a liver disease, cancer and an ophthalmological disease.

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