Caspase inhibitors and methods of use thereof

Abstract

To provide compounds that are caspase inhibitors, pharmaceutical compositions containing these compounds, and methods of using such compounds and pharmaceutical compositions.SOLUTION: Provided herein are compounds of formula (I), compositions comprising the compounds, and methods of treating various diseases by means of the compounds and compositions.SELECTED DRAWING: Figure 1

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. No. 6,229,699, the disclosure of which is incorporated herein by reference in its entirety.

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

[0003] (3.Background) There are 12 known human caspases. Caspase-1 is an interleukin-converting enzyme (I Also known as CE), it was the first human caspase identified. Based on these effects, apoptosis-inducing caspases (caspase 2, 3, 6, 7, 8, 9 and and 10) and inflammation-inducible caspases (caspase 1, 4, and 5). The functions of two additional human caspases (12 and 14) are less well characterized. .

[0004] Caspases are important members of the signaling pathways for apoptosis and cell disassembly. It is a family of cysteine ​​protease enzymes that are mediators of , Chem. Biol., 1998, 5, R97-R103). These signal transduction pathways vary depending on the cell type and stimuli. Although different in nature, all apoptotic pathways converge on common effector pathways, with the most important Caspases are involved in signal transduction pathways, leading to the proteolysis of proteins. It is involved in both the effector step and its initiation further upstream. Activation of the associated upstream caspases promotes the proliferation of other caspases involved in later apoptotic steps. The enzymes are activated one after another.

[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 this enzyme. First, the cleavage site The aspartic acid adjacent to the cleavage site is strongly required, which is essential for the IL-1β precursor and peptide substrate. Any substitution of this residue within the 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 a member of a protein complex known as the inflammasome. It is generated from its inactive precursor, procaspase-1, by the action of inflammasome. The biochemical function of the casposome is to generate active caspase-1. It converts an inactive precursor, pro-interleukin-1β (pro-IL-1β), into the active cytokine, interleukin-1β. converts pro-IL-18 to mature, active IL-1β. IL-1β is known as a pro-inflammatory master cytokine and is involved in many human diseases. IL-18 is also a pro-inflammatory cytokine implicated in human disease. Pase-1 also cleaves the protein gasdermin D, which causes the inflammatory process known as pyroptosis. Initiates a form of cell death. 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 It is known to regulate the production of pro-inflammatory cytokines and activate pyroptosis, Caspase-1 and IL-1β are involved in many inflammatory disease symptoms. Immunological diseases, CNS diseases, liver diseases, respiratory diseases, cardiovascular diseases, skin diseases, rheumatic diseases, kidney diseases It has been associated with diseases such as ophthalmological disorders and cancer. Flores, J. et al., Nature Comm. 9, 3 916 (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.1416-14 23 (2016); Guo B. et al., Sci Rep. 6, p. 36107 (2016); Stack, J. et al., J. Immun ol.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); Au dia, J. et al., Basic Res. Cardiol. 113, (5), pp. 32 (2018); Aira, L. et al., JI nvest.Derm.DOI: 10.1016 / j.jid.2018.11.031 (2018), Wooff, Y. et al., Sci.Rep.10, p.2263 (2020). Therefore, the inflammation of caspase-1, caspase-4, and caspase-5 Inhibitors of the pathogenic and pathogenic effects of HIV-1 may be beneficial in the treatment of several human diseases.

[0007] In view of the multiple uses of caspase inhibitors, selective inhibition of certain caspases is essential. There is a constant need to develop new, more effective compounds that can Summary of the Invention

[0008] (4. Overview) Provided herein are compounds, pharmaceutical compositions containing the compounds, and methods for treating a range of conditions, including but not limited to: Although not exclusively caspase-1, caspase-4, and / or caspase-5, certain and methods for their use in the treatment of diseases modulated by caspases. In aspects, compounds for use in the compositions and methods provided herein have the formula I or its enantiomers or mixtures of said enantiomers, or its pharmaceutical use and optionally, a 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 described in this specification. as defined elsewhere in this document).

[0009] Also provided herein are compounds of formula I and a pharmaceutically acceptable carrier. and a pharmaceutical composition comprising the compound.

[0010] In one embodiment, provided herein is a therapeutically effective amount of the compounds provided herein. The administration of the compound inhibits the production of inflammatory caspases (i.e., caspase-1, caspase ( ae)-4 and caspase-5)-related diseases or conditions, and / or inflammatory caspases The present invention relates to a method for treating a psychiatric disorder. Treatment can include alleviation, mitigation, and / or prevention. In some embodiments, the present invention relates to a condition or disease associated with inflammatory caspases and / or a method for treating inflammatory caspases. Modulation of this enzyme is associated with autoimmune, inflammatory, CNS, liver, respiratory, and cardiovascular diseases. In some embodiments, the inflammation is selected from the group consisting of skin diseases, rheumatic diseases, renal diseases, and cancer. Conditions or diseases associated with inflammatory caspases and / or modulation of inflammatory caspases may be autosomal recessive. Autoimmune diseases, inflammatory diseases, CNS diseases, liver diseases, respiratory diseases, cardiovascular diseases, skin diseases, rheumatoid arthritis The disease is selected from arthritis, renal disease, ophthalmological disease and cancer.

[0011] In one embodiment, provided herein is a method for treating a rheumatoid arthritis by administering a therapeutically effective amount of a compound of the present invention. caspase-1, caspase-4 and / or caspase-5-related diseases by administering or symptoms and / or modulation of caspase-1, caspase-4 and / or caspase-5 The treatment may include alleviation, mitigation, and / or prevention. In such cases, symptoms or diseases related to caspase-1, caspase-4, and / or caspase-5 are and / or modulation of caspase-1, caspase-4, and / or caspase-5 contributes to autoinflammation. symptoms, autoimmune diseases, inflammatory diseases, CNS diseases, liver diseases, respiratory diseases, cardiovascular diseases, skin diseases In one embodiment, the caspase-1 , symptoms or diseases related to caspase-4 and / or caspase-5, and / or caspase Modulation of caspase-1, caspase-4 and / or caspase-5 is a key factor in autoinflammatory and autoimmune diseases, Inflammatory diseases, CNS diseases, liver diseases, respiratory diseases, cardiovascular diseases, skin diseases, rheumatic diseases, The disease is selected from renal disease, ophthalmological disease and cancer.

[0012] In one embodiment, the compositions described herein are used to treat autoinflammatory diseases, neuroinflammatory diseases, The compounds are useful in the treatment, prevention, or amelioration of autoimmune diseases and other inflammatory conditions. In embodiments, the compositions described herein are useful in treating liver disease, particularly non-alcoholic steatohepatitis (NAS). H), non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), primary biliary liver cirrhosis It is useful for the treatment of primary hepatitis C (PBC), autoimmune hepatitis (AIH), and viral hepatitis. The compositions described herein are useful for treating gastrointestinal diseases, particularly inflammatory bowel disease (IBD), ulcerative colitis, and the like. In one embodiment, the compositions described herein are useful for the treatment of ulcerative colitis (UC) and Crohn's disease. The composition is effective in treating CNS disorders and neuroinflammatory diseases, particularly multiple sclerosis (MS), Alzheimer's disease, Hansen's disease, These compounds are useful in the treatment of Chinton's disease (HD), Parkinson's disease (PD), and epilepsy. The composition is effective in treating cardiovascular and metabolic diseases, particularly myocardial infarction (MI), atherosclerosis, and the like. In one embodiment, the compounds described herein are useful in the treatment of type 1 diabetes, type 2 diabetes, and type 3 diabetes. The composition is 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 disorders, particularly psoriasis and In one embodiment, the compositions described herein are useful for treating rheumatoid arthritis, rheumatoid arthritis, and acne. It is useful for the treatment of chronic diseases, particularly rheumatoid arthritis (RA), osteoarthritis (OA) and gout. Exemplary specific autoimmune diseases to which the compounds are applicable include systemic lupus erythematosus (SLE). -Des, polychondritis, scleredema, Wegener's granulomatosis, dermatomyositis, Steven- Johnson's syndrome, endocrine ophthalmopathy and Graves' disease may also be included.

[0013] In one embodiment, the compositions described herein also provide a method for treating asthma, steroid-resistant asthma, They are useful in the treatment, prevention or amelioration of emphysema and other obstructive or inflammatory airway diseases.

[0014] In one embodiment, the compositions described herein also provide a method for treating conditions such as age-related macular degeneration (AMD). It is useful for treating, preventing or alleviating ophthalmic diseases such as retinal degenerative diseases.

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

[0016] In one embodiment, the present disclosure provides a method for the treatment and / or prevention of cancer, comprising administering to a subject a therapeutic agent selected from the group consisting of steroids, steroid hormone ... Typical cancers include colorectal cancer (CRC), melanoma, gastric cancer (esophageal cancer), (including ovarian cancer), renal cell carcinoma (RCC), breast cancer, prostate cancer, head and neck cancer, bladder cancer, hepatocellular carcinoma (HCC), and ovarian cancer , cervical cancer, endometrial cancer, pancreatic cancer, neuroendocrine cancer, blood cancer (especially multiple myeloma, acute bone marrow cancer, These include medulloblastic leukemia (AML), and biliary tract cancer.

[0017] In one embodiment, the compounds are useful in the treatment of cancers that have at least a partial inflammatory basis. In one embodiment, the compounds are provided to at least partially alleviate inflammation. In another aspect, the compounds provided herein are useful for the treatment and / or prevention of cancers having an infectious basis. Provided are specific clinical applications for the administration of compounds for the treatment and / or prevention of cancer. In another aspect, the compounds provided herein are administered in combination with one or more therapeutic agents (e.g., administered to a subject in need thereof in conjunction with a chemotherapeutic agent (e.g., a chemotherapeutic agent), and / or in certain embodiments Subjects in have undergone / will undergo cytoreductive surgery in addition to administration of the compounds herein. .

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

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

[0020] In some embodiments, the compounds provided herein are useful in treating cryopyrin-associated periodic fever syndrome. CAPS, Familial Mediterranean Fever (FMF), Systemic Onset Juvenile Idiopathic Arthritis (SJIA), Hyperimmunoglobulin D Treatment or prevention of Hepatitis A-associated Syndrome (HIDS) and Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), Also, familial cold urticaria, neonatal-onset multisystem inflammatory disease, SJIA and FMF, and Mac It is used to treat or prevent Lewell's syndrome.

[0021] In practicing the method, an effective amount of a compound or composition containing a therapeutically effective concentration of the compound is administered. The amount is administered to an individual who exhibits symptoms of the disease or disorder to be treated. It is effective in bringing about the remission or elimination of one or more symptoms.

[0022] Also provided is a pharmaceutical composition comprising one or more containers filled with one or more ingredients of the pharmaceutical composition. Optionally, the packaging may be a pack or kit, including a packaging material for the manufacture of a pharmaceutical or biological product, may be accompanied by notices in the form prescribed by any governmental agency regulating its use or sale; This notice reflects agency approval for manufacture, use, or sale for human administration. The pack or kit may include information on the mode of administration, order of drug administration (e.g., separate, sequential), Information regarding the type of the object (or the object itself) may be labeled.

[0023] These and other aspects of the subject matter described herein are described in detail below with reference to the detailed description. This will be clear from the above. [Brief explanation 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] [Figure 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] [Figure 3]FIG. 3 shows the in vivo inhibition of the pro-inflammatory 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] [Figure 5] FIG. 5 provides the effect of twice-daily oral administration of the compound of Example 6 and a reference compound on histological parameters of the colon in an ulcerative colitis model. DETAILED DESCRIPTION OF THE INVENTION

[0029] 6. Detailed Description of the Embodiments (6.1.Definition) Unless otherwise specified, all technical and scientific terms used herein are understood to be within the skill of the art. All patents, applications, published applications, and other The publication is incorporated by reference in its entirety. In the event of multiple definitions, those in this section prevail unless otherwise stated.

[0030] As used herein, "halogen" refers to all halogens, i.e., halogen substituents include , 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 containing 1 to 6 carbon atoms (unless otherwise defined). As used herein, "alkyl" refers to a group derived from an alkane, including straight chain alkyl or branched alkyl. The term "alkyl" as used herein includes methyl, ethyl, tert-butyl, isopropyl, n-octyl Linear or branched C1-C 10 A straight or branched alkyl group is a chemical and can be attached at any possible point to create a stable compound. The lower alkyl includes methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc. It is a straight-chain or branched alkyl group containing 1 to 6, 1 to 4, or 1 to 2 carbon atoms. "Lower alkyl" means, unless otherwise indicated, one or more, e.g., 1, 2, 3, 4, or 5, alkyl groups. represents lower alkyl optionally and independently substituted with one, two, or three substituents; Attached at any available atom to form a stable compound, where the substituent is -F, -O H, -NH2, -NO2, -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH2, -C(S)-NH2, -S(O)2-NH2, -N(H)- C(O)-NH2, -N(H)-C(S)-NH2, -N(H)-S(O)2-NH2, -C(NH), -NH2, -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 )-Ro 、-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)-NH2、-N(R o )-C(S)-NH2、-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-NH2、-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 c , -R f , and -R g is selected from the group consisting of:

[0034] "Alkylene" means a straight or branched divalent group containing no unsaturation and consisting solely of carbon and hydrogen. "Lower alkylene" refers to, for example, methylene, ethylene, propylene, Straight or branched chains consisting only of carbon and hydrogen with 1 to 6 carbon atoms, such as n-butylene, containing no unsaturation refers to a branched divalent hydrocarbon chain. In certain embodiments, alkylene and lower alkylene are , substituted with one or more substituents as described above in the definition of alkyl groups.

[0035] "Lower alkenyl", alone or in combination, means an alkyl group having 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. , linear or branched C1-C containing 1 to 2 or only 1 carbon-carbon double bond 10 Carbon chain The carbon-carbon double bond may be contained in either the straight-chain or branched portion. The straight-chain or branched lower alkenyl group is chemically available and may be any possible position. Examples of lower alkenyl groups include ethenyl, propenyl, and methyl. The term "substituted lower alkenyl" includes, but is not limited to, substituted lower alkenyl ... Unless otherwise specified, one or more, e.g., 1, 2, 3, 4 or 5, as well as 1, 2 or 3 The substituents represent optionally independently substituted lower alkenyl, bonded at any available atom. to form stable compounds, where the substituents are -F, -OH, -NH2, -NO2, -CN, -C(O )-OH, -C(S)-OH, -C(O)-NH2, -C(S)-NH2, -S(O)2-NH2, -N(H)-C(O)-NH2, -N(H)-C(S)-NH2 , -N(H)-S(O)2-NH2, -C(NH)-NH2, -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)-NH2, -N(R o )-C(S)-NH2, -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-NH2, -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 f , and -R g Selected from the group consisting of It is selected.

[0036] "Lower alkynyl", alone or in combination, means a group having 2 to 6 carbon atoms (unless otherwise defined). and linear or branched carbons containing at least one or only one carbon-carbon triple bond. The term "alkynyl" refers to at least one or only one carbon-carbon Straight or branched C1-C containing triple bonds 10It means a carbon chain. The aryl group is chemically available and can be attached at any available point to create a stable compound. Examples of alkynyl groups include ethynyl, propynyl, butynyl, etc. "Lower alkynyl" means, unless otherwise indicated, one or more, e.g., 1, 2, 3, 4 or 5, alkyl groups. , which also represents a lower alkynyl optionally and independently substituted with 1, 2, or 3 substituents. , which is attached at any available atom to form a stable compound, where the substituent is -F, -OH, -NH2, -NO2, -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH2, -C(S)-NH2, -S(O)2-NH2, -N(H )-C(O)-NH2, -N(H)-C(S)-NH2, -N(H)-S(O)2-NH2, -C(NH)-NH2, -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)-Ro 、 -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)-NH2、 -N(R o )-C(S)-NH2、 -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-NH2、 -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 、及び -R g selected from the group consisting of.

[0037] "Cycloalkyl" refers to a saturated or unsaturated non-aromatic group having 3 to 10 ring members per ring, as well as 3 to 10 ring members per ring. 8 or 3-6 monocyclic, bicyclic or tricyclic carbocyclic ring systems, such as cyclopropyl, cyclopentyl, Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, cis- or trans-decalin, bicyclo[2.2.l]hept-2-ene, cyclohex-1-enyl, cyclo The term "(cycloalkyl) alkyl" refers to pent-1-enyl, 1,4-cyclooctadienyl, etc. "Cycloalkyl" means an alkyl group as defined above substituted with a cycloalkyl ring. Examples include (cyclohexyl)methyl, 3-(cyclopropyl)-n-propyl, 5-(cyclopentyl) 6-(adamantyl)hexyl, and the like.

[0038] "Substituted cycloalkyl" means, unless otherwise specified, one or more substituted cycloalkyl groups, e.g., 1, 2, 3, cycloalkyl optionally substituted independently with 4 or 5, as well as 1, 2, or 3, substituents; alkyl, and may be attached at any available atom to form a stable compound. Substituents include halogen, -OH, -NH2, -NO2, -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH2, and -C(S)-N. H2, -S(O)2-NH2, -N(H)-C(O)-NH2, -N(H)-C(S)-NH2, -N(H)-S(O)2-NH2, -C(NH)-NH2, -O- R 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)-NH2、-N(R o )-C(S)-NH2、-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(Ro )-S(O)2- NH2, -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 Shik "C cycloalkyl" refers to a cycloalkyl containing 3 to 6 carbon atoms, 3-5 "Cycloalkyl" is , represents a cycloalkyl having 3 to 5 carbon atoms.

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

[0040] "Substituted heterocycloalkyl" means, unless otherwise indicated, one or more, e.g., 1, Optionally independently substituted with 2, 3, 4, or 5, as well as 1, 2, or 3, substituents Heterocycloalkyl, which may be attached at any available atom to form a stable compound. where the substituent is a halogen, -OH, -NH2, -NO2, -CN, -C(O)-OH, -C(S)-OH, -C (O)-NH2, -C(S)-NH2, -S(O)2-NH2, -N(H)-C(O)-NH2, -N(H)-C(S)-NH2, -N(H)-S(O)2-NH2 , -C(NH)-NH2, -OR o , -SR o , -OC(O)-R o , -OC(S)-R o , -C(O)-R o , -C(S)-R o , -C(O)-O- R 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)-NH2、-N( R o )-C(S)-NH2、-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-NH2、-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 )-Ro , -R d , -R e , -R f , and -R g is selected from the group consisting of:

[0041] "Aryl," alone or in combination, refers to an aromatic hydrocarbon, such as phenyl or naphthyl. refers to a monocyclic or bicyclic ring system containing a ring element, optionally having, for example, 5 to 7 ring members, or, for example, 5 The term "substituted aryl" is used interchangeably with "substituted aryl" and "substituted aryl" as defined elsewhere. Unless otherwise specified, one or more, e.g., 1, 2, 3, 4 or 5, as well as 1, 2 or 3 The substituents are optionally independently substituted aryl, and are attached at any available atom. to form a stable compound, where the substituents are halogen, -OH, -NH2, -NO2, -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH2, -C(S)-NH2, -S(O)2-NH2, -N(H)-C(O)-NH2, -N(H)-C(S) -NH2, -N(H)-S(O)2-NH2, -C(NH)-NH2, -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 )-Ro 、-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)-NH2、-N(R o )-C(S)-NH2、-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-NH2、-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(Ro )-R o , -R d , -R e , -R f , and -R g Because In some embodiments, the substituents are selected from the group consisting of 1 to 3 halo, trihalomethyl, aryl, amino, protected amino, amino salt, monosubstituted amino, disubstituted amino, Carboxy, protected carboxy, carboxylate, hydroxy, protected hydroxy , salts of hydroxy groups, lower alkoxy, lower alkylthio, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, (cycloalkyl)alkyl, Substituted (cycloalkyl) alkyl, phenyl, substituted phenyl, phenyl alkyl In some embodiments, the substituents are selected from: Selected from trifluoromethyl, trichloromethyl, tribromomethyl and triiodomethyl In some embodiments, the substituents are one or more trifluoromethyl.

[0042] The term "substituted phenyl" refers to one or more "aryl" substituents selected from the "aryl" substituents identified above. In one embodiment, the substituents are halogen, hydroxyl, methyl ... protected hydroxy, cyano, nitro, trifluoromethyl, alkyl, alkoxy Coxy, acyl, acyloxy, carboxy, protected carboxy, carboxymethyl , protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (bisubstituted) (substituted) amino, carboxamide, protected carboxamide, N-(lower alkyl) carboxamide Protected N-(lower alkyl)carboxamides, protected N,N-di(lower alkyl)carboxamides Voxamide, N-((lower alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino, or is selected from substituted or unsubstituted phenyl groups, in the latter case biphenyl or naphthyl Examples of the term "substituted phenyl" include mono-, di-, tri-, and phenyl groups. - or tetra(halo)phenyl groups, for example 2-, 3- or 4-chlorophenyl, 2,6-dichlorophenyl Phenyl, 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-tetrabromophenyl, 2-, 3- or 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 (ii) phenyl groups, such as 2-, 3- or 4-hydroxyphenyl, 2,4-dihydroxyphenyl; phenyl groups, their protected hydroxy derivatives, etc.; nitrophenyl groups, e.g., 2-, 3- or 4-nitrophenyl groups; cyclophenyl; cyanophenyl groups, for example 2-, 3- or 4-cyanophenyl; mono- or di(a 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-isopropylphenyl, or 4-(n-propyl)phenyl, etc.; mono- or di(alkoxy)phenyl groups, for example, 2,6-dimethylphenyl; 2-, 3-, or 4-(isopropoxy)phenyl, 2-, 3-, or 4-(t-butyl)phenyl, 2-, 3- or 4-trifluoromethyl phenyl; mono- or dicarboxyphenyl or (protected carboxyphenyl group, For example, 2-, 3- or 4-carboxyphenyl or 2,4-di(protected carboxy)phenyl mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl phenyl, for example 2-, 3- or 4-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl 2-, 3- or 4-(aminomethyl)phenyl or 2,4-(protected or mono- or di(N-(methylsulfonylamino))phenyl , for example 2-, 3- or 4-(N-(methylsulfonylamino))phenyl. "Substituted phenyl" refers to a phenyl group that is disubstituted with different substituents, e.g., 3- Methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromo Phenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy oxy-4-chlorophenyl, etc.

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

[0044] "Heteroaryl," alone or in combination, refers to a monocyclic heterocyclic group containing 5 or 6 ring atoms. An aromatic ring structure or bicyclic aromatic group having 8 to 10 atoms, independently selected from O, S, and N. containing one or more, for example 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from the group consisting of: Optionally fused to a cycloalkyl, for example, having 5 to 7 ring members, or, for example, having 5 to 6 ring members. Heteroaryl also includes sulfinyl, sulfonyl, and N-oxy groups on tertiary ring nitrogens. It is also intended to include oxidized S or N, such as oxidized S or N. The point of attachment of the heteroaryl ring structure (substituted or unsubstituted) is such that the product is formed. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridinyl, and the like. thienyl, pyrazinyl, quinoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl yl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxalyl Zolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl aryl, tetrazolyl, imidazolyl, triazolyl, furanyl, pyrrolidinyl, thiazolyl Zolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, pyridyl, oxa thiadiazinyltetrazolo, 1,5-[b]pyridazinyl and purinyl , as well as benzo-fused derivatives such as benzoxazolyl, benzothiazolyl, benzyl "Nitrogen-containing heteroaryl" includes: midazolyl, benzofuryl, and indolyl. It refers to heteroaryl where at least one heteroatom is N. In some cases, for example, When the R group of a nitrogen combines with the nitrogen to form a 5- or 7-membered nitrogen-containing heteroaryl, In this case, any heteroatom in such a 5- or 7-membered heteroaryl is N. "Heteroaryl substituted with" means, unless otherwise indicated, one or more, e.g., 1, 2, 3, 4 or 5 heteroaryls, optionally independently substituted with 1, 2, or 3 substituents, It is a molecule that bonds with any available atom to form a stable compound. Substituents include halogen, -CF3, -OH, -NH2, -NO2, -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH2, -C( S)-NH2, -S(O)2-NH2, -N(H)-C(O)-NH2, -N(H)-C(S)-NH2, -N(H)-S(O)2-NH2, -C(NH)-NH2 , -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)-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)-NH2、-N(R o )-C(S)-NH2 、-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-NH2, -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 above-mentioned optionally substituted heteroaryl rings include, for example, "aryl" and "phenyl" groups. In certain embodiments, the substituents are 1 to 3 of halo, Trihalomethyl, amino, protected amino, amino salt, monosubstituted amino, disubstituted amino protected amino, carboxy, protected carboxy, carboxylate, hydroxy, protected hydroxy, salts of hydroxy groups, lower alkoxy, lower alkylthio, lower alkyl, Substituted lower alkyl, cycloalkyl, substituted cycloalkyl, (cycloalkyl (cycloalkyl)alkyl, substituted (cycloalkyl)alkyl, phenyl, substituted phenyl, The group is selected from phenylalkyl and substituted phenylalkyl groups.

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

[0047] "Pyridyl", "pyridazinyl", "pyrimidyl" and "pyrazinyl" as defined above Substituents for the "" group include, for example, "aryl," "phenyl," and "heteroaryl" groups. In some embodiments, the substituents are 1 to 3 halogen atoms. trihalomethyl, amino, protected amino, amino salt, monosubstituted amino, disubstituted amino Substituted amino, carboxy, protected carboxy, carboxylate, hydroxy, protected hydroxy, salts of hydroxy groups, lower alkoxy, lower alkylthio, lower alkyl alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, (cycloa (cycloalkyl)alkyl, substituted (cycloalkyl)alkyl, phenyl, substituted phenyl In one embodiment, the alkyl group is selected from alkyl, phenyl, phenylalkyl, and substituted phenylalkyl groups. In such cases, the substituents are trifluoromethyl, trichloromethyl, tribromomethyl and tri In some embodiments, the substituents are selected from one or more trifluoromethyl. It is methyl.

[0048] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl In the description of optional substituents for aryl, phenyl, napthyl and heteroaryl, The variable R used in o , R p , R c , R d , R e , R f and R g is defined as follows: Each R o , Rp and R c is independently R d , R e , R f and R g or selected from the group consisting of Or R p and R c are combined with the nitrogen to which they are attached to form a 5- to 7-membered heterocyclic ring. alkyl or 5- or 7-membered nitrogen-containing heteroaryl, and The nitrogen-containing alkyl or 5- or 7-membered heteroaryl is selected from the group consisting of halogen, —NO2, —CN, —OH , -NH2, -OR u , -SR u , -N(H)-R u , -N(R u )-R u , -R x , and -R y selected from the group consisting of , optionally with one or more, for example 1, 2, 3, 4 or 5, as well as 1, 2 or 3, substituents is replaced by; Each R d is independently lower alkyl, and the lower alkyl is selected from the group consisting of fluoro, -OH , -NH2, -NO2, -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH2, -C(S)-NH2, -S(O)2-NH2, -N(H)-C (O)-NH2, -N(H)-C(S)-NH2, -N(H)-S(O)2-NH2, -C(NH)-NH2, -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)-Rk 、-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)-NH2、-N(R k )-C(S)-NH2、-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-NH2、-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 i , and -R j One or more, for example 1, 2, 3, 4 or 5, also 1, 2, or optionally substituted with 3 substituents; Each R e is independently lower alkenyl, and the lower alkenyl is selected from the group consisting of fluoro, -O H, -NH2, -NO2, -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH2, -C(S)-NH2, -S(O)2-NH2, -N(H)- C(O)-NH2, -N(H)-C(S)-NH2, -N(H)-S(O)2-NH2, -C(NH)-NH2, -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)-NH2、-N(R k )-C(S)-NH2、-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-NH2、-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 one or more, for example 1, 2, 3, 4 or 5, also selected from the group consisting of optionally substituted with 2 or 3 substituents; Each R f is independently lower alkynyl, and the lower alkynyl is selected from the group consisting of fluoro, -O H, -NH2, -NO2, -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH2, -C(S)-NH2, -S(O)2-NH2, -N(H)- C(O)-NH2, -N(H)-C(S)-NH2, -N(H)-S(O)2-NH2, -C(NH)-NH2, -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-Rk , -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)-NH2, -N(R k )-C(S)-NH2, -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-NH2, -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 one or more, for example 1, 2, 3, 4 or 5, also selected from the group consisting of optionally substituted with 2 or 3 substituents; Each R g are independently cycloalkyl, heterocycloalkyl, aryl, and hexacycloalkyl. cycloalkyl, heterocycloalkyl, aryl, Aryl and heteroaryl are halogen, -OH, -NH2, -NO2, -CN, -C(O)-OH, -C(S)-OH , -C(O)-NH2, -C(S)-NH2, -S(O)2-NH2, -N(H)-C(O)-NH2, -N(H)-C(S)-NH2, -N(H)-S(O)2- NH2, -C(NH)-NH2, -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(Rk )-C(O)-NH2, -N(R k ) -C(S)-NH2, -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-NH2, -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 one or more selected from the group consisting of Optionally substituted with, for example, 1, 2, 3, 4 or 5, as well as 1, 2 or 3, substituents. the law of nature; 〇Here, R k , R m , and R n is independent in each case, R h , R i , and R j Selected from the group consisting of Selected or R m and R nare combined with the nitrogen to which they are attached to form 5- to 7-membered heterocycles. and forming a cycloalkyl or a 5- or 7-membered nitrogen-containing heteroaryl, The heterocycloalkyl or 5- or 7-membered nitrogen-containing heteroaryl may be selected from the group consisting of halogen, -NO2 , -CN, -OH, -NH2, -OR u , -SR u , -N(H)-R u , -NR u R u , -R x , and -R y Selected from the group consisting of one or more, for example 1, 2, 3, 4 or 5, likewise 1, 2 or 3, substituents is optionally substituted with; Here, each R h are independently lower alkyl and are selected from fluoro, -OH, -NH, -NO 2, -CN, -C(O)-OH, -C(S)-OH, -C(O)-NH2, -C(S)-NH2, -S(O)2-NH2, -N(H)-C(O)-NH2, -N (H)-C(S)-NH2, -N(H)-S(O)2-NH2, -C(NH)-NH2, -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(Rr )-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)-NH2、-N(R r )-C(S)-NH2、-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-NH2、-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)-Rr , -N(R r )-R r , -R i , and -R j Consists of one or more, for example 1, 2, 3, 4 or 5, also 1, 2 or 3, selected from the group optionally substituted with substituents; Here, each R i is independently selected from the group consisting of lower alkenyl and lower alkynyl The lower alkenyl or lower alkynyl is selected from fluoro, -OH, -NH2, -NO2, - CN, -C(O)-OH, -C(S)-OH, -C(O)-NH2, -C(S)-NH2, -S(O)2-NH2, -N(H)-C(O)-NH2, -N(H)- C(S)-NH2, -N(H)-S(O)2-NH2, -C(NH)-NH2, -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(Rr )-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)-NH2, -N(R r )-C(S)-NH2, -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-NH2, -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 Selected from the group consisting of one or more, for example 1, 2, 3, 4 or 5, likewise 1, 2 or 3, substituents is optionally substituted with; Here, each R j are independently cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein the cycloalkyl, heterocycloaryl, Alkyl, aryl, and heteroaryl are halogen, -OH, -NH2, -NO2, -CN, -C(O)-OH , -C(S)-OH, -C(O)-NH2, -C(S)-NH2, -S(O)2-NH2, -N(H)-C(O)-NH2, -N(H)-C(S)-NH2, -N (H)-S(O)2-NH2, -C(NH)-NH2, -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-le, -N(H)-C(O)-N(H)-R r , -N(H)-C(S)-N(H)-R r , -N(R r )-C(O)-NH2, -N(R r )-C(S)-NH2, -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-NH2, -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 Selected from the group consisting of one or more, for example 1, 2, 3, 4 or 5, likewise 1, 2 or 3 substitutions selected optionally substituted with a group; Here, each R r , R s , and R t is, independently in each occurrence, lower alkyl, C 3-6 a Lukenil, C 3-6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl and heterocycloalkyl The lower alkyl is selected from the group consisting of -R y , Fluoro, -OH, -NH2, Lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted and lower alkylthio, monoalkylamino, dialkylamino, and cycloalkyl. one or more, for example 1, 2, 3, 4 or 5, selected from the group consisting of amino Optionally substituted with 1, 2 or 3 substituents, and 3-6 Alkenyl or C 3-6 Alkynyl is -R y , fluoro, lower alkyl, fluoro-substituted lower alkyl, low lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino one or more, for example 1, 2, 3, 4 or 5, also selected from the group consisting of , optionally substituted with 2 or 3 substituents, and the cycloalkyl, heterocyclo Chloroalkyl, aryl, and heteroaryl are substituted with halogen, -OH, -NH2, -NO2, -CN, low lower alkyl, fluoro-substituted lower alkyl, lower alkoxy, fluoro-substituted lower lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkyl one selected from the group consisting of amino, dialkylamino, and cycloalkylamino or more, for example, 1, 2, 3, 4 or 5, as well as 1, 2 or 3, substituents. Or R s and R t are combined with the nitrogen to which they are attached to form 5- to 7-membered Form a heterocycloalkyl or a 5- or 7-membered nitrogen-containing heteroaryl, The 5-membered heterocycloalkyl or 5- or 7-membered nitrogen-containing heteroaryl may be selected from the group consisting of halogen, -NO2, -CN, -OH, -NH2, -OR u , -SR u , -N(H)-R u , -N(R u )-R u , -R x , and -R y A group consisting of one or more, for example 1, 2, 3, 4 or 5, also 1, 2 or 3, selected from is optionally substituted with a substituent of Here, each R u are independently lower alkyl, C 3-6 Alkenyl, C 3-6 Alkynyl from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; The lower alkyl is selected from -R y , fluoro, -OH, -NH2, lower alkoxy, fluoro fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio , monoalkylamino, dialkylamino, and cycloalkylamino; one or more, for example 1, 2, 3, 4 or 5, likewise 1, 2 or 3 substitutions selected and optionally substituted with a C 3-6 Alkenyl or C 3-6 Alkynyl is -R y ,centre Fluoro, -OH, -NH2, lower alkyl, fluoro-substituted lower alkyl, lower alkoxy , fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkoxy consisting of alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino one or more, for example 1, 2, 3, 4 or 5, also 1, 2 or 3, selected from the group and the cycloalkyl, heterocycloalkyl, , aryl, and heteroaryl are halogen, -OH, -NH2, -NO2, -CN, lower alkyl, Fluoro-substituted lower alkyl, lower alkoxy, fluoro-substituted lower alkoxy , lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dia one or more alkylamino groups selected from the group consisting of alkylamino, alkylamino, and cycloalkylamino, e.g., optionally substituted with, for example, 1, 2, 3, 4 or 5, as well as 1, 2 or 3, substituents; Here, each R x consists of lower alkyl, lower alkenyl and lower alkynyl The lower alkyl is selected from the group consisting of -R y , fluoro, -OH, -NH2, lower alkoxy, Fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkyl The group consisting of thio, monoalkylamino, dialkylamino, and cycloalkylamino one or more, for example 1, 2, 3, 4 or 5, also 1, 2 or 3, selected from and the lower alkenyl or lower alkynyl is optionally substituted with a substituent of -R y , fluoro, -OH, -NH2, lower alkyl, fluoro-substituted lower alkyl, lower alkoxy oxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino one or more, for example 1, 2, 3, 4 or 5, also 1, 2 or less, selected from the group consisting of is optionally substituted with three substituents; Here, each R y is a cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, Aryl and heteroaryl are substituted with halogen, -OH, -NH2, -NO2, -CN, lower alkyl, fluoro, fluoro-substituted lower alkyl, lower alkoxy, fluoro-substituted lower alkoxy, Lower alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkyl one or more, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, , 2, 3, 4 or 5, as well as 1, 2 or 3 substituents.

[0049] In some embodiments, optionally substituted lower alkyl, optionally substituted lower alkene, Nil, optionally substituted C 3-6 alkenyl, optionally substituted lower alkynyl, or optionally Substituted C 3-6 In all cases of alkynyl, fluoro, -NO2, -CN, -OR 1a , -SR 1 a , -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 , Shi Selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted with one or more, also 1, 2 or 3 groups or substituents, Here, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are halogenated groups. -NO2, -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, —NH2, lower alkoxy, Fluoro-substituted lower alkoxy, lower alkylthio, fluoro-substituted lower alkyl Ruthio, monoalkylamino, dialkylamino, and -R 1b selected from the group consisting of from lower alkyl, which is similarly substituted with one, two or three groups or substituents; Optionally substituted with one or more, as well as one, two or three groups or substituents selected from the group consisting of and optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, alkyl, optionally substituted 5- to 7-membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted 5- or 7-membered nitrogen-containing heteroaryl; In all cases of aryl, halogen, -NO2, -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(R1a )-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, -NH2, lower alkoxy, fluoro-substituted lower alkoxy, lower alkyl thio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino , and -R 1b one or more, also one, two or three groups or substituents selected from the group consisting of one or more, as well as one or two, selected from the group consisting of lower alkyl substituted with a group or 3 groups or substituents; 1a is optionally fluoro, - OH, -NH2, lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro -substituted lower alkylthio, monoalkylamino, dialkylamino, and -R 1b and the like, substituted with one or more groups or substituents selected from the group consisting of: Hydrogen, -R 1b and lower alkyl, and wherein -R 1b is cycloalkyl, heterocycloalkyl, aryl and heteroaryl are halogen , -CN, -OH, -NH2, lower alkoxy, fluoro-substituted lower alkoxy, lower alkyl Thio, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and cycloalkylamino, one or more, also 1, 2 or 3 cycloalkyl, heterocycloalkyl, aryl ... is selected from the group consisting of aryl and heteroaryl.

[0050] In some embodiments, optionally substituted lower alkyl, optionally substituted lower alkene, Nil, 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(R1a )-S(O)2-R 1a , -S(O )-R 1a , -S(O)2-R 1a , cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally one or more, as well as one, two or three groups or substituents selected from the group consisting of and optionally substituted, wherein cycloalkyl, heterocycloalkyl, aryl, and heterocycloalkyl are Tetraaryl is a 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, -NH2, lower alkoxy, fluoro-substituted lower alkoxy, lower Alkylthio, fluoro-substituted lower alkylthio, monoalkylamino, dialkyl Amino, and -R 1b one or more, also one, two or three groups selected from the group consisting of is selected from the group consisting of lower alkyl substituted with a substituent, optionally substituted with 1, 2 or 3 groups or substituents; and optionally substituted cyclohexyl cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted 5- to 7-membered heterocycloalkyl cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or In all cases of optionally substituted 5- or 7-membered nitrogen-containing heteroaryl, 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 Because and substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group one or more, also one, two or three groups selected from the group consisting of lower alkyl, is optionally substituted with a substituent; 1a is hydrogen, -R 1b and optionally fluoro, -OH , -NH2, lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio, fluoro O-substituted lower alkylthio, monoalkylamino, dialkylamino, and -R 1b mosquito and substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of: and wherein -R 1b is a cycloalkyl , heterocycloalkyl, aryl, and heteroaryl, wherein , cycloalkyl, heterocycloalkyl, aryl and heteroaryl are halogen, -CN, -OH, -NH2, lower alkoxy, fluoro-substituted lower alkoxy, lower alkylthio O, fluoro-substituted lower alkylthio, monoalkylamino, dialkylamino, and and cycloalkylamino, one or more, also one, two or three and optionally substituted with a group or substituent of the formula:

[0051] As used herein, "lower alkoxy" refers to -OR z represents a group (wherein R z is lower alkyl "Substituted lower alkoxy" refers to any of the substituted lower alkoxy groups shown herein, e.g. Substituted cycloalkyl, heterocycloalkyl, and heterocycloalkyl groups that are attached at a suitable atom to provide a stable compound. as in the description of compounds of formula I, including the descriptions of alkyl, aryl and heteroaryl. , R z represents a lower alkoxy group, which is a lower alkyl group substituted with one or more substituents. In embodiments, the substitution of lower alkoxy is 1, 2, 3, 4 or 5 substituents, as well as 1, 2, 3, 4 or 5 substituents. or three substituents. For example, "fluoro-substituted lower alkoxy" is Lower alkyl refers to a lower alkoxy in which one or more fluorine atoms are substituted, and some In an embodiment, lower alkoxy is a group containing 1, 2, 3, 4 or 5 fluorine atoms, as well as 1, 2 or 3 alkyl groups. or substituted with three fluorine atoms. Substitution on the alkoxy is chemically feasible, It is understood that attachment may be made at any available atom to provide a stable compound.

[0052] All possible substitutions defined above include those shown herein, e.g., compounds of formula I A subset of those substitutions, as described in For example, the term "fluoro-substituted "Phenyl" refers to a phenyl group substituted with one or more fluorine atoms, in which case e.g. Phenyl is substituted with 1, 2, 3, 4 or 5 fluorine atoms, e.g., 2,3,5,6-tetrafluorophenyl. Any substitution made in accordance with the above definitions is chemically feasible. It is also understood that the bond may be at any available atom to provide a stable compound.

[0053] It is understood that the compounds provided herein may contain chiral centers. Chiral centers such as may be of either the (R) or (S) configuration, or The compounds provided herein may therefore be enantiomerically pure or may be a mixture of enantiomers. or a mixture of stereoisomers or diastereoisomers. Those skilled in the art will appreciate that for compounds that undergo epimerization in vivo, administration of the compound in its (R) form will It will be recognized that this is equivalent to administering the compound in its (S) form.

[0054] As used herein, "substantially pure" means a substance that is substantially pure, as defined by the skilled artisan to assess such purity. Used thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography ( readily detectable impurities as determined by standard analytical methods such as HPLC and mass spectrometry (MS). is sufficiently homogeneous that it appears to be free of the substance, or that further purification is insufficient to remove the substance Without detectably altering the physical and chemical properties, such as enzymatic and biological activity It means to prepare a compound that is substantially chemically pure. Methods for purifying compounds for the purpose of obtaining the desired product are known to those skilled in the art. The pure compound may be a mixture of stereoisomers. In such cases, further purification may involve The present disclosure provides a method for the preparation of such compounds, which may increase the specific activity of the compounds. It is intended to include all isomers as well as their racemic and optically pure forms. Optically active (+) and (-), (R) and (S), or (D) and (L) isomers are chiral synthons or chiral They can be prepared using reagents and resolved using conventional techniques such as reverse phase HPLC. If the compounds described in the document 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. Likewise, all tautomers are also intended to be included.

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

[0056] The singular forms "a," "an," and "the" are used unless the context clearly indicates otherwise. Includes plural referents unless otherwise indicated.

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

[0058] As used herein, "biological activity" refers to the in vitro or in vivo activity of a compound, or refers to a physiological response reaction that occurs as a result of in vivo administration of a compound, composition, or other mixture. Thus, biological activity refers to the therapeutic efficacy and pharmacokinetics of such compounds, compositions, and mixtures. Biological activity includes biological behavior. It can be observed in in vitro and in vitro systems.

[0059] As used herein, "pharmaceutically acceptable derivatives" of a compound include salts, esters, and derivatives thereof. Esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, salts Such derivatives include derivatives of such compounds, solvates, hydrates, or prodrugs. They can be readily prepared by those skilled in the art using known methods for derivatization. The compounds may be administered to animals or humans without substantial toxic effects and have medicinal properties. The compound is either an active compound or a prodrug. Examples include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine , choline, ammonia, diethanolamine and other hydroxyalkylamines, ethyl Diamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para -chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and Other alkylamines, piperazine, and tris(hydroxymethyl)aminomethane Salts of amines, including but not limited to: lithium, potassium, and sodium Salts of alkali metals, including but not limited to barium, calcium, and salts of alkaline earth metals, including but not limited to magnesium and zinc; salts of transition metals, including, but not limited to; and sodium hydrogen phosphate and Inorganic salts include, but are not limited to, disodium phosphate, etc. Further examples include, but are not limited to, hydrochloride and sulfate salts. Salts of mineral acids; as well as acetates, lactates, malates, tartrates, citrates, and ascorbic acid Examples of suitable salts include succinate, butyrate, valerate, mesylate, and fumarate. Pharmaceutically acceptable esters include, but are not limited to, salts of organic acids. Although not specified, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids, and acidic groups including but not limited to alkyl, alkenyl, alkynyl, and boronic acids. These include aryl, aryl, arylalkyl, and cycloalkyl esters. Acceptable solvates and hydrates include those which contain one or more solvent or water molecules, or from 1 to about 100, or 1 A complex of a compound with about 10, or 1 to about 2, 3, or 4 molecules of a solvent or water. Exemplary prodrugs are described in the article "Current Prodrugs" by J. Rautio, N.A. Meanwell, L. di, and MJ. Hageman. The expanding role of prodrugs in modern drug design and development "in contemporary drug design and development drugs", Nat Rev Drug Discov.2018;1 7(8):559-587, the entire contents of which are incorporated herein by reference. It is included.

[0060] As used herein, "treatment" refers to the treatment of a disease or disorder, or one of the diseases or disorders. means any method that relieves or otherwise beneficially alters the above symptoms. Treatment also includes any pharmaceutical use of the compositions herein, such as use to treat cancer. References herein to "treatment" also include prevention, remission or palliation.

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

[0062] As used herein, the administration of a particular compound or pharmaceutical composition to treat the symptoms of a particular disorder. "Remission" or "palliation" are used interchangeably and refer to either permanent or temporary, persistent or Any transient symptom that may result from or be associated with the administration of the compound or composition It refers to mitigation.

[0063] As used herein, "complications" refer to symptoms that occur in association with a condition or disease. Complications may be a direct result of the condition or disease, or may be the cause of the condition or disease. It may also be related to the presence of a primary condition or disease. In this case, complications of the disease may appear as symptoms, and in this case, The terms are used interchangeably herein.

[0064] Unless otherwise specified, the terms "manage" and "not managing" used herein "Managing" and "management" refer to the management of a specific disease or disorder. Preventing the recurrence of a disease or disorder in a patient who has previously suffered from the disease or disorder; and / or , to extend the time that a patient who has had the disease or disorder remains in remission. These terms encompass the threshold, onset, and / or duration of the disease or disorder. or altering the way a patient responds to the disease or disorder. do.

[0065] As used herein, the term "in combination" refers to the use of more than one therapy (e.g., , caspase inhibitors and other agents). The use of the term "in combination" refers to a therapy (e.g., a caspase inhibitor, There is no restriction on the order in which the first treatment (anticoagulant, anti ... Therapeutic approaches (e.g., caspase inhibitors and other agents) may be used in combination with other therapies (e.g., caspase inhibitors and and other medications) prior to administration (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 in combination with, other therapy Following the implementation of (e.g., 5 min, 15 min, 30 min, 45 min, 1 hr, 2 hr, 4 hr, 6 hr, 12 hr , 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks The study can be administered to subjects with disabilities within 12 weeks of receiving the study.

[0066] The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, Administration of compounds to a subject using intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. This includes administering the substance.

[0067] As used herein, "selection of caspase-1, caspase-4, and / or caspase-5" refers to "Potential inhibitors" are those that inhibit the activity of caspase-1, caspase-4, and / or caspase-5. more selectively than to caspase-3, caspase-6, and / or caspase-7; In one embodiment, the compound provided herein is The substance has at least two-fold higher binding affinity for caspase-1 compared to other caspases. In certain embodiments, the compounds provided herein inhibit caspase-3, caspase-6, , and / or at least 5-fold, 10-fold, 50-fold, 100-fold, 1000-fold or exceedingly high binding affinity for caspase-1, caspase-4, and / or caspase-5 It has sexuality.

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

[0069] Abbreviations used herein for protecting groups, amino acids and other compounds are Unless otherwise specified, their common usage, accepted abbreviations, or the IUPAC / IUB Committee on Biochemical Nomenclature (see Biochem. 1972, 11:942-944).

[0070] 6.2. Caspase Inhibitor Compounds In one embodiment, provided herein is a method for treating a pulmonary arthritis, comprising: a compound having formula I, or an enantiomer thereof, or a mixture of said enantiomers, is a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof. be: [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 R3 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 is -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. Re; Each R a is independently alkylene or a direct bond; R b is hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted substituted hydroxyalkyl, optionally substituted alkoxyalkyl, optionally substituted silyl cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally is a substituted heterocyclyl; Each R c is independently hydrogen or optionally substituted alkyl; Each R d are independently alkyl, aryl, cycloalkyl, heteroaryl, Tetracyclyl 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 2are each independently hydrogen, optionally substituted alkyl, or optionally substituted substituted cycloalkyl; or ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. Forms a 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 chosen as follows: i) Z 1 is hydrogen or optionally substituted alkyl; and Z 2 is aryl, cyclo alkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted. or ii) Z 1 and Z 2 are optionally substituted together with the nitrogen atom on which they are substituted. Forms a saturated or unsaturated ring C).

[0071] In one embodiment, provided herein is a compound of Formula I, or an enantiomer thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, is a hydrate, co-crystal, clathrate or polymorph; wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl, -Ra 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 substituted with a group; R 3 , Y 1 , Y 2 and Y 3 is selected as follows: i) Y 1 is R 3 together to form an optionally substituted saturated or unsaturated bicyclic ring B, The group, when present, contains 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 is -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. Re; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are 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, silyl chloroalkyl, aryl, heteroaryl or heterocyclyl; Each R c are independently hydrogen or alkyl; Each R d are independently alkyl, aryl, cycloalkyl, heteroaryl, Tetracyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 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 teeth ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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 contains 1 to 4 substituents Q 1Replace with It has been; R 10 is alkylene; Z 1 and Z 2 is selected as follows: i) Z 1 is hydrogen or alkyl; and Z 2 is an aryl, cycloalkyl, or hetero aryl or heterocyclyl, each of which is optionally 1 to 4 substituents Q 3 is replaced by or ii) Z 1 and Z 2 are optionally substituted together with the nitrogen atom on which they are substituted. A saturated or unsaturated ring C is formed, and the substituents on the ring C, if present, are 1 to 3 Q 3 Select from be selected; 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 SR 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 1 1 S(O) t R 16 Each Q is selected from3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, is a hydrate, co-crystal, clathrate or polymorph; 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 substituted with a group; R 3 , Y 1 , Y 2 and Y 3 is selected as follows: i) Y 1 is R 3 together to form an optionally substituted saturated or unsaturated ring B, If present, 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 is -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. Re; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are independently alkyl, halo, haloalkyl, aryl or haloaryl; R a is 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 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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; 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 contains 1 to 4 substituents Q 1 Replace with It has been; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z2 is aryl or heteroaryl, each of which optionally contains 1 to 4 substituents Q 3 Replace with It has been; 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)NH2; 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, is a hydrate, co-crystal, clathrate or polymorph; 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, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally alkyl and substituted with 1 or 2 groups selected from halo; R 3 , Y 1 , Y 2 and Y 3 is selected as follows: i) Y 1 is R 3 together to form an optionally substituted saturated or unsaturated ring B, If present, 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 is -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. Re; R a is 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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; 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 halo, alkyl, and halo. substituted with 1 to 4 substituents selected from alkyl; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally contains 1 to 4 substituents Q 3 Replace with It has been; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, Aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and —C(O)NH2; R 11 is 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, hydrate, co-crystal, clathrate or polymorph: [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 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are 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, silyl chloroalkyl, aryl, heteroaryl or heterocyclyl; Each R c are independently hydrogen or alkyl; Each R d are independently alkyl, aryl, cycloalkyl, heteroaryl, Tetracyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 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 teeth ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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 contains 1 to 4 substituents Q 1 Replace with It has been; R 10 is alkylene; Z 1 and Z 2 is selected as follows: i) Z 1 is hydrogen or alkyl; and Z 2 is an aryl, cycloalkyl, or hetero aryl or heterocyclyl, each of which is optionally 1 to 4 substituents Q 3 is replaced by or ii) Z 1 and Z 2 are optionally substituted together with the nitrogen atom on which they are substituted. A saturated or unsaturated ring C is formed, and the substituents on the ring C, if present, are 1 to 3 Q 3 Select from be selected; 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 SR 12 ,- R 11 OR11 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, is a hydrate, co-crystal, clathrate or polymorph; 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 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, heteroaryl; each Q 1 teeth Any 1 to 3 Qs 2groups; each Q 2 are independently alkyl, halo, is alkyl, aryl, or haloaryl; Each R a is independently alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, silyl chloroalkyl, aryl, heteroaryl or heterocyclyl; Each R c are independently hydrogen or alkyl; Each R d are independently alkyl, aryl, cycloalkyl, heteroaryl, Tetracyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 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 teeth ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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 contains 1 to 4 substituents Q 1 Replace with It has been; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z 2 is aryl, cycloalkyl, heteroaryl or heterocyclyl, which may optionally contain 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 SR 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, Hydrate, co-crystal, clathrate or polymorph 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 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are independently alkyl, halo, haloalkyl, aryl or haloaryl; Each R a is independently alkylene or a direct bond; Each R b are 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 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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; R 3 , R 4 , R 5 , R 6 , R 7 and R 8are each independently hydrogen or alkyl; R 9 is aryl or heteroaryl, each of which optionally contains 1 to 4 substituents Q 1 Replace with It has been; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally contains 1 to 4 substituents Q 3 Replace with It has been; 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)NH2; 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, Hydrate, co-crystal, clathrate or polymorph 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, heteroaryl. alkyl or -C(O)R dwherein the alkyl and aryl groups are optionally alkyl and substituted with 1 or 2 groups selected from halo; R a is 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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; 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 halo, alkyl, and halo. substituted with 1 to 4 substituents selected from alkyl; R 10 is alkylene; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally contains 1 to 4 substituents Q 3 Replace with It has been; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, Aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and —C(O)NH2; 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph [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 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are 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, silyl chloroalkyl, aryl, heteroaryl or heterocyclyl; Each R c are independently hydrogen or alkyl; Each R d are independently alkyl, aryl, cycloalkyl, heteroaryl, Tetracyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 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 teeth ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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 2is aryl, cycloalkyl, heteroaryl or heterocyclyl, which may optionally contain 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 SR 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph 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, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally alkyl and substituted with 1 or 2 groups selected from halo; R a is 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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; 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 contains 1 to 4 substituents Q 3 Replace with It has been; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, Aryl, heteroaryl, -R 11OR 12 , -C(O)R 15 and —C(O)NH2; R 11 is 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph 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, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally alkyl and substituted with 1 or 2 groups selected from halo; R a is 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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; R3 , 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 to form an optionally substituted saturated or unsaturated ring B, If present, 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 is -N(Z 1 )(Z 2 ) is; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally contains 1 to 4 substituents Q 3 Replace with It has been; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, Aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and —C(O)NH2; R 11is 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, Hydrate, co-crystal, clathrate or polymorph [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, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally alkyl and substituted with 1 or 2 groups selected from halo; R a is 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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; R 3 , 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 contains 1 to 4 substituents Q 3 Replace with It has been; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, Aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and —C(O)NH2; R 11 is 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, hydrate, co-crystal, clathrate or polymorph: [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(Rc )(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 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are 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, silyl chloroalkyl, aryl, heteroaryl or heterocyclyl; Each R c are independently hydrogen or alkyl; Each R d are independently alkyl, aryl, cycloalkyl, heteroaryl, Tetracyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 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 teeth ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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 SR 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; Each Q 5 is independently alkyl, halo, or haloalkyl; J is O or S; t is 0 to 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, Hydrate, co-crystal, clathrate or polymorph 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, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally alkyl and substituted with 1 or 2 groups selected from halo; R a is 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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or alkyl; R 10 is alkylene; Z 1is 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; Each R 11 is independently 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).

[0084] In one embodiment, provided herein is a compound of formula VI, or an enantiomer thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, hydrate, co-crystal, clathrate or polymorph: [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 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are 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 substituted with a group; R a is alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, silyl chloroalkyl, aryl, heteroaryl or heterocyclyl; R 1 and R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or teeth ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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, which may optionally contain 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 SR 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; R 10 is -CH2- or -CH2-CH2-; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, Hydrate, co-crystal, clathrate or polymorph (wherein Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl) or -C(O)R d wherein the alkyl and aryl groups are optionally selected from alkyl and halo. substituted with one or two groups; R dis 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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; 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 contains 1 to 4 substituents Q 3 Replace with It has been; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, Aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 or —C(O)NH2; Each Q 5 is independently alkyl, halo, or haloalkyl; R 10 is -CH2- or -CH2-CH2-; R 11 is 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, Hydrate, co-crystal, clathrate or polymorph (Wherein, Y is hydrogen, methyl, —C(O)R d wherein the methyl is optionally phenyl, chloro substituted with phenyl 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 are the carbon atoms on which they are substituted, along with the cyclopentyl ring form; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or methyl; R 10 is -CH2- or -CH2-CH2-; Q 5 is fluoro, methyl or trifluoromethyl; Z 1 is hydrogen; Z 2 is phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl, iridyl and benzoisothiazolyl; each optionally containing one or two Q 3 basis and each Q 3 are independently chloro, fluoro, methyl, or methoxy. , trifluoromethoxy, -C(O)CH3, cyano, -C(O)NH2, benzyl and tetrazolyl selected; and m is 0 to 4).

[0087] In one embodiment, provided herein is a compound of formula VII, or an enantiomer thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph: [ka] (In the formula, R d is an alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl Ru or -R a OR b and; Each R d is any 1 to 3 Q 1 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are independently alkyl, halo, haloalkyl, aryl or haloaryl; R a is alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, silyl chloroalkyl, aryl, heteroaryl or heterocyclyl; R 1 and R 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; or teeth ii) R 1 and R 2are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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, which may optionally contain 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 SR 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; R 10 is -CH2- or -CH2-CH2-; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph (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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; 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 contains 1 to 4 substituents Q 3 Replace with It has been; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, Aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and —C(O)NH2; R 10 is -CH2- or -CH2-CH2-; R 11 is 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph (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 are the carbon atoms on which they are substituted, along with the cyclopentyl ring form; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or methyl; R 10 is -CH2- or -CH2-CH2-; Q 5 is fluoro, methyl or trifluoromethyl; Z 1 is hydrogen; Z 2 is phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl, iridyl and benzoisothiazolyl; each optionally containing one or two Q 3 basis and each Q 3 are independently chloro, fluoro, methyl, or methoxy. , trifluoromethoxy, -C(O)CH3, cyano, -C(O)NH2, benzyl and tetrazolyl selected; and m is 0 to 4).

[0090] In one embodiment, provided herein is a compound of formula VIII, or an enantiomer thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph: [ka] (In the formula, R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; R b is any 1 to 3 Q 1 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are 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 teeth ii) R 1 and R 2are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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, which may optionally contain 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 SR 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; R 10 is -CH2- or -CH2-CH2-; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph (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 teeth ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are 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 2is aryl, cycloalkyl, heteroaryl or heterocyclyl, which may optionally contain 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 SR 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; R 10 is -CH2- or -CH2-CH2-; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph (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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; 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 contains 1 to 4 substituents Q 3 Replace with It has been; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, Aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and —C(O)NH2; R 10 is -CH2- or -CH2-CH2-; R 11 is 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph (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 The carbon atoms on which they are substituted form a 3- to 5-membered cycloalkane. Forms an alkyl 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 contains 1 to 4 substituents Q 3 Replace with It has been; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, Aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and —C(O)NH2; R 10 is -CH2- or -CH2-CH2-; R 11 is 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph (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 are the carbon atoms on which they are substituted, along with the cyclopentyl ring form; R 3 , R 4 , R 5 and R 6 are each independently hydrogen or methyl; R 10 is -CH2- or -CH2-CH2-; Q 5 is fluoro, methyl and trifluoromethyl; Z 1 is hydrogen; Z 2 is phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl, iridyl and benzoisothiazolyl; each optionally containing one or two Q 3 basis and each Q 3 are independently chloro, fluoro, methyl, or methoxy. , trifluoromethoxy, -C(O)CH3, cyano, -C(O)NH2, benzyl and tetrazolyl selected; and m is 0 to 4).

[0095] In one embodiment, provided herein is a compound of formula IX, or an enantiomer thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, Hydrate, co-crystal, clathrate or polymorph [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 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are 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, silyl chloroalkyl, aryl, heteroaryl or heterocyclyl; Each R care independently hydrogen or alkyl; Each R d are independently alkyl, aryl, cycloalkyl, heteroaryl, Tetracyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 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 teeth ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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, which may optionally contain 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 OR11 OR 12 , -R 11 N(R 13 )(R 14 ), -R 11 SR 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, Hydrate, co-crystal, clathrate or polymorph 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, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally alkyl and substituted with 1 or 2 groups selected from halo; R a is alkylene or a direct bond; R b is hydrogen, alkyl or aryl; Rd 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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; 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 contains 1 to 4 substituents Q 3 Replace with It has been; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, Aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and —C(O)NH2; R 11 is 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, Hydrate, co-crystal, clathrate or polymorph 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, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally alkyl and substituted with 1 or 2 groups selected from halo; R a is 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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; 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 contains 1 to 4 substituents Q 3 Replace with It has been; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, Aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and —C(O)NH2; R 11 is 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, Hydrate, co-crystal, clathrate or polymorph [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 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q2 are independently alkyl, halo, haloalkyl, aryl or haloaryl; R a is alkylene or a direct bond; R b is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, silyl chloroalkyl, aryl, heteroaryl or heterocyclyl; R c is 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 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 teeth ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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, which may optionally contain 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 SR 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, Hydrate, co-crystal, clathrate or polymorph 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 teeth ii) R 1 and R2 are saturated or unsaturated, together with the carbon atoms on which they are substituted. Forming harmony 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 contains 1 to 4 substituents Q 3 Replace with It has been; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, Aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and —C(O)NH2; R 11 is 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, Hydrate, co-crystal, clathrate or polymorph 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 teeth ii) R1 and R 2 are saturated or unsaturated, together with the carbon atoms on which they are substituted. Forming harmony 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 contains 1 to 4 substituents Q 3 Replace with It has been; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, Aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and —C(O)NH2; R 11 is 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, hydrate, co-crystal, clathrate or polymorph: [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 -Ra 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 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are 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, silyl chloroalkyl, aryl, heteroaryl or heterocyclyl; Each R c are independently hydrogen or alkyl; Each R d are independently alkyl, aryl, cycloalkyl, heteroaryl, Tetracyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 substituted with a group; R 1 and R 2 is selected as follows: i) R 1 and R 2are each independently hydrogen, alkyl, or cycloalkyl; or teeth ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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 SR 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, Hydrate, co-crystal, clathrate or polymorph 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, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally alkyl and substituted with 1 or 2 groups selected from halo; R a is 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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; 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; R 11 is 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, Hydrate, co-crystal, clathrate or polymorph 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, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally alkyl and substituted with 1 or 2 groups selected from halo; R a is alkylene or a direct bond; R b is hydrogen, alkyl or aryl; R d is aryl or aryloxy; R 1 and R 2is selected as follows: i) R 1 and R 2 are each independently hydrogen or alkyl; or ii) R 1 and R 2 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph: [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 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are 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, silyl chloroalkyl, aryl, heteroaryl or heterocyclyl; Each R c are independently hydrogen or alkyl; Each R d are independently alkyl, aryl, cycloalkyl, heteroaryl, Tetracyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 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 teeth ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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 SR 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph 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, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally alkyl and substituted with 1 or 2 groups selected from halo; R a is 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 2 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; 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; R11 is 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph 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, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally alkyl and substituted with 1 or 2 groups selected from halo; R a is 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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph [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 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q2 groups; each Q 2 are 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, silyl chloroalkyl, aryl, heteroaryl or heterocyclyl; Each R c are independently hydrogen or alkyl; Each R d are independently alkyl, aryl, cycloalkyl, heteroaryl, Tetracyclyl or -R a OR b and; Each R d is any 1 to 3 Q 1 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 teeth ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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; Z1 is hydrogen or alkyl; Z 2 is aryl, cycloalkyl, heteroaryl or heterocyclyl, which may optionally contain 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 SR 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph 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, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally alkyl and substituted with 1 or 2 groups selected from halo; R a is 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 represents a cycloalkyl ring together with the carbon atom on which it is substituted. Form; 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 to form an optionally substituted saturated or unsaturated ring B, If present, 1 to 3 Q 1 selected from the group Y 2is 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 is -N(Z 1 )(Z 2 ) is; Z 1 is hydrogen or alkyl; Z 2 is aryl or heteroaryl, each of which optionally contains 1 to 4 substituents Q 3 Replace with It has been; Each Q 3 are independently alkyl, haloalkyl, haloalkoxy, halo, cyano, Aryl, heteroaryl, -R 11 OR 12 , -C(O)R 15 and —C(O)NH2; R 11 is 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph (wherein Q 5 is trifluoroalkyl and the remaining variables are as described herein).

[0110] In one embodiment, provided herein are compounds of formula I, II, III, IV, V, VI, VII, VIII IX, X, XI, XII or XIII, or an enantiomer or enantiomer thereof. a mixture of mers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or clathrate thereof or a polymorph (wherein R 10 is -CH2- or -CH2-CH2-, and the remaining substituents are (As described in the subsection).

[0111] In one embodiment, provided herein are compounds of formula I, II, III, IV, V, VI, VII or is a compound of formula VIII, IX, X, XI, XII or XIII, or an enantiomer thereof or the enantiomer thereof a mixture of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal thereof; It is a clathrate or polymorph (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 are the carbon atoms on which they are substituted, along with the cyclopentyl ring and the remaining substituents are as described herein).

[0112] In one embodiment, provided herein are compounds of Formula I or II, or derivatives thereof an antiomer or a mixture of said enantiomers, or a pharmaceutically acceptable salt thereof; solvates, hydrates, co-crystals, clathrates or polymorphs (wherein R 9 is aryl or and n is heteroaryl, each of which is optionally selected from halo, alkyl, and haloalkyl. and the remaining substituents are as described herein. (It is).

[0113] In one embodiment, provided herein are compounds of Formula I or II, or derivatives thereof an antiomer or a mixture of said enantiomers, or a pharmaceutically acceptable salt thereof; solvates, hydrates, co-crystals, clathrates or polymorphs (wherein R 9 The phenyl and pyrimidinyl, each of which is optionally selected from halo, alkyl, and haloalkyl. and the remaining substituents are as described herein. be).

[0114] In one embodiment, provided herein are compounds of formula I, II, III, IV, VI, VII or V III, or an enantiomer thereof, or a mixture of said enantiomers, or A pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph (formula Medium, Z 2 is selected from 6-10 membered aryl or heteroaryl; each is optionally 1 or Two Qs 3 groups, and each Q 3 are independently halo, alkyl, haloal alkyl, arylalkyl, alkoxy, alkylcarbonyl, haloalkoxy, cyano, is selected from aryl, heteroaryl and aminocarbonyl, and the remaining substituents are as described herein).

[0115] In one embodiment, provided herein are compounds of Formula I, II, III, IV or V or its enantiomers or mixtures of said enantiomers, or its pharmaceutically acceptable salts and the compound is a tolerable salt, solvate, hydrate, co-crystal, clathrate or polymorph (wherein R10 -C H2- or -CH2-CH2-; and Z 2 is selected from 6- to 10-membered aryl or heteroaryl each optionally containing one or two Q 3 groups, and each Q 3 is independent, halo, alkyl, haloalkyl, arylalkyl, alkoxy, alkylcarbonyl, selected from haloalkoxy, cyano, aryl, heteroaryl and aminocarbonyl and the remaining substituents are as described herein).

[0116] In one embodiment, provided herein are compounds of Formula I, II, III, IV or V or its enantiomers or mixtures of said enantiomers, or its pharmaceutically acceptable salts and the compound is a tolerable salt, solvate, hydrate, co-crystal, clathrate or polymorph (wherein R 10 -C H2- or -CH2-CH2-; and Z 2 is selected from 6- to 10-membered aryl or heteroaryl each optionally containing one or two Q 3 groups, and each Q 3 is independent, halo, alkyl, haloalkyl, arylalkyl, alkoxy, alkylcarbonyl, selected from haloalkoxy, cyano, aryl, heteroaryl and aminocarbonyl wherein heteroaryl contains one or two heteroatoms selected from nitrogen and sulfur; and the remaining substituents are as described herein).

[0117] In one embodiment, provided herein are compounds of formula I, II, III, IV, VI, VII or V III, or an enantiomer thereof, or a mixture of said enantiomers, or A pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph (formula Medium, Z 2 is phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl, isoquinolinyl and benzisothiazolyl; each optionally containing one or two Q 3 groups, and each Q 3 are independently halo, alkyl, haloalkyl, a Aryl alkyl, alkoxy, alkyl carbonyl, haloalkoxy, cyano, aryl , heteroaryl, and aminocarbonyl, and the remaining substituents are as defined herein. (As described in

[0118] In one embodiment, provided herein is a compound of Formula I, II, III, or VI, or or a mixture of said enantiomers, or a pharmaceutically acceptable salt thereof. a salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof, 10 is -CH2- or -CH2-CH2-; and Z 2 are phenyl, pyridinyl, pyrimidyl, naphthyl, and in selected from benzothiazolyl, quinolinyl, isoquinolinyl and benzisothiazolyl; This can optionally be one or two Q 3 groups, and each Q 3 are independent, halo, al alkyl, haloalkyl, arylalkyl, alkoxy, alkylcarbonyl, haloalkoxy oxy, cyano, aryl, heteroaryl and aminocarbonyl, and The substituents are as defined herein.

[0119] In one embodiment, provided herein are compounds of formula I, II, III, IV, VI, VII or V III, or an enantiomer thereof, or a mixture of said enantiomers, or A pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate or polymorph (formula Medium, Z 2 is phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl, isoquinolinyl and benzisothiazolyl; each optionally containing one or two Q 3 groups, and each Q 3 are independently chloro, fluoro, methyl, methoxy -C(O)CH3, -C(O)NH2, 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 or a mixture of said enantiomers, or a pharmaceutically acceptable salt thereof. a salt, solvate, hydrate, co-crystal, clathrate or polymorph thereof, 10 is -CH2- or -CH2-CH2-; and Z 2 are phenyl, pyridinyl, pyrimidyl, naphthyl, and in selected from benzothiazolyl, quinolinyl, isoquinolinyl and benzisothiazolyl; This can optionally be one or two Q 3 groups, and each Q 3 are independently chloro, fluoro Fluoro, methyl, methoxy, trifluoromethoxy, -C(O)CH3, cyano, -C(O)NH2, benzo and tetrazolyl, and the remaining substituents are as described herein. be).

[0121] In one embodiment, provided herein is a compound of formula XIV, or an enantiomer thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph: [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 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are 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, silyl chloroalkyl, aryl, heteroaryl or heterocyclyl; Each R c are independently hydrogen or alkyl; R d is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -R a ORb and; Each R d is any 1 to 3 Q 1 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 teeth ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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 contains 1 to 4 substituents Q 1 Replace with It has been; 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 SR 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph; 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 substituted with a group; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Q 1 is any 1 to 3 Q 2 groups; each Q 2 are 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, silyl chloroalkyl, aryl, heteroaryl or heterocyclyl; Each R c are 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 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 teeth ii) R 1 and R 2 are optionally substituted groups along with the carbon atoms on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from be selected; 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 contains 1 to 4 substituents Q 1 Replace with It has been; 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 11N(R 13 )(R 14 ), -R 11 SR 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with groups, Reno Q 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; R 13 and R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is a cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with; Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl the law of nature; 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph; wherein X is C=O; and Y is -R a OR b and; R a is 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. and; R10 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 thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, hydrate, co-crystal, clathrate or polymorph: [ka] where the variables are as described herein.

[0125] In one embodiment, provided herein is a compound of formula XV, or an enantiomer thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, is a hydrate, co-crystal, clathrate or polymorph; wherein X is C=O; and Y is -R a OR b and; R a is 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph: [ka] (wherein each Q 7 is halo, x is 0 to 4, and the remainder of the variables are as defined herein. as listed).

[0127] In one embodiment, provided herein is a compound of formula XI, or an enantiomer thereof: or a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof, is a hydrate, co-crystal, clathrate or polymorph; wherein X is C=O; and Y is -R a OR b and; R a is 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph: [ka] (wherein each Q7 is halo, x is 0 to 4, and the remainder of the variables are as described herein. as will be stated).

[0129] In one embodiment, provided herein is a compound of Formula XVII, or an enantiomer thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph; (Wherein, Y is -R a OR b and; R a is 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof a complex, hydrate, co-crystal, clathrate or polymorph: [ka] (wherein each Q 7 is halo, and the remainder of the variables are as described herein. be).

[0131] In one embodiment, provided herein is a compound of formula XVIII, or an enantiomer thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof a complex, hydrate, co-crystal, clathrate or polymorph; wherein X is C=O; and Y is -R a OR b and; R a is 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph: [ka] (wherein each Q 7 is halo, and the remainder of the variables are as described herein. be).

[0133] In one embodiment, provided herein is a compound of formula XIX, or an enantiomer thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph; (Wherein, Y is -R a OR b and; R a is alkylene or a direct bond; Rb 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 thereof: a mixture of said enantiomers, or a pharmaceutically acceptable salt or solvate thereof , hydrate, co-crystal, clathrate or polymorph; (Wherein, Y is -R a OR b and; R a is 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 inhibit the activity of caspase-1, caspase-4, and / or caspase-5. The compounds are used in methods for the treatment of conditions associated with or modulated by

[0136] Thus, in one embodiment, provided herein are compounds comprising the compounds provided herein. administering to the subject a method for treating caspase-1, caspase-4 and / or caspase-1-mediated ischemic heart failure. The present invention relates to a method for treating or preventing a disease modulated by phospholipase-5.

[0137] The compounds provided herein and / or pharmaceutical compositions thereof can be used to treat or prevent Disease states that may be affected include, but are not limited to, inflammatory diseases, autoimmune diseases, proliferative diseases, This includes disorders, infections, and degenerative diseases.

[0138] In one embodiment, the compounds provided herein and / or pharmaceutical compositions thereof Inflammatory diseases which may be treated or prevented include, but are not limited to, osteoarthritis, acute myocardial infarction, and rheumatoid arthritis. These conditions include acute pancreatitis, chronic pancreatitis, asthma, and adult respiratory distress syndrome.

[0139] In one embodiment, the compounds provided herein and / or pharmaceutical compositions thereof Inflammatory diseases that can be treated or prevented include, but are not limited to, clitorises, Autoinflammatory diseases such as opioid-associated periodic syndromes (CAPS), multiple sclerosis (MS), and Parkinson's disease This includes chronic and acute diseases such as neuroinflammatory disorders such as Son's disease and Alzheimer's disease. Treatment of acute inflammatory diseases such as septic shock, sepsis, and adult respiratory distress syndrome is also are covered by the methods provided herein.

[0140] In one embodiment, the compounds provided herein and / or pharmaceutical compositions thereof Autoimmune diseases that can be treated or prevented include, but are not limited to, glomerulonephritis , rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune Epidemic gastritis, insulin-dependent diabetes mellitus (type I), autoimmune hemolytic anemia, autoimmune neutrophils Cytopenia, 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, the compounds provided herein and / or pharmaceutical compositions thereof Diseases that can be treated or prevented include, but are not limited to, osteoporosis and multiple myeloma. Includes destructive bone disorders such as myeloma-related bone disorder.

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

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

[0144] Other diseases that involve an inflammatory or apoptotic component may also be treated with the compounds provided herein. These diseases can be systemic diseases or diseases affecting the liver or other organs. It may also be a disease with local effects on the body, for example, excessive consumption of food or alcohol or HBV V, HCV, HGV, yellow fever virus, dengue virus, and Japanese encephalitis virus This may be caused by

[0145] In one embodiment, provided herein are methods for administering a compound provided herein to a subject.

[0023] A method of treating or preventing a disease in a subject comprising administering to a subject a therapeutically effective amount of a compound selected from the group consisting of inflammatory bowel disease, or inflammatory diseases, inflammatory bowel disease, sepsis and septic shock, degenerative diseases (Alzheimer's disease) Huntington's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinal and bulbar sclerosis atrophy, prion disease, and dementia); cerebral hypoxia, anoxia, and hyperoxia; patent ductus arteriosus or MC caused by hemodynamic abnormalities from more direct routes including the left common carotid artery. Ischemic multiple lesions in the cortical or lenticulostriatal branches of A, the middle cerebral artery (MCA), or Ischemic lesions in the left cerebral hemisphere; focal arterial infarction, retinal pericyte apoptosis, retinal neuropathy Neuronal apoptosis, glaucoma, retinal degenerative diseases, and age-related macular degeneration due to focal ischemia (AMD) MD) Retinal damage, diabetic retinopathy, epilepsy, apoptosis in spinal cord injury, Apoptosis in the pathological conditions of traumatic brain injury, retinal ischemia, and focal cerebral ischemia Cytotoxic T cell and natural killer cell mediation of cisplatin, autoimmune disease, and transplant rejection apoptosis, heart failure, cardiomyopathy, viral or bacterial infection of the heart, myocardial ischemia, Cardiac cell death, including myocardial infarction and myocardial ischemia, coronary artery bypass grafting, and chemotherapy or mitochondrial drug toxicity as a result of HIV therapy, viral infection, or bacterial Cell death during sexual transmission, cell death from the follicle stage to the oocyte stage, cell death from the oocyte stage to the mature egg stage death, and sperm cell death (e.g., ovarian tissue freezing and transplantation procedures, artificial insemination) or to preserve the fertility of women and men after chemotherapy or to preserve the viability of female and male animals To preserve reproductive potential, macular degeneration and glaucoma, acute hepatitis, chronic active hepatitis, hepatitis B, and and hepatitis C, hair loss and male pattern baldness, caused by radiation therapy, chemotherapy or emotional stress Hair loss, skin damage (high levels of radiation, heat, burns, chemicals, sun exposure, and autoimmune diseases) autoimmune diseases), bone marrow cell death in myelodysplastic syndromes (MDS), pancreatitis, respiratory failure Haemostatic syndrome, or osteoarthitis, rheumatoid arthritis, psoriasis, glomerulonephritis, atherosclerosis atherosclerosis, as well as graft-versus-host disease, a disease state associated with increased inflammation is selected from.

[0146] In some embodiments, provided herein are methods for treating and / or preventing cancer. Methods of using the compounds herein. Exemplary cancers include lung cancer, colorectal cancer (CRC), melanoma, and the like. Gastric cancer (including esophageal cancer), renal cell carcinoma (RCC), breast cancer, prostate cancer, head and neck cancer, bladder cancer, hepatocellular carcinoma Cancer (HCC), ovarian cancer, cervical cancer, endometrial cancer, pancreatic cancer, neuroendocrine cancer, blood cancer (especially multiple This includes myeloma, acute myeloblastic leukemia (AML), and biliary tract cancer.

[0147] In one embodiment, provided herein are anti-inflammatory drugs that have at least a partial inflammatory basis. The present invention is directed to improving the treatment of cancers described herein, such as lung cancer. In some embodiments, provided herein are compositions having at least a partial inflammatory basis. The method of any of the inventions described herein for the treatment and / or prevention of cancer, e.g., a cancer described herein, such as lung cancer. In another aspect, provided herein are uses of compounds for the treatment and / or prevention of cancer. Specific clinical dosing regimens for the administration of the compounds herein for the prevention of In this manner, subjects suffering from cancers that have at least a partial inflammatory basis, including lung cancer, are treated with this method. In addition to administering the compounds of the present invention, one or more therapeutic agents (e.g., chemotherapeutic agents) may be administered; and / or have undergone / plan to undergo cytoreductive surgery.

[0148] In some embodiments, a therapeutically effective amount of a compound provided herein is administered to a subject. and administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of acetaminophen, benzodiazepine ...

[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 useful in treating cryopyrin-associated periodic fever syndrome (CAPS), Familial Mediterranean fever (FMF), systemic juvenile idiopathic arthritis (SJIA), hyperimmunoglobulin D syndrome (HID) S) and the treatment or prevention of tumor necrosis factor receptor-associated periodic syndrome (TRAPS), especially familial Cold urticaria, neonatal-onset multisystem inflammatory disease, SJIA and FMF, and Muckle-Wells syndrome It is used to treat or prevent the syndrome.

[0151] In some embodiments, the compounds provided herein are useful in any of the above-listed methods. It may be used in the following cases.

[0152] 6.4. Pharmaceutical Compositions The pharmaceutical compositions provided herein may be administered in a therapeutically effective amount, e.g., as described in Section 4.4. , caspase-1, caspase-4 and / or caspase-5, or one or more symptoms modulated by, or caspase-1, caspase-4 and / or caspase- prevention, treatment, or prophylaxis of one or more symptoms of conditions associated with or modulated by rhase-5; and one or more compounds provided herein that are useful in the treatment or alleviation of inflammatory bowel disease, as well as pharmaceutical compositions. The composition contains a suitable carrier that is acceptable to the patient.

[0153] The compounds may be administered orally in the form of liquids, suspensions, tablets, dispersible tablets, pills, capsules, powders, or the like. , sustained release formulations, or elixirs, or sterile solutions or suspensions for parenteral administration and manufactured into suitable pharmaceutical preparations, such as liquids, transdermal patches, and dry powder inhalants. In one embodiment, the compounds provided herein can be formulated into pharmaceutical compositions using techniques and methods well known in the art. and formulated into pharmaceutical compositions using procedures (e.g., Remington's Pharmaceuticals). (See "The Artificial Intelligence of the Brain," 20th ed., Mack Publishing, Easton PA (2000)).

[0154] The composition comprises an effective concentration of one or more compounds or pharmaceutically acceptable derivatives thereof. is mixed with a suitable pharmaceutical carrier or vehicle. The compound, as described above, Formulated as the corresponding salt, ester, acid, base, solvate, hydrate, or prodrug The concentration of the compound in the composition can be determined by the method described in Section 4.4. and treating, preventing, or preventing one or more symptoms of a condition modulated by one or more of the caspases described herein. The compound is effective to deliver an amount that prevents or alleviates the symptoms.

[0155] In one embodiment, the composition is formulated for single dosage administration. To achieve this, a weight fraction of the compound is used in a concentration effective to alleviate or relieve the symptoms to be treated. The substance is dissolved, suspended, dispersed, or mixed in the selected vehicle. Pharmaceutical carriers or vehicles suitable for administration of the compounds to be administered include those suitable for the particular mode of administration. These include all of the carriers known to those skilled in the art.

[0156] Additionally, the compound may be formulated as the sole pharmaceutically active ingredient in the composition; or may be combined with other active ingredients. Tissue-targeted liposomes, such as tumor-targeted liposomes, Liposomal suspensions containing hydroxybenzoates may also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared according to methods known in the art. Briefly, liposomes such as multilamellar vesicles (MLVs) can be prepared as described. The cells were cultured in a flask containing egg phosphatidylcholine and brain phosphatidylserine (7:3 molar ratio). The compounds provided herein can be formed by drying down the Add a solution of phosphate buffered saline (PBS) containing no divalent cations until the lipid film is dispersed. The flask is shaken at RT. The resulting vesicles are washed to remove unencapsulated compound. , pelleted by centrifugation, and then resuspended in PBS.

[0157] The active compound is therapeutically effective without causing undesirable side effects in the treated patient. In a pharmaceutically acceptable carrier in an amount sufficient to be effective. The appropriate concentration can be determined by testing the compound in in vitro and in vivo systems known in the art. These can be determined empirically and dosages for humans can be extrapolated from such studies.

[0158] The concentration of the active compound in the pharmaceutical composition determines the rate of absorption, inactivation and excretion of the active compound. The excretion rate, the physicochemical properties of the compound, the dosing schedule and dosage, and other factors known to those skilled in the art. It will depend on the factors.

[0159] In one embodiment, the therapeutically effective dosage is from about 0.1 ng / ml to about 50-100 μg / ml, about 0.5 ng / ml ~ approx. 80μg / ml, approx. 1ng / ml ~ approx. 60μg / ml, approx. 5ng / ml ~ approx. 50μg / ml, approx. 5ng / ml ~ approx. 40μg / m l, about 10ng / ml to about 35μg / ml, about 10ng / ml to about 25μg / ml, about 10ng / ml to about 10μg / ml, about 25ng / m l ~ approx. 10μg / ml, approx. 50ng / ml ~ approx. 10μg / ml, approx. 50ng / ml ~ approx. 5μg / ml, approx. 100ng / ml ~ approx. 5μg / m l, about 200ng / ml to about 5μg / ml, about 250ng / ml to about 5μg / ml, about 500ng / ml to about 5μg / ml, about 1μg / m 1 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 The pharmaceutical composition should produce a serum concentration of the active ingredient of 0.1 mg / ml. , about 0.001 mg to about 2000 mg of the compound per kg of body weight per day, about 0.0 0.02 mg to about 1000 mg of compound per kg of body weight per day, about 0.005 mg to about 500 mg of 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, and about 0.005 mg to about 250 mg of the compound per kg of body weight per day 200 mg of compound, approximately 0.005 mg to approximately 100 mg of compound per kg of body weight per day About 0.001 mg to about 0.005 mg of compound per gram of body weight per day, and about 0.01 mg to about 100 mg of compound per kg of body weight per day Compound, about 0.02 mg to about 100 mg per kg of body weight per day Compound, about 0.02 mg to about 100 mg per kg of body weight per day 0.05 mg to about 100 mg of 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, and about 0.75 mg to about 100 mg of the compound per kg of body weight per day of compound, about 1 mg to about 100 mg per kg of body weight per day, about 1 mg to about 100 mg per kg of body weight per day 1 mg to about 10 mg of compound per kg of body weight per day, about 0.001 mg to about 5 mg of compound per kg of body weight per day About 200 mg to about 2000 mg of the compound per kg of body weight, or about 10 mg to about 100 mg per kg of body weight per day The pharmaceutical dosage unit form should provide a dosage of the compound of: About 1mg to about 1000mg, about 1mg to about 800mg, about 5mg to about 800mg, about 1mg to about 100mg, about 1mg to about 50mg, About 5 mg to about 100 mg, about 10 mg to about 50 mg, about 10 mg to about 100 mg, about 25 mg to about 50 mg, and about 10 mg to about 5 00mg of the essential active ingredient or combination of essential ingredients.

[0160] The active ingredient may be administered at once, or may be divided into a number of smaller doses that are administered at intervals of time. The exact dosage and duration of treatment will depend on the effect of the disease being treated. may be modified using known testing protocols or in vivo or in vitro. It is understood that the concentration and It should be noted that dosage values ​​may also vary with the severity of the symptoms to be alleviated. The specific dosing regimen for any particular subject will depend on the individual needs and the administration of the composition. should be adjusted over time according to the professional judgment of the person administering or supervising the administration. The concentration ranges described herein are exemplary only and are not intended to be limiting of the scope of the claimed compositions. It should further be understood that no limitation on the scope or practice of the composition is intended.

[0161] Pharmaceutically acceptable derivatives include acids, bases, and esters, salts, esters, hydrates, Derivatives include solvates, as well as prodrug forms. Derivatives are compounds whose pharmacokinetic properties are: It is selected to outperform the corresponding neutral compound.

[0162] From the above, an effective concentration or amount of one or more compounds or pharmaceuticals thereof described herein is The therapeutically acceptable derivative may be combined with a pharmaceutical carrier or suitable for systemic, targeted local, or topical administration. The compound is mixed with a vehicle to form a pharmaceutical composition. , related to or modulated by caspase-1, caspase-4, and / or caspase-5 to alleviate one or more symptoms of, or to treat or prevent the recurrence of, a condition The concentration of the active compound in the composition is determined by the rate of absorption of the active compound, the amount of Rates of activation and excretion, dosage regimen, dose, particular formulation, and other factors known to those skilled in the art. It will depend on the child.

[0163] The compositions can be administered orally, parenterally, by intravitreal injection, through drug-impregnated contact lenses, or rectally. Targeted local administration by inhalation spray, nasally, buccal, vaginally, by an implanted reservoir or via a suitable route, including via a nasogastric or orogastric tube. In some embodiments, administration is by oral route. In another embodiment, administration is by parenteral route. For oral administration, capsules and tablets are used. The compositions may be in liquid, semi-liquid, or solid form and may be formulated to suit each route of administration. In one embodiment, the modes of administration include parenteral and oral modes of administration. In some embodiments, oral administration is contemplated.

[0164] Solutions or preparations used for parenteral, intravitreal, intradermal, subcutaneous or targeted topical application The suspension contains the following ingredients: water for injection, saline solution, fixed oil, polyethylene glycol alcohol, glycerin, propylene glycol, dimethylacetamide, or other synthetic solvents a sterile diluent; antibacterial agents such as benzyl alcohol and methylparaben; ascorbic acid and Antioxidants such as sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); vinegar buffers such as acid salts, citrates, and phosphates; and buffers such as sodium chloride or glucose. Parenteral preparations may be made of glass, plastic, or other suitable materials. or other suitable material, ampoules, disposable syringes, or single or multi-dose bottles. It can be enclosed in Ial.

[0165] If the compound exhibits insufficient solubility, methods for solubilizing the compound can be used. Such methods are known to those skilled in the art and include, but are not limited to, dimethyl sulfoxide Use a co-solvent such as DMSO, use a surfactant such as TWEEN®, or carbonated water and dissolving the compound in an aqueous sodium hydroxide solution.

[0166] The mixture obtained by mixing or adding compounds may be a solution, suspension, emulsion, etc. The form of the resulting mixture may vary depending on the intended mode of administration and the selected carrier or vehicle. The effective concentration depends on many factors, including the solubility of the compound in the blood. sufficient to alleviate the symptoms of the injury or condition and can be determined experimentally. do.

[0167] The pharmaceutical composition may be a tablet containing a suitable amount of the compound or a pharmaceutically acceptable derivative thereof. tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions and for administration to humans and animals in unit dosage forms (unit dose forms), such as suspensions and oil / water emulsions. The pharmaceutically active compounds and derivatives thereof are provided for administration in unit dosage forms or As used herein, unit dosage form is intended for use in human subjects and animals. Refers to physically separate units suitable for an object, individually packaged as known in the art. Each unit dose is prepared as desired together with the required pharmaceutical carrier, vehicle, or diluent. It contains a predetermined quantity of a therapeutically active compound sufficient to produce a therapeutic effect. Examples of unit dosage forms include: , ampoules and syringes, and individually packaged tablets or capsules. Dosage forms may also be administered in fractions or multiples thereof. Multiple dosage forms may be administered in separate units. A plurality of identical unit dosage forms packaged in a single container to be administered in dosage form. Examples include vials, bottles, or pint or gallon bottles of tablets or capsules. Thus, multiple-dosage form refers to multiple unit doses that are not segregated in packaging. be.

[0168] Sustained release preparations can also be made. Suitable examples of sustained release preparations include those provided herein. a semipermeable matrix of solid hydrophobic polymers containing the compound to be administered, The compounds may be in the form of molded products, 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, L-glucan Copolymer of glutamic acid and ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, LUPR ON DEPOT™ (an injection composed of lactic acid-co-glycolic acid copolymer and leuprolide acetate) degradable lactic acid-co-glycolic acid polymers such as poly-D-(-)-3- hydroxybutyric acid. Polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid , allowing release of molecules for periods exceeding 100 days, while certain hydrogels may release molecules for shorter periods. If the encapsulated compounds are kept in the body for a long time, they will release the proteins. may denature or aggregate as a result of exposure to moisture at 37°C, resulting in loss of biological activity. Depending on the mechanism of action involved, changes in the structure of the compound may occur. Rational strategies for stability can be devised. For example, if the aggregation mechanism is thio-disulfide If it turns out that the stabilization is due to the formation of intermolecular SS bonds via sulfhydryl exchange, modifying the aryl residues, freeze-drying from an acidic solution, controlling the water content, By using suitable additives and developing specific polymer matrix compositions, More can be achieved.

[0169] Active ingredient 0.001%~100%, Active ingredient 0.002%~100%, Active ingredient 0.005%~90%, Active ingredient Minutes 0.01%~100%, active ingredients 0.05%~100%, active ingredients 0.05%~90%, active ingredients 0.1%~100 %, active ingredient 0.1%~1%, active ingredient 0.1%~0.5%, active ingredient 1%~100%, active ingredient 1%~9 9%, active ingredient 1%~98%, active ingredient 1%~97%, active ingredient 1%~96%, active ingredient 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 %, 60%-95% active ingredient, or 75%-100% active ingredient, composed of a non-toxic carrier A dosage form or composition can be prepared which contains the active ingredient together with the remainder. To this end, pharmaceutically acceptable, non-toxic compositions include, for example, pharmaceutical grade mannitol, lactose, and the like. Tocopherol, starch, magnesium stearate, talcum, cellulose derivatives, croscarmellose Sodium rumellose, glucose, sucrose, magnesium carbonate or saccharin sodium The compound is formed by incorporating any of the commonly employed excipients, such as sodium. Such compositions include, but are not limited to, solutions, suspensions, tablets, capsules, powders, and the like. However, sustained release formulations such as implants and microencapsulated delivery systems, as well as collagen Polyethylene vinyl acetate, polyanhydride, polyglycolic acid, polyorthoester, poly These compositions include biodegradable, biocompatible polymers such as lactic acid, polylactic acid, and the like. Methods for preparing such compositions are well known to those skilled in the art. Contemplated compositions contain from 0.001% to 100% of the active ingredient, in one embodiment. In one embodiment, the active ingredient may be contained in an amount of 75 to 95%.

[0170] The active compound or a pharmaceutically acceptable derivative may be administered in a time-release formulation or coating. and preparing the compound with a carrier, such as a steroid, that protects the compound from rapid elimination from the body. can be done.

[0171] The compositions may include other active compounds to obtain desired combinations of properties. A compound provided herein, or a pharmaceutically acceptable derivative thereof, as described herein. The body may also utilize other pharmacological agents known in the general art to be of value in treating the same condition. and administering the compound to a subject with a condition modulated by one or more caspases for therapeutic or prophylactic purposes. Such combination therapy can be advantageously administered in combination with the compositions provided herein. and should be understood to constitute a further aspect of the method of treatment.

[0172] (Composition for oral administration) Oral pharmaceutical dosage forms are either solid, gel, or liquid. Solid dosage forms include tablets, capsules, and Oral tablet types include compressed, chewable, and lozenges. Zenji tablets and tablets, which may be enteric coated, sugar coated, or filled. The capsules may be hard or soft gelatin capsules. On the other hand, granules and powders may be non-combustible with other ingredients in combination known to those skilled in the art. It may be provided in a foaming or effervescent form.

[0173] In some embodiments, the formulation is a solid dosage form such as a capsule or tablet. Capsules, troches, etc. may contain the following ingredients: binder; diluent; disintegrant; lubricant; flow agent; sweetener; and flavoring agents, or compounds of a similar nature.

[0174] Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, and gum arabic. Lubricants include talc, denatured milk, gelatin solution, sucrose, and starch paste. Pu, magnesium or calcium stearate, lycopodium, and stearin Diluents include, for example, lactose, sucrose, starch, kaolin, salt Glidants include, but are not limited to, mannitol, and dicalcium phosphate. Disintegrants include colloidal silicon dioxide, but not croscarmellose sodium. um, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose Coloring agents include, for example, approved, certified, water-soluble FD and C dyes, their and any of the water-insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol, and artificial sweeteners such as saccharin; Flavorings include natural flavors extracted from plants such as fruits, as well as any number of spray-dried flavorings. Natural flavors, including but not limited to peppermint and methyl salicylate Humectants include synthetic blends of compounds that produce a pleasant sensation, such as monosodium glutamate. Propylene glycol tearic acid, sorbitan monooleate, diethylene monolaurate Contains ethylene glycol, and polyoxyethylene laural ether. The metic coating contains fatty acids, fats, waxes, shellac, and ammoniated ceramics. Film coatings include hydroxybenzoates, cellulose acetate phthalates, and cellulose acetate phthalates. Ethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 40 00, and cellulose acetate phthalate.

[0175] If oral administration is desired, the compound is administered in a composition that protects it from the acidic environment of the stomach. For example, the composition may be provided in a form that maintains its integrity in the stomach and in the intestine. The compositions can also be formulated in enteric coatings that release the active compound. It may also be formulated in combination with an acidic agent or other such ingredient.

[0176] When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, The dosage unit form may contain a liquid carrier such as a fatty oil. Various other materials that modify the physical form, including coatings of sugars and other enteric agents, may be added. The compounds may also be formulated as elixirs, suspensions, syrups, wafers, etc. It can also be administered as a component of a syrup, sprinkles, chewing gum, etc. The formulation may contain, in addition to the active compounds, sucrose as a sweetening agent, and certain preservatives, dyes, , and coloring agents, and flavoring agents.

[0177] The active ingredient may also contain other active ingredients that do not impair the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient can also be mixed with other materials, or materials that complement the desired action. or a pharmaceutically acceptable derivative thereof. Higher concentrations of up to about 98% by weight It is also possible to contain the active ingredient

[0178] The pharmaceutically acceptable carrier contained in the tablet may be a binder, lubricant, diluent, disintegrant, adhesive, or the like. Coloring agents, flavoring agents, and wetting agents. Enteric-coated tablets are They resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines. Film-coated tablets are compressed tablets to which various layers of materials acceptable for the treatment of ulcerative colitis have been applied. , polymer, or other suitable coating. Manufactured by more than one compression cycle using the pharmaceutically acceptable material described above. Coloring agents may also be used in the above dosage forms. Flavoring and sweetening agents may also be used in the compressed tablets. Flavoring and sweetening agents are used in tablets, sugar-coated tablets, multiple compressed tablets, and chewable tablets. It is particularly useful in forming tablets and lozenges.

[0179] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, and non-effervescent granules reconstituted from non-effervescent granules. These include solutions and / or suspensions prepared from effervescent granules, as well as effervescent preparations reconstituted from effervescent granules. Aqueous liquid preparations 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 preparations include solvents. Syrups are made from sugars, e.g. For example, it is a concentrated aqueous solution of sucrose, which may contain a preservative. A two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically acceptable carriers used in formulations include non-aqueous liquids, emulsifying agents, and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Liquid Oral Dosage Forms Pharmaceutically acceptable substances used in non-effervescent granules for reconstitution include diluents. Contains sweeteners, syrups, and wetting agents. Used in effervescent granules for reconstitution into a liquid oral dosage form. Pharmaceutically acceptable substances that may be used include organic acids and a source of carbon dioxide. 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, methylparaben and propylparaben, benzoic acid adduct (b enzoic add), sodium benzoate, and alcohol. Examples of non-aqueous liquids that may be used include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, Acacia, tragacanth, bentonite, and polyoxyethylene monooleate sol Suspending agents include surfactants such as sodium carboxymethyl cellulose. Diluents include cereals containing gluten, pectin, tragacanth, Veegum, and acacia. Sweeteners include sucrose, syrup, glycerin, and lactose. Wetting agents include propylene glycol, propylene glycol, and artificial sweeteners such as saccharin. ethylene glycol, sorbitan monooleate, diethylene glycol monolaurate, and and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. The agent may contain any of the approved, certified water-soluble FD and C dyes and mixtures thereof. Flavoring agents include natural flavors extracted from fruits and other plants, and flavoring agents that produce a pleasant taste. This includes synthetic combinations of compounds.

[0182] For solid dosage forms, e.g., solutions in propylene carbonate, vegetable oils, or triglycerides The suspension may also be enclosed in a gelatin capsule. Such liquid crystal displays are disclosed in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. The dosage form may be made of, for example, polyethylene, so that it can be easily measured for administration. The solution in ethanol is diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water. It is possible.

[0183] Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving the active compound or salt in a solvent such as vegetable oil, glycol, triglyceride, or the like. Glycerides, propylene glycol esters (e.g., propylene carbonate), and other such The compound is dissolved or dispersed in such a carrier, and the solution or suspension is then filled into hard or soft gelatin capsules. Other useful formulations include, but are not limited to: However, the compounds provided herein, 1,2-dimethoxymethane, diglyme, triglyme, tet Lagrim, Polyethylene Glycol-350-Dimethyl Ether, Polyethylene Glycol-55 0-dimethyl ether, polyethylene glycol-750-dimethyl ether (wherein 350, 550 , and 750 refer to the approximate average molecular weight of polyethylene glycol), Without limitation, dialkylated mono- or poly-alkylene glycols, In addition, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), propyl gallate L-Pil, Vitamin E, Hydroquinone, Hydroxycoumarin, Ethanolamine, Lecithin , cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and one or more antioxidants such as dithiocarbamates. Included.

[0184] Other formulations include, but are not limited to, those containing pharmaceutically acceptable acetals. The alcohol used in these formulations is not intended to be used as any medicinal agent. Water-miscible solvents having one or more hydroxyl groups that are acceptable to the Acetals include, but are not limited to, propylene glycol and ethanol. However, di( (lower alkyl) acetals.

[0185] In all embodiments, the tablet and capsule formulations vary the dissolution of the active ingredient. To achieve this, the material may be coated as known to those skilled in the art. For example, they may contain conventional additives such as phenyl salicylate, waxes, and cellulose acetate phthalate. The drug may be coated with a conventional enterically digestible coating agent.

[0186] (injections, liquids, and emulsions) Parenteral, generally characterized by injection either subcutaneously, intramuscularly, intravitreally, or intravenously Injectables are administered either as liquid solutions or suspensions or as either as a solid form suitable for solution or suspension in liquid prior to injection, or as an emulsion. The formulation may be prepared in any conventional form. Suitable excipients include, for example, water, The solution may be saline, glucose, glycerol, or ethanol. The pharmaceutical compositions may also contain wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and For example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and other such agents such as cyclodextrins. Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained. are also contemplated herein. Briefly, the compounds provided herein are The solid inner matrix is, for example, polymethylmethacrylate. Poly(butyl methacrylate), plasticized or unplasticized polyvinyl chloride, Plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisoprene Isobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone Rubber, Polydimethylsiloxane, Silicone-Carbonate Copolymer, Acrylic Acid and hydrophilic polymers such as hydrogels of esters of methacrylic acid, collagen, cross-linked polyvinyl alcohol, vinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate, The outer polymeric membrane may be, for example, polyethylene, Polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer -, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neo Prene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, ethylene propylene and copolymers of propylene and vinyl chloride, ionomer polyethylene terephthalate Butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene Ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol The compound is released from the outer polymer in a release rate controlling step. The percentage of active compound in such parenteral compositions can vary depending on the specific The nature of the compound is highly dependent on the individual's physical characteristics, as well as the activity of the compound and the needs of the subject.

[0187] Parenteral administration of the compositions includes intravenous, intravitreal, subcutaneous, and intramuscular administration. Preparations for oral administration include ready-to-inject sterile solutions, which must be combined with a solvent immediately before use. sterile dry soluble products such as freeze-dried powders, including tablets for subcutaneous injection; A sterile, dry, ready-to-inject suspension that can be combined with a vehicle immediately prior to use. This includes aqueous and non-aqueous solutions, as well as sterile emulsions. It's okay to have one.

[0188] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and glucose, polyethylene glycol, and polypropylene glycol and the like. and mixtures thereof.

[0189] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, and the like. Kuru, antimicrobial agent, isotonic agent, buffering agent, antioxidant, local anesthetic, suspending and dispersing agent, emulsifier , sequestering or chelating agents, as well as other pharmaceutically acceptable substances.

[0190] Examples of aqueous vehicles include Sodium Chloride Injection, Ringer's Injection, and Isotonic Dextrose Injection. Non-aqueous parenteral vehicles include sterile water injection, and lactated Ringer's injection. Examples include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations are added to parenteral preparations packaged in multi-dose containers. Antimicrobial agents include phenols or cresols, mercurials, benzyl alcohols, etc. Cholesterol, chlorobutanol, methyl and propyl esters of p-hydroxybenzoic acid These include thimerosal, benzalkonium chloride, and benzethonium chloride. Solubilizing agents include sodium chloride and glucose. Buffering agents include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine. Suspending and dispersing agents include carboxymethylcellulose, sodium hydroxypropyl methylcellulose, and polyvinylpyrrolidone Emulsifiers include polysorbate 80 (TWEEN® 80). Ion sequestering or chelating agents include EDTA. Pharmaceutical carriers also include water-miscible vehicles. Ethyl alcohol, polyethylene glycol, and propylene glycol for ethanol Contains sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0191] The concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose will depend on the age, weight, and other factors of the patient or animal, as is known in the art. Depends on the condition and symptoms.

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

[0193] Specifically, intravenous, intravitreal, or intra-arterial injection of a sterile aqueous solution containing the active compound. Another embodiment is to administer as much as necessary to produce the desired pharmacological effect. It is a sterile aqueous or oily solution or suspension containing an active material for injection as appropriate.

[0194] Injectables are designed for local and systemic administration. In some embodiments, therapeutically effective dosages is at least about 0.1% w / w and up to about 90% w / w of the tissue(s) being treated or greater than 1% w / w. The components may be administered at once or may be divided into a number of smaller doses to be administered at intervals of time. The exact dosage and duration of treatment will vary depending on the function of the tissue being treated. and can be determined using known testing protocols or in vivo or in vitro. It is understood that concentrations and dosages can be determined empirically by extrapolation from test data. It should be noted that the value of may also vary depending on the age of the individual being treated. The specific dosing regimen for a particular subject will depend on the individual needs and the person or persons administering the formulation. should be adjusted over time according to the professional judgment of the person supervising the administration of the drug product The concentration ranges described herein are exemplary only and are not intended to be limiting of the scope of the claimed formulations. It should be further understood that no limitation in scope or practice is intended.

[0195] The compounds may be suspended in micronized or other suitable form and may be derivatized to make them more soluble. The resulting mixture may be used to produce an easily active product or to produce a prodrug. The form will depend on the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration depends on many factors, including the severity of the condition. and can be determined experimentally.

[0196] (lyophilized powder) Also of interest herein are solutions, emulsions, and other mixtures for administration. These are lyophilized powders that can be reconstituted as a solid or gel. and can also be formulated.

[0197] The sterile, lyophilized powder contains a compound provided herein, or a pharmaceutically acceptable derivative thereof. The conductor is prepared by dissolving it in a suitable solvent. The solvent may be a powder or may be prepared from a powder. It may contain excipients that improve the stability or other pharmacological components of the resulting reconstituted solution. Excipients that can be used include, but are not limited to, glucose, sorbitol, l), fructose, corn syrup, xylitol, glycerin, glucose, sucrose The solvent may also include citrate, sodium phosphate, or other suitable agents. a buffer such as potassium phosphate or other such buffers known to those skilled in the art at nearly neutral pH Subsequent sterile filtration of the solution under standard conditions known to those skilled in the art may be performed. and subsequent lyophilization to provide the desired formulation. It will be dispensed into vials for lyophilization. Each vial contains a single dose (10-1000 mg or 1 The lyophilized powder may contain 0.00-500 mg or multiple doses of the compound. The lyophilized powder may be stored at about 4°C to room temperature. The solution can be stored under suitable conditions such as:

[0198] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, use approximately 1-50 mg, 5-35 mg, or 1 mL of sterile water or other suitable carrier. Alternatively, add approximately 9-30 mg of lyophilized powder, the exact amount depending on the compound selected. Such amounts can be determined empirically. (Targeted local administration) The targeted topical mixture is prepared as described for local and systemic administration. The mixture may be in the form of a solution, suspension, emulsion, etc., and may be in the form of a cream, gel, ointment, etc. preparations, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes tablets, foams, aerosols, irrigation solutions, sprays, suppositories, dressings, transdermal patches , contact lenses, or any other formulation suitable for targeted topical application.

[0199] The compound or a pharmaceutically acceptable derivative thereof may be administered for targeted local application, such as by inhalation. These compounds can be formulated as aerosols for the treatment of inflammatory diseases, particularly asthma. U.S. Patent Nos. 4,044,126 and 4,414,222, which describe aerosol formulations for the delivery of steroids. (See US Patent Nos. 4,364,923 and 4,364,929.) These formulations for administration to the respiratory tract are suitable for use with nebulizers. The compound may be in the form of an aerosol or liquid formulation, alone or in combination with an inert carrier such as lactose. It may also be an ultrafine powder for combined insufflation. In such cases, the particles of the formulation should be less than 50 microns. or will have a diameter of less than 10 microns.

[0200] The compounds can be formulated for topical or targeted local application, for example, as gels, capsules, or the like. For targeted topical application to the skin and mucous membranes, including the ophthalmic area, in the form of creams and lotions. and for application to the eye, or for intracisternal or intrathecal application, etc. Targeted local administration can be achieved by transdermal delivery, as well as by administration to the eye or mucosa, or Also intended for inhalation therapy. A nasal solution in combination with an acceptable excipient may also be administered.

[0201] These solutions, especially those intended for ophthalmic use, are generally 0.01% to 10% isotonic solutions containing suitable salts. It can be formulated as a solution (pH approximately 5-7).

[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. It is illustrated.

[0203] For example, pharmaceutical dosage forms for rectal administration include rectal suppositories, capsules, and tablets for systemic effect. As used herein, rectal suppositories mean solid objects for insertion into the rectum, which The suppository melts or softens at body temperature, releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances used in the formulation include bases or vehicles and substances that increase the melting point. Examples of bases include cocoa butter, glycerin, gelatin, and carbohydrate. (polyoxyethylene glycol), and mono-, di-, and triglycerides of fatty acids Suitable mixtures include: Combinations of various bases may be used. Raising the melting point of suppositories Medications include spermaceti and wax. Rectal suppositories may be prepared either compressed or molded. In one embodiment, the weight of a rectal suppository is about 2 to 3 grams.

[0204] Tablets and capsules for rectal administration have the same pharmaceutically acceptable properties as formulations for oral administration. It is produced by the same method using the same materials.

[0205] (Sustained Release Composition) Active ingredients, such as the compounds provided herein, may be administered by controlled release means or delivery means, which are well known to those of ordinary skill in the art. The drug can be administered by a delivery device, such as, but not limited to, U.S. Pat. No. 3,845,770; No. 3,916,899; No. 3,536,809; No. 3,598,123; No. 4,008,719; No. 5,674,533 No. 5,059,595; No. 5,591,767; No. 5,120,548; No. 5,073,543; No. 5,639,476; No. 5,354 ,556;No.5,639,480;No.5,733,566;No.5,739,108;No.5,891,474;No.5,922,356;No.5 ,972,891;No.5,980,945;No.5,993,855;No.6,045,830;No.6,087,324;No.6,113,943 ; No. 6,197,350; No. 6,248,363; No. 6,264,970; No. 6,267,981; No. 6,376,461; No. 6,419,9 61; 6,589,548; 6,613,358, and 6,699,500. , each of which is incorporated herein by reference. Such dosage forms include, for example, Hydropropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems , multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof. to provide sustained or controlled release of one or more active ingredients to achieve a desired release profile at various rates. Any suitable file known to those skilled in the art, including those described herein, may be provided. Suitable controlled-release formulations may be readily selected for use with the active ingredients provided herein. Thus, the compositions provided include, but are not limited to, controlled release. Suitable oral dosage forms include tablets, capsules, gel caps, and caplets. The present invention encompasses single unit dosage forms suitable for administration.

[0206] All controlled-release pharmaceutical products are designed to deliver drug therapy faster than their corresponding non-controlled counterparts. Ideally, medical treatments have a common goal of improving upon what is achieved. The use of optimally designed controlled release preparations in the treatment of rheumatoid arthritis can cure or control symptoms in the shortest amount of time. The advantages of controlled-release formulations include the use of minimal drug substance to control the These include prolonging the drug's active effect, reducing dosing frequency, and improving subject compliance. Additionally, controlled-release formulations may be formulated to provide a controlled release drug with a time to onset of activity or other characteristics such as blood levels of the drug. can be used to influence and thus influence the occurrence of side effects (e.g., adverse effects) It can have an effect.

[0207] Most controlled-release formulations deliver the optimal amount of drug (active ingredient) that immediately produces the desired therapeutic effect. and another to maintain this level of therapeutic or prophylactic effect over an extended period of time. These drugs are designed to release a constant amount of drug slowly and continuously. To maintain this, drugs must be metabolized and excreted from the body at a rate that replaces the amount of drug being excreted. The controlled release of the active ingredient can include, but is not limited to, The cells are stimulated by various conditions, including pH, temperature, enzymes, water, or other physiological conditions or compounds. It can be exciting.

[0208] In some embodiments, the drug is administered by intravenous infusion, an implantable osmotic pump, a transdermal patch, a liposome, or the like. In one embodiment, a pump can be used. (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 yet another embodiment, the controlled release system is administered to a subject in a controlled manner. The device can be placed in a suitable location as determined by a qualified medical professional, i.e., Only a fraction of the systemic dose is required (e.g., Goodson, Medical Applications o (See Controlled Release, vol. 2, 1984, pp. 115-138). Other controlled release systems include those described by Langer et al. The active ingredient is a solid inner matrix. The solid inner matrix can be, for example, a polymethylmethacrylate. Poly(butyl methacrylate), plasticized or unplasticized polyvinyl chloride, Plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisoprene Isobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone Rubber, Polydimethylsiloxane, Silicone-Carbonate Copolymer, Acrylic Acid and hydrophilic polymers such as hydrogels of esters of methacrylic acid, collagen, cross-linked polyvinyl alcohol, vinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate, The outer polymeric membrane may be, for example, polyethylene, Polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer -, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neo Prene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, ethylene propylene and copolymers of propylene and vinyl chloride, ionomer polyethylene terephthalate Butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene Ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol The active ingredient is then released in a release rate-controlling step. The active compound in such parenteral compositions diffuses through the outer polymeric membrane in a stepwise fashion. The case will be highly dependent on its specific nature and the needs of the subject.

[0209] (Targeted formulation) The compounds provided herein, or pharmaceutically acceptable derivatives thereof, are useful in treating a subject. They can be formulated to target specific tissues, receptors, or other areas of the body. Such targeting methods are well known to those skilled in the art. All such targeting methods are Non-limiting examples of targeting methods are contemplated herein for use in See, for example, U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, No. 6,139,865, No. 6,131,570, No. 6,120,751, No. 6,071,495, No. 6,060,082, No. 6,0 No. 48,736, No. 6,039,975, No. 6,004,534, No. 5,985,307, No. 5,972,366, No. 5,900,25 See Nos. 2, 5,840,674, 5,759,542, and 5,709,874.

[0210] In one embodiment, liposomes, including tissue-targeted liposomes, such as tumor-targeted liposomes, Suspensions may also be suitable as pharmaceutically acceptable carriers. These are well known to those skilled in the art. For example, liposome preparations can be prepared according to the methods described in U.S. Pat. No. 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLVs) can be prepared as described in The phosphatidylsomes were incubated in a flask containing egg phosphatidylcholine and brain phosphatidylserine (7:3 molar ratio). The compounds provided herein can be formed by drying down a mixture of 100% ethylenediamine and 100% propylenediamine. A solution of the mixture in phosphate buffered saline (PBS) lacking divalent cations was added, and the flask was filled with the lipid film. The resulting vesicles are washed to remove any unencapsulated compound. The cells are then pelleted by centrifugation and resuspended in PBS.

[0211] Dosage and Unit Dose Form In human therapy, the physician will determine the appropriate dose depending on the prophylactic or therapeutic treatment and the subject being treated. The doctor will determine what is best for you based on your age, weight, stage of disease, and other factors. The dosage regimen will be determined. Typically, the dosage is about 1 to about 1000 mg per day for an adult, or The daily dose for one adult is about 5 to about 250 mg, or about 10 to 50 mg for one adult. In certain embodiments, the dose is from about 5 to about 400 mg per adult per day or from about 5 to about 400 mg per adult per day. A dosage rate of about 50 to about 500 mg per day is also contemplated.

[0212] In certain embodiments, a compound effective in treating colon cancer or preventing one or more symptoms thereof. The amount of the composition will depend on the nature and severity of the disease or condition, as well as the route by which the active ingredient is administered. The frequency and dosage will also vary depending on the specific therapy being administered (e.g., therapeutic or prophylactic agent), the severity of the disorder, disease, or condition, the route of administration, and the age of the subject; Varies depending on factors specific to each subject, depending on body mass, weight, response, and past medical history. Effective doses are determined based on dose-response data obtained from in vitro or animal model test systems. It can be estimated from the curve.

[0213] Exemplary dosages of the compositions include milligrams or micrograms per kg of subject or sample animal weight. The therapeutic agent may include a chemotherapeutic agent and a caspase inhibitor in a dose of about 0.001 to 1000 mg / mL. Kg, about 0.01 to 100 mg / Kg, about 0.01 to 50 mg / Kg, about 0.1 to 25 mg / Kg, or about 0.1 to 10 mg / Kg). In one embodiment, the dosage administered to a subject is between 0.20 mg / Kg and 2.00 mg / Kg of the subject's body weight. g / Kg or between 0.30 mg / Kg and 1.50 mg / Kg.

[0214] In one embodiment, a caspase inhibitor as described herein and, optionally, an applicable If necessary, the recommended dosage of co-administered chemotherapy drugs for the conditions described herein may be increased. The daily dosage range may be administered as a single, once-daily dose or as multiple doses divided over the course of a day. When administered as a daily dose, the chemotherapy drug and caspase inhibitor each amount is about 0.1 mg to about 1000 mg. In one embodiment, the daily dosage ranges from 2 to 100 mg / day in equally divided doses. Specifically, the daily dose ranges from about 10 mg to about 200 mg per day, more specifically, Specifically, between about 10 mg and about 150 mg per day, or even more specifically, between about 25 mg and about 150 mg per day. As will be apparent to one skilled in the art, in some cases, It may be necessary to use dosages of the active ingredients outside the ranges disclosed herein. The clinician or treating physician will determine how and when to interrupt, adjust, or discontinue therapy in relation to the subject's response. It should be noted that you will know when to terminate.

[0215] As would be readily known by one of ordinary skill in the art, different therapeutically effective amounts may be used for different diseases and conditions. and symptoms thereof, as well as the prevention, management, treatment, or amelioration of such disorders. an amount sufficient to inhibit the release of steroid hormones, but not to cause the adverse effects associated with the compounds described herein. An amount insufficient to reduce the adverse effects or an amount sufficient to reduce the adverse effects may also be used as described above. The dosage and administration frequency schedule is encompassed by the invention. When multiple doses of a compound are administered, not all of the doses need to be the same. For example, the dosage administered to a subject can be increased to improve the prophylactic or therapeutic effect of the compound. and the dosage is reduced to reduce one or more side effects suffered by a particular subject. That's fine.

[0216] In one embodiment, a method for preventing, treating, managing, or treating a disorder, or one or more symptoms thereof, in a subject is provided. The dosage of the compounds described herein is administered to alleviate the symptoms of rheumatoid arthritis, and is based on the body weight of the subject. 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. In another embodiment, the disorder in a subject, or one or more thereof, The compounds provided herein are administered to prevent, treat, manage, or alleviate the symptoms described above. The dosage of the compound 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 2 0mg, 0.1mg~15mg, 0.1mg~10mg, 0.1mg~7.5mg, 0.1mg~5mg, 0.1~2.5mg, 0.25mg~20m g, 0.25~15mg, 0.25~12mg, 0.25~10mg, 0.25mg~7.5mg, 0.25mg~5mg, 0.5mg~2.5mg , 1mg to 20mg, 1mg to 15mg, 1mg to 12mg, 1mg to 10mg, 1mg to 7.5mg, 1mg to 5mg, or 1mg to 2.5 The unit dose is in mg.

[0217] In one embodiment, the treatment or prevention comprises a caspase inhibitor, and optionally, where applicable, The treatment begins with one or more loading doses of co-administered chemotherapy drugs, followed by one or more maintenance doses. In such an embodiment, the loading dose may be, for example, It can be about 60 to about 400 mg or about 100 to about 200 mg per day for 1 day to 5 weeks. One or more maintenance doses may be continued. Each maintenance dose is independently administered at a dose of about 10 mg to 100 mg per day. about 200 mg, more specifically between about 25 mg and about 150 mg per day, or even more specifically between about 1 It can be between about 25 mg and about 80 mg per day, or between about 25 mg and about 50 mg per day. Maintenance Doses can be administered daily, each as a single dose or as divided doses. do.

[0218] In certain embodiments, a caspase inhibitor provided herein, and optionally, an applicable If possible, the dose of the co-administered chemotherapeutic agent should be adjusted 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 according to techniques available to those skilled in the art. Determinable by measurement or based on the subject's physical characteristics, such as height, weight, and age In one embodiment, the concentration is about 300 to about 4000 ng / mL, about 400 to about 1600 ng / mL, or about 60 A sufficient amount of the compound of the present invention to achieve a steady-state concentration in the blood or serum of a subject of 0 to about 1200 ng / mL. The compound provided herein is administered. The loading dose is about 1200 to about 8000 ng / m for 1 to 5 days. The dose can be administered to achieve a blood or serum steady-state concentration of about 2000 to about 4000 ng / mL. The sustained dose is about 300 to about 4000 ng / mL, about 400 to about 1600 ng / mL, or about 600 to about 1200 ng / mL. Dosages can be administered to achieve a steady state concentration in the blood or serum.

[0219] In some embodiments, repeated administrations of the same compound may be administered, and each administration comprises at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months In other embodiments, the same prophylactic or therapeutic agent may be administered repeatedly. Administration should be at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, or 2 months. The intervals may be one month, 75 days, three months, or six months.

[0220] In certain aspects, provided herein are compounds or pharmaceuticals thereof in a form suitable for administration. Such forms are described in detail above. In certain embodiments, the unit dose is 1 to 1000 mg, 5 to 250 mg, or 10 to 50 mg of active ingredient. In particular embodiments, the unit dose comprises about 1, 5, 10, 25, 50, 100, 125, 25 Such unit dosages may be determined by methods well known to those skilled in the art. It can be manufactured according to the technology.

[0221] (6.5.Manufactured products) The compound or a pharmaceutically acceptable derivative may be used in packaging materials, The compounds provided herein are used in the treatment, prevention, or amelioration of a condition or one or more symptoms associated therewith. The compound or a pharmaceutically acceptable derivative thereof, as well as the compound or a medicament thereof The pharmaceutical acceptable derivatives may be used in the treatment, prevention or amelioration of a condition or one or more symptoms of that condition. The product may be packaged as an article of manufacture including a label indicating its intended use.

[0222] The articles of manufacture provided herein include packaging materials for use in packaging pharmaceutical products. Packaging materials for such purposes are well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907 and 5,052,558. See US Pat. Nos. 5,033,252 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to: However, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, etc. Syringes, bottles, and any packaging suitable for the selected formulation and intended mode of administration and treatment A variety of formulations of the compounds and compositions provided herein are contemplated.

[0223] (6.6. Kit) Also provided are kits for using the compounds provided herein in methods of treatment. The kit includes a caspase inhibitor or a composition thereof and a compound capable of inhibiting one or more caspases. Providing information to healthcare providers about its use to treat or prevent conditions that are modulated by The instructions may be in printed form or in electronic form such as a CD or DVD. or a website address where such instructions can be obtained. A unit dose of a caspase inhibitor or composition thereof, when administered to a subject, The plasma level of a therapeutically or prophylactically effective compound or composition is at least In some embodiments, the compound or The compositions may be administered as sterile, aqueous pharmaceutical compositions or as dry powder (e.g., lyophilized) compositions. It may be included.

[0224] 6.7. Overview of Compound Preparation The compounds provided herein can be prepared by the general process outlined in the scheme below. In Schemes 1 to 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, and R n and R o are each independently hydrogen, optionally 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 heterocycle or heterocyclic ring. forming heteroaryl rings, each of which is optionally substituted).

[0229] The following examples set forth certain exemplary embodiments and are intended to be illustrative and not limiting. It is not intended to [Example]

[0230] 7. Working Example The following examples are offered by way of illustration and not by way of limitation. The procedures shown in the accompanying examples can be modified to arrive at the desired products. Example 1 [ka]

[0231] Ethyl 2-((2,6-difluorophenyl)amino)-2-oxoacetate (3): Triethylamino A solution of 2,6-difluoroaniline (25.0 g, 193.8 mmol, 1 equiv.) in 27.2 mL of 2,6-difluoroaniline (25.0 g, 193.8 mmol, 1 equiv.) was added to the reaction mixture. A solution of ethyl oxalyl chloride (21.6 mL, 193.8 mL) in THF (1 L) was added at 0-5°C. (mmol, 1 equiv.) was added dropwise over 60 min, maintaining the temperature below 5° C. The reaction was allowed to warm to room temperature. The reaction was warmed and stirred for 24 hours. The reaction was filtered through Celite and 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 layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired product. The product was obtained as a beige oil (44.8 g, quantitative yield).

[0232] 2-((2,6-difluorophenyl)amino)-2-oxoacetic acid (4): 1N lithium hydroxide (233 mL, 23 3 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 hours, the reaction was cooled to 0°C and acidified with concentrated HCl to pH 2. The reaction mixture was saturated with sodium chloride and extracted with ethyl acetate (6 x 200 mL). The organic layer was 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 reacted with compound 4 (19.4 g, 96.5 mmol, 1.0 equiv.), HOA To a suspension of t (18.4 g, 135 mmol, 1.4 equiv.) in acetonitrile (1.0 L) was added the mixture. 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 The mixture was stirred at room temperature overnight. LC-MS analysis showed the reaction was complete. The mixture was concentrated under reduced pressure. The wet solid was diluted with ethyl acetate (300 mL) and water (100 mL). The two layers were separated and the aqueous layer The extract was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with saturated brine (50 mL) and The crude product was extracted with dichloromethane (200 ml), dried over sodium hydroxide, filtered and concentrated under reduced pressure. L) and adsorbed onto Celite (30 g). Interchim automated system (330 g column). Purified by eluting with dichloromethane in a 0-5% gradient of ethyl acetate over 20 min. This gave compound 7 as a white solid (18.2 g, 62.8% yield).

[0234] (2-((2,6-difluorophenyl)amino)-2-oxoacetyl)-L-alanine (8): 1N hydroxylation Lithium (1.0 N, 71.5 mL, 71.5 mmol, 1.2 equiv.) was added to compound 7 (17.9 g, 59.6 mmol, 1.0 After stirring for 48 hours, LC-MS analysis showed The reaction was shown to be 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 mixture was mixed with a toluene solution (400 mL) of 100% ethyl acetate at 40°C for 30 minutes, concentrated under reduced pressure, and then heated under vacuum. Drying at 40° C. overnight gave 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): 7-Chloroisoquinolin-1-ol (18 g, 100.2 mmol, 1.0 equiv.), cesium carbonate (65.3 g, 2 00 mmol, 2.0 equiv) and t-butyl bromoacetate (29.3 g, 22 mL, 150 mmol, 1.5 equiv) The mixture was stirred in dimethylformamide (500 mL) for 24 hours at 80° C. The solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (1000 mL) and washed with water (3×300 mL). The resulting oil was dried over sodium chloride, filtered and concentrated under reduced pressure. The material was dissolved in ethanol (500 mL) and adsorbed onto silica gel (100 g). The material was divided into four equal portions. The eluate was then run on an Interchim HPLC system (silica gel column, 330 g) with a 0-50% gradient. Purification by eluting with ethyl acetate and heptane gave the desired product as a white solid (25.8 g, 8 8% yield).

[0236] 2-(7-chloro-1-oxoisoquinolin-2(1H)-yl)acetic acid (Compound 15): Compound 14B (14.3 g, 4 A mixture of 100% ethanol (9.1 mmol) and trifluoroacetic acid (27.9 g, 18.8 mL, 245 mmol, 5.0 equiv.) was added to dichloromethane. The mixture was stirred in chloromethane (300 mL) for 48 hours at room temperature, and the solvent was removed under reduced pressure. The solid was triturated with methyl t-butyl ether (500 mL), suction filtered, and the methyl t-butyl ether The solid was dried under vacuum at room temperature overnight to give the desired product. The product was obtained as a white solid (8.1 g, 69% yield).

[0237] [ka] tert-Butyl (S)-(5-(benzyloxy)-1-bromo-2-oxopentan-3-yl)carbamate Compound (19-3): Isobutyl chloroformate (6.59 mL, 50.8 mmol, 1.5 equiv.) was dissolved in Boc-O-benzyl-L-chloroformate. Moselin (19-1) (10.5 g, 33.9 mmol, 1 equiv.) and N-methylmorpholine (5.96 mL, 54.2 mmol) To a solution of 1,2-dimethyl-3,4-trimethyl-2,4-trimethyl-1 ... Filter through Celite and concentrate under reduced pressure to give the mixed anhydride as a colorless oil (13.9 g). , which was used in the following.

[0238] Diazomethane Preparation: N-methyl-N'-nitroso-p-toluenesulfonamide (Diazald A solution of 21.8 g, 101.6 mmol, 1 equiv. (HCO3) in diethyl ether (113 mL) was added through an addition funnel. To the solution, potassium hydroxide (17.1 g, 304.8 mmol, 3 equiv.) was added to ethanol (34 mL) and water (27 mL). ) in an oil bath at 65°C. The receiving flask was cooled in an ice bath and Diazald ( When all of the Diazald® solution had been added, additional Diazald® solution was added. Ethyl ether (10 mL) was added through the addition funnel until the distillate was clear (remaining diazometabolites). After cooling to room temperature, the mixture in the distillation flask was slowly added with acetic acid to remove the yellow color. Quench until disappearance.

[0239] The freshly prepared mixed anhydride (13.9 g, 33.9 mmol, 1 equiv.) was dissolved in diethyl ether (7 The solution (5 mL) was placed in a flask with a clear-seal joint and heated 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 heated at 0° C. for 15 minutes. The mixture was stirred for 30 minutes, warmed to room temperature, and stirred for 30 minutes. The reaction was cooled to 0°C. Meanwhile, 48% H A mixture of aqueous Br (26.8 mL, 237 mmol, 7 equiv.) and acetic acid (26.8 mL) was cooled to 0°C and The mixture was stirred at 0° C. for 15 minutes, warmed to room temperature, and The mixture was stirred for 30 minutes, diluted with diethyl ether (100 mL) and washed with water (3 x 100 mL). The residue was purified by an InterChim automated chromatograph. The eluate was then passed through a chromatographic system (SorbTech silica gel column, 220 g) at a 0-40% gradient. The mixture was purified by eluting with ethyl acetate and 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) (C) Pentan-3-yl)carbamate (19-4): Potassium fluoride (5.46 g, 94.0 mmol, 4 equiv.) , compound 19-3 (9.0 g, 23.5 mmol, 1 equivalent) and 2,3,5,6-tetrafluorophenol (4.29 g To a solution of 28.8 mmol, 1.1 equiv) in DMF (120 mL) was added. After stirring at room temperature for 16 hours, the reaction was diluted with acetic acid. Dilute with ethyl acetate (100 mL) and wash 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 by Intermediate on a rChim automated chromatography system (SorbTech silica gel column, 220 g). Compound 19-4 was purified by eluting with heptane using a 10-40% gradient of ethyl acetate 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)pentane-2 -one hydrochloride (19-5): 4M HCl in 1,4-dioxane (3.5 mL, 13.8 mmol, 1.2 equiv.) was added to the reaction mixture. To a solution of compound 19-4 (5.40 g, 11.5 mmol, 1 equiv) in acetonitrile (60 mL) was added dropwise at 5°C. The mixture was then allowed to warm to room temperature and stirred overnight. LCMS indicated the reaction was not complete. An additional 4M HCl in 1,4-dioxane (2.30 mL, 9.2 mmol, 0.8 equiv.) was added, The mixture was stirred for 6 hours, at which time LCMS showed the reaction was complete. Concentration under reduced pressure gave 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) (B) 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 reacted with compound 8 (1.17 g, 4.30 mmol, 1.0 equiv.) and HOAt (0.702 g, 5.16 mmol, 1.2 equiv.) 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.) Amount of HCl was added and the mixture was stirred at room temperature overnight. LC-MS analysis showed that the reaction was complete. The mixture was diluted with ethyl acetate (40 mL) and added 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 product was run on an Interchim automated system (40 g column) using a 10-70% gradient of acetic acid. Purification by elution with ethyl acetate and heptane gave compound 19-6 (Example 1) as a bright yellow solid. (1.90 g, 71% yield) (mass analysis 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)oxa Amidopropyl amide (19-7, Example 2): Compound (1.30 g, 2.08 mmol, 1.0 equiv.) and 10% palladium (activator) The mixture was then mixed with tetrahydrofuran (18 mL) and methanol (18 mL) and then cooled to 50°C. The mixture was hydrogenated at 45 psi (310.3 kPa) for 3 hours. LC-MS analysis indicated the reaction was complete. The mixture was filtered through Celite (20 g) and additional methanol (25 mL) was added. The crude product was purified twice on an Interchim automated system. Two 40 g caps were washed with HCl. The first purification step was carried out on a 40 g silica gel column using 0-10% gradation. The material was then further separated on a second silica gel column. Purified on a 40 g gel column, eluted 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. A 0-50% gradient was applied to the system (Teledyne ISCO Column Gold C18 50G column). Purification with acetonitrile and elution with water gave 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): 60 in mineral oil Sodium hydride (6.02 g, 150.5 mmol, 2.2 equiv.) in % dispersion form was added to compound 42-1 (15.0 g , 68.4 mmol, 1 equiv) in anhydrous N,N-dimethylacetamide (100.0 mL) was added at 0°C. After stirring at 0°C for 1.5 hours, 4-chlorobenzyl bromide (15.465 g, 75.3 mmol, 1.1 equivalents) was added. The reaction was stirred at room temperature for 16 hours, and the reaction mixture was diluted with ice-cold water (200 mL) and diluted with diethyl ether. The aqueous layer was acidified with 3M HCl (30 mL) to pH 3.4 and ethyl acetate was added. The organic layer was washed with saturated brine (1 L) and water (3 x 1 L) and added sodium sulfate. The crude material was adsorbed onto Celite (30 g) and concentrated under reduced pressure. and loaded onto an Interchim automated chromatography system (Sorbtech silica gel column, 330 g). Compound 4 was purified by eluting with a 0-10% gradient of methanol with dichloromethane over 10 min. 2-2a was obtained 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 dissolved in compound 42-2a (1.7 g, 4.9 mmol, 1.0 equiv.). After stirring at room temperature for 10 minutes, methyl iodide (0.617 mL, 9.9 mmol, 2 0.0 equiv.) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (500 mL). The organic layer was extracted with sodium sulfate (10 mL) and washed with saturated brine (3×500 mL) and water (500 mL). The crude material was adsorbed onto Celite (4 g) and concentrated under reduced pressure. Im automated chromatography system (Sorbtech silica gel column, 80 g) was used to measure 0-6 Purification by eluting with 0% ethyl acetate in heptane gave compound 42-3a as a colorless oil. Obtained (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 compound 42-3a (1. 4 g, 3.9 mmol, 1.0 equiv.) was added slowly over 45 min, maintaining the temperature below -72 °C. After stirring at −78° C. for 45 minutes, acetic acid (9 mL) was added dropwise at −78° C. The reaction mixture was dissolved in saturated brine (800 mL). The organic layer was diluted with saturated aqueous bicarbonate (3×500 mL) and extracted with ethyl acetate (500 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 by Interchim automated chromatography. A 0-40% gradient of acetic acid was applied to a filtration system (Sorbtech silica gel column, 80 g). Purification by elution with ethyl acetate and heptane gave 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.) in a methacrylonitrile solution of potassium hydroxide (0.68 g, 12.0 mmol, 1.0 equiv.). The resulting mixture was stirred at room temperature for 18 hours, after which the solvent was removed under reduced pressure. The residue was concentrated under vacuum at room temperature. The potassium salt of 2,3,5,6-tetrafluorophenol was obtained as a white solid by drying at room temperature for 16 hours. Obtained (2.4 g, 97% yield).

[0248] tert-Butyl (S)-(5-((4-chlorobenzyl)oxy)-2-oxo-1-(2,3,5,6-tetrafluoroethylene) (42-5a): Sodium iodide (0.6 g, 4.0 m mol, 1.5 equivalents) and the potassium salt of 2,3,5,6-tetrafluorophenol (0.813 g, 4.0 mmol , 1.5 equiv) was 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 hours, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (500 mL) and saturated 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 using an Interchim automated chromatography system. A 0-40% gradient of ethyl acetate was applied to the stem (Sorbtech silica gel column, 80 g). The compound was purified by elution with 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 (equivalent) 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 warmed to room temperature and stirred for 24 hours. 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 was obtained 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-tetrafluoro (1-oxopropan-2-yl)-N-(2-hydroxybenzophenoxy)pentan-3-yl)amino 2 -(2,6-difluoro (phenyl)oxalamide (42-A, Example 3):

[0251] EDC·HCl (0.286 g, 1.5 mmol, 1.1 eq) was added to compound 8 (0.369 g, 1.4 mmol, 1.0 eq) and To a suspension of HOAt (0.221 g, 1.6 mmol, 1.2 equiv.) in acetonitrile (10 mL) was added HCl. The mixture was stirred at room temperature until all solids were dissolved. Compound 42-6a (0.6 g, 1.4 mmol, 1.0 eq.) Amount) and triethylamine (0.378 mL, 2.7 mmol, 2.0 equiv.) were added successively, and the mixture was heated to room temperature. The mixture was stirred at rt for 20 h. The mixture was diluted with ethyl acetate (250 mL) and added with saturated aqueous sodium bicarbonate. (250 mL) and saturated brine (250 mL). The organic layer was dried over sodium sulfate and filtered. The crude material was adsorbed onto Celite (4 g) and purified by Interchim automated chromatography. The eluate was separated by a 0-60% gradient on a chromatographic system (Sorbtech silica gel column, 80 g). Purification by eluting with ethyl acetate and heptane gave 42-A (Example 3) as a white solid (0.59 g, 65% yield), (Mass Spec 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 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 hours, 3-bromomethylthiophene (9.5 g, 53.6 mmol, 1.1 equiv.) The reaction mixture was diluted with ice-cold water (150 mL) and ethyl acetate was added. The aqueous layer was acidified with 3M HCl (16 mL) to pH 3.0 and ethyl acetate was added. The organic layer was washed with saturated brine (1 L) and water (3 x 1 L) and extracted with sodium sulfate. The crude material was adsorbed onto Celite (30 g) and concentrated under reduced pressure. , on an Interchim automated chromatography system (Sorbtech silica gel column, 330 g). Compound 42-2d was purified by eluting with 0-100% ethyl acetate in heptane. Obtained as a viscous pale 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 dissolved in compound 42-2d (2.34 g, 7.4 mmol). , 1.0 equiv.) in DMF (12 mL). After stirring at room temperature for 10 minutes, methyl iodide (0.923 mL, 1 4.8 mmol, 2.0 equiv) was added and the reaction was stirred at room temperature for 24 hours. The organic layer was diluted with saturated brine (3×250 mL) and washed with water (250 mL). The crude material was adsorbed onto Celite (5 g) and concentrated under reduced pressure. and loaded onto an Interchim automated chromatography system (Sorbtech silica gel column, 80 g). Compound 42-3d was purified by eluting with heptane using a 0-50% gradient of ethyl acetate over 10 min. Obtained 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 hexane (9.5 mL, 15.2 mmol, 5.0 equiv.) was dissolved in TH Diisopropylamine (2.34 mL, 16.7 mmol, 5.5 equiv.) in F (15 mL) was added at -78 °C. The reaction mixture was warmed to 0 °C for 5 min, cooled to -78 °C, and dissolved in compound 42-3d (1.0 g) in THF (15 mL) at -78 °C. , 3.0 mmol, 1.0 equiv) was added slowly 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 diluted with ethyl acetate (500 mL). The organic layer was washed with saturated bicarbonate solution (3 x 500 mL) and water (250 mL). The ethyl layer was dried over sodium sulfate (100 g) and concentrated under reduced pressure. The gel was adsorbed onto silica gel (4 g) and analyzed by an Interchim automated chromatography system (Sorbtech silica gel). Purification was performed on a column (80 g) using a 0-80% gradient of ethyl acetate with heptane elution. Compound 42-4d was obtained as a light yellow oil (0.938 g, 82% yield).

[0255] tert-Butyl (S)-(2-oxo-1-(2,3,5,6-tetrafluorophenoxy)-5-(thiophene-3- (Iylmethoxy)pentan-3-yl)carbamate (42-5d): Sodium iodide (0.56 g, 3.7 m mol, 1.5 equivalents) and the potassium salt of 2,3,5,6-tetrafluorophenol (0.763 g, 3.7 mmol , 1.5 equiv.) was 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 hours, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (500 mL). The organic layer was dried over sodium sulfate (50 g), filtered, and The crude material was concentrated under reduced pressure and adsorbed onto Celite (4 g) and purified by Interchim automated chromatography. A 0-40% gradient was applied to a chromatography system (Sorbtech silica gel column, 80 g). Purification by elution with ethyl acetate in heptane gave compound 42-5d as a light yellow oil (0.75 4 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 (equivalent) 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 hours. The mixture was concentrated under reduced pressure. The solid was triturated with heptane (3 x 10 mL), decanted, and dried under vacuum to give Compound 42-6d was obtained 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-tetramethyl- (trifluorophenoxy)-5-(thiophen-3-ylmethoxy)pentan-3-yl)amino)propanol (42-D, Example 4): EDC·HCl (0.146 g, 0.8 mmol, 1.1 equiv.) acetone of compound 8 (0.189 g, 0.7 mmol, 1.0 equiv.) and HOAt (0.113 g, 1.0 mmol, 1.2 equiv.) 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) were added. 1, 2.0 equiv.) was added successively and the mixture was stirred at room temperature for 20 hours. The mixture was diluted with 250 mL of saturated sodium bicarbonate solution and washed with 250 mL of saturated brine. The organic layer was dried over sodium sulfate (100 g), filtered, and concentrated under reduced pressure. The eluate was adsorbed onto lysates (3 g) and analyzed using an Interchim automated chromatography system (Sorbtech series). The solution was loaded onto a gel column (25 g) and eluted with heptane using a 0-90% gradient of ethyl acetate. Purification gave 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 dissolved in N-(tert-butoxycarbonyl )-O-methyl-L-homoserine (57-1) (1.0 g, 4.29 mmol, 1 equiv.) and N-methylmorpholine (0.7 To a solution of 150 mL of HCl (5 mL, 6.86 mmol, 1.6 equiv.) in THF (18 mL) was added dropwise at -10°C. The mixture was stirred at -10°C for 20 min. Afterwards, the reaction was filtered through Celite and concentrated under reduced pressure to give the combined anhydride as a colorless oil. was obtained and used in the following:

[0259] Diazomethane Preparation: N-methyl-N'-nitroso-p-toluenesulfonamide (Diazald A solution of 2.76 g, 12.87 mmol, 1 equiv. (HCOOH) in diethyl ether (10 mL) was added via an addition funnel. To prepare the reaction mixture, potassium hydroxide (2.54 g, 38.6 mmol, 3 equiv.) was added to ethanol (6 mL) and water (5 mL). The mixture was added to a receiver to collect the ethereal solution of diazomethane in an oil bath at 65°C. The flask was cooled in an ice bath and Diazald (registered trademark) 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 was added. Ether (3 mL) was added through the addition funnel until the distillate was clear (no residual diazomethane). After cooling to room temperature, the mixture in the distillation flask was slowly diluted with acetic acid until the yellow color disappeared. Quenched until.

[0260] The freshly prepared mixed anhydride (1.37 g, 4.29 mmol, 1 equiv.) in diethyl ether (2 The solution (5 mL) was placed in a flask with a ground joint and cooled to 0°C in an ice bath. A freshly prepared diazomethane ethereal solution (approximately 12.87 mmol, 3 equiv.) was added to the addition funnel. The resulting mixture was stirred at 0° C. for 15 minutes, and then cooled. The reaction was allowed to warm to room temperature and stirred for 30 minutes. The reaction was cooled to 0°C. Meanwhile, 48% aqueous HBr (4.0 A mixture of (mL, 30.0 mmol, 7 equiv.) and acetic acid (4.0 mL) was cooled to 0°C and the above reaction mixture was The mixture was stirred at 0° C. for 15 minutes, warmed to room temperature, and stirred for 30 minutes. The mixture was diluted with diethyl ether (10 mL), washed with water (3 × 15 mL), and diluted with sodium sulfate. The residue was purified by automated chromatography on an InterChim column. A 0-40% gradient of acetic acid ethanol was applied to a 120 g SorbTech silica gel column. Purification by eluting with heptane at 25° C. gave 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)penta[4-(2-methyl ... (3-phenyl-3-yl)carbamate (57-4): Potassium fluoride (502 mg, 8.64 mmol, 4 equiv.) was added to compound 5 7-3 (0.67 g, 2.16 mmol, 1 equiv.) and 2,3,5,6-tetrafluorophenol (395 mg, 2.38 After stirring at room temperature for 16 hours, the reaction was diluted with ethyl acetate (1 The mixture was diluted with saturated aqueous sodium bicarbonate (20 mL) and washed with saturated aqueous sodium chloride (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using an InterChim automated column. A 0-40% gradient was measured using a hydrolysis chromatography system (SorbTech silica gel column, 120 g). Purification by gradient ethyl acetate to heptane elution gave compound 57-4 as a colorless oil (0 0.53 g, 62% yield).

[0262] (S)-3-amino-5-methoxy-1-(2,3,5,6-tetrafluorophenoxy)pentan-2-one salt Acid salt (57-5): 4M HCl in 1,4-dioxane (0.34 mL, 1.34 mmol, 1.0 equiv.) was added to compound 57- To a solution of 4 (0.53 g, 1.34 mmol, 1 equiv.) in acetonitrile (10 mL) was added dropwise at 5° C. The mixture The mixture was allowed to warm to room temperature and stirred overnight. LCMS showed that the reaction was not complete. 4M HCl in 1,4-dioxane (0.34 mL, 1.34 mmol, 1.0 equiv.) was added to the mixture, and the mixture was stirred for 6 h. The mixture was concentrated under reduced pressure to give the compound 2. Product 57-5 was obtained 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-tetramethyl- Trifluorophenoxy)pentan-3-yl)amino)-1-oxopropan-2-yl)oxal Amide (Compound 57-A, Example 5): EDC·HCl (0.305 g, 1.59 mmol, 1.1 equiv.) was added to compound 8 (0 HOAt (0.393 g, 1.446 mmol, 1.0 equiv.) and HOAt (0.237 g, 1.74 mmol, 1.2 equiv.) 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.) (equivalents) were added successively and the mixture was stirred at room temperature overnight. LC-MS analysis indicated that the reaction was complete. The mixture was diluted with ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (20 mL) and saturated aqueous sodium bicarbonate (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by running it on an Interchim automated chromatography system (120 g column). Purification was performed by eluting with heptane using a 0-60% gradient of ethyl acetate to give 57-A (Example 5) as a white solid. Obtained as a solid (0.51 g, 64% yield) (mass spec m / z=550.1 (M+H)).

[0264] Example 6 [ka] Benzyl (S)-6-bromo-4-((tert-butoxycarbonyl)amino)-5-oxohexanoate Compound (58-3): Isobutyl chloroformate (5.84 mL, 45.0 mmol, 1.5 equiv.) was reacted with (S)-5-(benzyloxy)- (tert-butoxycarbonyl)-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). After stirring at -10°C for 20 minutes, the reaction mixture was filtered through Celite and Concentration at rt gave the mixed anhydride as a colorless oil which was used in the next step.

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

[0266] The above freshly prepared mixed anhydride (12.70 g, 30.0 mmol, 1 equiv.) was dissolved in diethyl ether ( The solution (110 mL) was placed in a flask with a ground joint and cooled to 0°C in an ice bath. A freshly prepared diazomethane ethereal solution (approximately 90.0 mmol, 3 equiv.) was added to the addition funnel. The resulting mixture was stirred at 0° C. for 15 minutes, and then cooled. The reaction was allowed to warm to room temperature and stirred for 30 minutes. The reaction was cooled to 0°C. Meanwhile, 48% aqueous HBr (24 A mixture of (210.0 mL, 210.0 mmol, 7 equiv.) and acetic acid (24.0 mL) was cooled to 0°C and the above reaction mixture was The mixture was stirred at 0° C. for 15 minutes, warmed to room temperature, and stirred for 30 minutes. The mixture was diluted with diethyl ether (80 mL), washed with water (3 × 100 mL), and The residue was purified by automated chromatography on an InterChim column. A 0-40% gradient of acetic acid ethanol was applied to a 220 g SorbTech silica gel column. Purification by eluting with heptane at 25° C. gave 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-tetrafluoroethylene) (4.83 g, 83.08 mmol, 4 equiv.) hexanoate (58-4) , compound 58-3 (8.6 g, 20.77 mmol, 1 equivalent) 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 hours, the reaction Dilute with ethyl acetate (150 mL), 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 The mixture was run on an InterChim automated chromatography system (SorbTech silica gel column, 220 g). Compound 58-4 was purified by eluting with heptane using a 0-40% gradient of ethyl acetate to give a colorless Obtained as an oil (6.13 g, 59% yield).

[0268] (S)-3-amino-5-methoxy-1-(2,3,5,6-tetrafluorophenoxy)pentan-2-one salt Acid salt (58-5): 4M HCl in 1,4-dioxane (3.1 mL, 12.3 mmol, 1.0 equiv.) was added to compound 58-4. (6.13 g, 12.28 mmol, 1 equiv.) in acetonitrile (80 mL) was added dropwise at 5° C. The mixture was allowed to warm to room temperature and stirred overnight. LCMS showed that the reaction was not complete. 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. The mixture was stirred for 1 hour (at which time LCMS showed the reaction was complete). Compound 58-5 was obtained as a light yellow solid (6.2 g, 100% yield).

[0269] Benzyl (S)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamide) )propanamido)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoate(58- 6): EDC HCl (0.483 g, 2.52 mmol, 1.1 equiv.) was dissolved in compound 8 (0.623 g, 2.29 mmol, 1.0 equiv.). A suspension of HOAt (0.374 g, 2.75 mmol, 1.2 equiv.) and HOAt (0.374 g, 2.75 mmol, 1.2 equiv.) in acetonitrile (15 mL) was added. 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 sequentially, and the mixture The mixture was stirred at room temperature overnight. LC-MS analysis showed that the reaction was complete. The mixture was diluted with ethyl acetate ( The mixture was diluted with saturated aqueous sodium bicarbonate (30 mL) and washed with saturated aqueous sodium chloride (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Interchim An automated chromatography system (80 g column) was run with a 0-60% gradient of acetic acid. Purification by elution with ethyl acetate and heptane gave compound 58-6 as a white solid (0.72 g, 48% yield). rate).

[0270] (S)-4-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamide))propanol 5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid (compound 58-A, Example 6: Compound 58-6 (0.72 g, 1.10 mmol, 1 eq.) and 10% palladium on carbon (0.07 A suspension of 2 g (50% wet) in a mixture of THF (11 mL) and ethyl acetate (3.5 mL) was heated at 25 psi (172. The reaction mixture was hydrogenated at 4 kPa for 2 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was subjected to an Interchim automated chromatography system (120 g column) to obtain a 0-1 Purification using a dichloromethane gradient with 0% methanol gave compound 58-A (Example 6). was obtained 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 Compound 25-1 (6.18 g, 20.0 mmol, 1.0 equiv.) in DMF (2 After stirring at room temperature for 15 minutes, methyl iodide (2.49 mL, 40.0 mmol, 2.0 equiv.) was added to the solution. The reaction mixture was diluted with ethyl acetate (100 mL) and stirred at room temperature for 16 hours. (3×50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over sodium sulfate and The crude material was purified by filtration and concentrated under reduced pressure using an Interchim automated chromatography system. The column was loaded onto a Sorbtech silica gel column (120 g) and eluted with a 0-35% gradient of ethyl acetate. Purification by elution with butane gave 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 mmol) in tetrahydrofuran (10 mL). (equivalent) to a solution of compound 56-1 (1.29 g, 4.0 mmol, 1.0 equiv.) in tetrahydrofuran (20 mL). The freshly prepared lithium diisopropylamide solution was added slowly at -78°C. The solution was added slowly over 30 minutes while maintaining the temperature below -70°C. After stirring at -78°C for 45 minutes, Acetic acid (1.7 mL) in trihydrofuran (10 mL) was slowly added while maintaining the temperature at -65°C. After stirring at -78°C for 10 minutes, 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 x 50 mL) and water (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. m automated chromatography system (Sorbtech silica gel column, 120 g) Compound 56-2 was purified by eluting with heptane at 0% ethyl acetate gradient to give a bright yellow oil. (0.92 g, 67% yield).

[0273] Lithium diisopropylamide solution preparation: 1.6 M n-BuLi in hexane (12.25 mL, 20. 0 mmol, 5.0 equiv.) in THF (20 mL) The reaction was warmed to 0°C for 30 minutes and cooled to -40°C.

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

[0275] (S)-3-Amino-5-(benzyloxy)-1-(2,3,5,6-tetrafluorophenoxy)pentane-2 -one hydrochloride (25-5): 4M HCl in 1,4-dioxane (0.80 mL, 3.20 mmol, 1.2 equiv.) was added to the reaction mixture. Compound 25-4 (1.25 g, 2.65 mmol, 1.0 equiv.) was added dropwise to a solution of 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. Additionally, 4M HCl in 1,4-dioxane (0.53 mL, 2.12 mmol, 0.8 equiv.) was added. was added and the mixture was stirred for 6 hours, at which time LCMS showed the reaction was complete. 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) (B) 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 dissolved in 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 ) suspension. The mixture was stirred at room temperature until all solids were dissolved. Compound 25-5 (1 (0.08 g, 2.65 mmol, 1.0 equiv.) and triethylamine (0.74 mL, 5.3 mmol, 2.0 equiv.) 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 added 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 product was run on an Interchim automated system (120 g column) using a 0-60% gradient of acetic acid. Purification by elution with ethyl acetate and heptane gave compound 19-6 as a light 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)oxa Amidopropyl amide (19-7): A solution of 19-6 (1.02 g) in tetrahydrofuran (10 mL) and methanol (10 mL) was prepared. , 1.63 mmol, 1.0 equiv) and 10% palladium on activated carbon (102 mg, 50% wet) The mixture was hydrogenated at 45 psi (310.3 kPa) for 3 hours. 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 run on an Interchim automated system (120 g column) using a 0-80% gradient. The mixture was purified by eluting with ethyl acetate and heptane to give compound 19-7 as a white solid (350 mg, 4 0% yield).

[0278] (S)-3-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamide))propanol 4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentylphenylcarbonyl Phenyl chloroformate (56-A, Example 7): Phenyl chloroformate (0.13 mL, 1.05 mmol, 1.0 equiv.) was added to the reaction mixture. Compound 19-7 (565 mg, 1.05 mmol, 1.0 eq.), pyridine (0.84 mL, 10.5 mmol, 10.0 eq.) and and 4-dimethylaminopyridine (81 mg, 0.66 mmol, 0.63 equiv.) in 12 mL of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. Additional phenylchloroform was added to the mixture at 0°C. Mate (0.20 mL, 1.58 mmol, 1.5 equiv) was added to the reaction. The reaction mixture was stirred at room temperature for 2 h ( (LCMS analysis indicated the reaction was complete at that time.) The reaction mixture was diluted with water (2 x 10 mL) and stirred. The combined aqueous layers were extracted with dichloromethane (2 x 10 mL). The combined organic layers were The organic layer was washed with saturated aqueous ammonium chloride (2 × 10 mL) and saturated brine (10 mL). The residue was purified by InterChim automated chromatography. A 0-25% gradient was applied to a 120 g SorbTech silica gel column. The product was purified by eluting with dichloromethane in ethyl acetate. Trituration gave compound 56-A (Example 7) as a yellow solid (160 mg, 17% yield) (quality Quantitative analysis m / z=656.2(M+H)).

[0279] Example 8 (S)-3-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamide))propanol benzoic acid ester ( 56-B, Example 8): Benzoyl chloride (0.34 mL, 2.97 mmol, 2.5 equiv.) was added to compound 19-7 (635 mg , 1.19 mmol, 1.0 equiv), pyridine (0.95 mL, 11.9 mmol, 10.0 equiv) and 4-dimethylamine To a solution of 12 mL of benzopyridine (91 mg, 0.75 mmol, 0.63 equiv.) in dichloromethane was added at 0° C. After stirring at room temperature for 2 hours, the reaction mixture was washed with water (2 x 10 mL). The combined organic layers were extracted with saturated aqueous ammonium chloride (2 x 10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on an InterChim automated chromatography system (SorbTech silica gel) The column was loaded with 120 g of ethyl acetate and eluted with dichloromethane using a 0-25% gradient. The product was triturated with diethyl ether (10 mL) to give compound 56-B (exemplified Example 8) was obtained 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): Triethylamino A solution of 2,6-difluoroaniline (25.0 g, 193.8 mmol, 1 equiv.) in 27.2 mL of 2,6-difluoroaniline (25.0 g, 193.8 mmol, 1 equiv.) was added to the reaction mixture. A solution of ethyl oxalyl chloride (21.6 mL, 193.8 mL) in THF (1 L) was added at 0-5°C. (mmol, 1 equiv.) was added dropwise over 60 min, maintaining the temperature below 5° C. The reaction was allowed to warm to room temperature. The reaction was warmed and stirred for 24 hours. The reaction was filtered through Celite and the Celite was washed with methyl t-butyl ether. Wash the combined organic layers with 1N HCl (2 x 200 mL) and water (400 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the desired product. It was obtained as a beige oil (44.8 g, quantitative yield).

[0281] 2-((2,6-difluorophenyl)amino)-2-oxoacetic acid (4): 1N lithium hydroxide (233 mL, 23 3 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 hours, the reaction was cooled to 0°C and acidified with concentrated HCl to pH 2. The reaction mixture was saturated with sodium chloride and extracted with ethyl acetate (6 x 200 mL). The organic layer was 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 compound 4 (2.99 g , 14.88 mmol, 1.0 equiv.), 1-hydroxy-7-azabenzotriazole (2.85 g, 20.83 mmol The mixture was stirred at room temperature until all the solids were dissolved. Benzyl glycinate hydrochloride (3.0 g, 14.88 mmol, 1.0 equiv.) and N- Methylmorpholine (3.01 g, 29.76 mmol, 2.0 equiv) was 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 extracted with acetic acid. The mixture was diluted with ethyl acetate (60 mL) and water (20 mL). The two layers were separated and the aqueous layer was washed with ethyl acetate (2×15 mL). The combined organic layers were washed with saturated brine (100 mL), dried over sodium sulfate, and The residue was purified by filtration using an InterChim automated chromatography system (So Dichloromethane was extracted with 0-5% ethyl acetate on a rbTech silica gel column (220 g). The product was purified by elution with methane. The column was loaded onto a SorbTech silica gel column (220 g) and eluted with a 0-50% gradient of ethyl acetate. Purification by elution with butane gave compound 60-1 as a white solid (1.90 g, 37% yield).

[0283] (2-((2,6-difluorophenyl)amino)-2-oxoacetyl)glycine(60-2):tetrahydro Compound 60-1 (1.86 g, 5.34 mmol, 1.0 mL) in toluene (11.5 mL) and ethyl acetate (3.5 mL) A mixture of 10% palladium (186 mg, 50% wet) and 10% palladium on activated carbon (186 mg, 50% wet) was heated to 25 psi (172. The mixture was hydrogenated at 4 kPa for 2 h. LC-MS analysis showed the reaction was complete. Filtration through light (15 g) gave compound 60-1 as a white solid (1.31 mg, 95% yield).

[0284] Benzyl (S)-4-(2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamide)) a Cetoamido))-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 compound 60-2 (0.474 g, 1.84 mmol, 1.0 equiv) and 1-hydroxy-7-azabenzotriazole (0.301 g, 2.21 mm ol, 1.2 equiv.) in acetonitrile (15 mL). The mixture was allowed to stand at room temperature until all solids Compound 58-5 (0.80 g, 1.84 mmol, 1.0 equiv.) and triethylamine were added to the solution and stirred until the solution was dissolved. Mine (0.51 mL, 3.68 mmol, 2.0 equiv.) was added sequentially and the mixture was stirred at room temperature overnight. MS analysis indicated the reaction was complete. The mixture was diluted with ethyl acetate (40 mL) and saturated carbonate The organic layer was washed with aqueous sodium bicarbonate (30 mL) and saturated brine (30 mL). The organic layer was dried over sodium sulfate. The crude product was purified by Interchim automated chromatography. The system (120 g column) was loaded and eluted with heptane using a 0-70% gradient of ethyl acetate. The resulting mixture was purified 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 tetrafluorophenoxy)-5-oxo-6-(2,3,5,6-tetrafluorophenoxy)hexanoic acid (60-A, Example 9): ... Compound 60-3 (0.42 g, 0.657 mmol, 1 mL) in dihydrofuran (15 mL) and ethyl acetate (5 mL) A mixture of 1.0 eq.) and 10% palladium on activated carbon (42 mg, 50% wet) was heated at 25 psi (172 The mixture was hydrogenated at 0.4 kPa for 2 hours. LC-MS analysis indicated the reaction was complete. The crude product was filtered through light (15 g) and washed with additional methanol (25 mL). A 0-10% gradient was run on an Erchim automated chromatography system (80 g column). The product was purified by eluting with dichloromethane in diethyl ether (10 mL ) to give compound 60-A (Example 9) as a white solid (210 mg, 58% yield) Mass spectrometry m / z=550.1(M+H)).

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

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

[0288] The freshly prepared mixed anhydride (12.7 g, 30.0 mmol, 1 equiv.) was dissolved in diethyl ether (1 The solution (10 mL) was placed in a flask with a ground joint and cooled to 0°C in an ice bath. A freshly prepared diazomethane ethereal solution (approximately 90.0 mmol, 3 equiv.) was added to the addition funnel. The resulting mixture was stirred at 0° C. for 15 minutes, and then cooled. The reaction was allowed to warm to room temperature and stirred for 30 minutes. The reaction was cooled to 0°C. Meanwhile, 48% aqueous HBr (24 A mixture of (210.0 mL, 210.0 mmol, 7 equiv.) and acetic acid (24.0 mL) was cooled to 0°C and the above reaction mixture was The mixture was stirred at 0° C. for 15 minutes, warmed to room temperature, and stirred for 30 minutes. The mixture was diluted with diethyl ether (120 mL), washed with water (3 x 120 mL), and The residue was purified by automated chromatography on an InterChim column. A 0-30% gradient of acetic acid was applied to a 220 g SorbTech silica gel column. Purification by elution with ethyl acetate and heptane gave compound 58-3 as a white solid (7.26 g, 59% yield). rate).

[0289] Benzyl (S)-6-(3,5-bis(trifluoromethyl)phenoxy)-4-((tert-butoxycarbonyl) (Nyl)amino)-5-oxohexanoate (59-1): Potassium fluoride (3.93 g, 67.6 mmol, 4 equiv.) Amount of 58-3 (7.0 g, 16.9 mmol, 1 equivalent) and 3,5-bis(trifluoromethyl)phenyl To a solution of ethanol (2.8 mL, 18.6 mmol, 1.1 equiv.) in DMF (70 mL) was added. 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 by chromatography on an InterChim automated chromatography system (RediSepRf silica gel column, 220 g) and purified using a 0-25% gradient of ethyl acetate with heptane elution to give compound 59. -1 was obtained as a white solid (6.0 g, 63% yield).

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

Claims

1. A compound having formula I, or an enantiomer thereof, or a mixture of said enantiomers, a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate or polymorph thereof: 【Chemistry 1】 (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 group, when present, contains 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. Re; Each Q 1 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 groups; each Q 2 are 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, chloroalkyl, aryl, heteroaryl or heterocyclyl; Each R c is independently hydrogen or alkyl; Each R d are independently alkyl, aryl, cycloalkyl, heteroaryl, Tetracyclyl 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; teeth ii) R 1 and R 2 are optionally substituted along with the carbon atom on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from to be selected; 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 Replace with It has been; R 10 is alkylene; Z 1 And Z 2 is selected as follows: i) Z 1 is hydrogen or alkyl; and Z 2 is an aryl, cycloalkyl, or heterocyclic group. aryl or heterocyclyl, each of which is optionally 1 to 4 substituents Q 3 Replaced by or ii) Z 1 and Z 2 are optionally substituted together with the nitrogen atom on which they are substituted A saturated or unsaturated ring C is formed, and the substituents on the ring C, if present, are 1 to 3 Q 3 Select from to be selected; 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with RenoQ 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, a alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl. the law of nature; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 of alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, a alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl. the law of nature; J is O or S; and t is between 0 and 2).

2. X and Y are selected as follows: i) X is C=O; and Y is -R a OR b or ii) X is -O-; Y is hydrogen, alkyl, aryl, arylalkyl, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with 1 or 2 groups selected from 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, If present, it is one to three 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. Re; 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 represents a cycloalkyl ring together with the carbon atom on which they are substituted. Form; 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 selected from halo, alkyl and halo. substituted with 1 to 4 substituents selected from alkyl; 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 Replace with It has been; 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.

3. A compound according to claim 1 or 2 having the formula II, or an enantiomer or an enantiomer thereof. A mixture of thiomers or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or encapsulant thereof. Conjugates or polymorphs: 【Chemistry 2】 。

4. X and Y are selected as follows: i) X is C=O; and Y is -R a OR b or ii) X is -O-; Y is hydrogen, alkyl, aryl, arylalkyl, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with 1 or 2 groups selected from 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 represents a cycloalkyl ring together with the carbon atom on which they are substituted. Form; 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 selected from halo, alkyl and halo. substituted with 1 to 4 substituents selected from alkyl; 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 Replace with It has been; 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 The compound according to any one of claims 1 to 3, wherein is hydroxyl or alkyl.

5. R 9 is phenyl or pyrimidinyl, each of which is optionally selected from halo, alkyl and haloa.

5. The compound according to claim 1, wherein the compound is substituted with 1 to 4 substituents selected from alkyl, aryl ... The compounds listed above.

6. A compound according to any one of claims 1 to 3 having the formula II, or an enantiomer or or a mixture of said enantiomers, or a pharma- ceutical acceptable salt, solvate, or hydrate thereof. , cocrystals, clathrates or polymorphs: 【Chemistry 3】 (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 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 groups; each Q 2 are 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, chloroalkyl, aryl, heteroaryl or heterocyclyl; Each R c is independently hydrogen or alkyl; Each R d are independently alkyl, aryl, cycloalkyl, heteroaryl, Tetracyclyl 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; teeth ii) R 1 and R 2 are optionally substituted along with the carbon atom on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from to be selected; 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, which optionally contains 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with RenoQ 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, a alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl. the law of nature; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 of alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, a alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl. the law of nature; J is O or S; t is 0 to 2; and m is 0 to 4).

7. A compound of claim 6 having the formula V, or an enantiomer thereof or a mixture of said enantiomers. or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, clathrate or Polymorph: 【Chemistry 4】 。

8. X and Y are selected as follows: i) X is C=O; and Y is -R a OR b or ii) X is -O-; Y is hydrogen, alkyl, aryl, arylalkyl, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with 1 or 2 groups selected from 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 represents a cycloalkyl ring together with the carbon atom on which they are substituted. Form; 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; Each R 11 is independently 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 8. The compound of claim 7, wherein n is 0 to 2.

9. X and Y are selected as follows: i) X is C=O; and Y is -R a OR b or ii) X is -O-; Y is hydrogen, alkyl, aryl, arylalkyl, heteroaryl. alkyl or -C(O)R d wherein the alkyl and aryl groups are optionally substituted with 1 or 2 groups selected from 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 represents a cycloalkyl ring together with the carbon atom on which they are substituted. Form; 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 selected from halo, alkyl and halo. substituted with 1 to 4 substituents selected from 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; Each Q 5 is independently alkyl, halo, or haloalkyl; m is 0 to 4; and The compound according to any one of claims 1 to 4, wherein n is 0 to 2.

10. A compound according to any one of claims 1 to 4 having the formula VIII, or an enantiomer or or a mixture of said enantiomers, or a pharma- ceutical acceptable salt, solvate, or hydrate thereof. Complexes, cocrystals, clathrates or polymorphs: 【Chemistry 5】 (Wherein, each Q 6 is independently alkyl, halo, or haloalkyl; and m is 0 to 4).

11. 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 are 3- to 5-membered cycloalkyl groups together with the carbon atom on which they are substituted. Forms an alkyl 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 Replace with It has been; 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 6 is independently alkyl, halo, or haloalkyl; and 11. The compound of claim 10, wherein m is 0 to 4.

12. R 10 The compound of any one of claims 1 to 11, wherein is lower alkylene.

13. R 10 is methylene or ethylene.

14. i) R 1 and R 2 are each independently hydrogen or methyl; or ii) R 1 and R 2 are substituted on the cyclopentyl ring together with the carbon atom on which they are substituted. The compound according to any one of claims 1 to 13, which forms

15. Z 2 is phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl, isopropyl and benzoisothiazolyl; each of which is optionally selected from one or two Q 3 base and each Q 3 are independently halo, alkyl, haloalkyl, aryl alkyl, alkoxy, alkylcarbonyl, haloalkoxy, cyano, aryl, Any one of claims 1 to 6 or 10, selected from heteroaryl and aminocarbonyl The compound according to claim 1,

16. A compound according to any one of claims 1 to 4 having the formula XIV, or an enantiomer or or a mixture of said enantiomers, or a pharma- ceutical acceptable salt, solvate, or hydrate thereof. , cocrystals, clathrates or polymorphs: 【Chemistry 6】 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 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy , cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1 is any 1 to 3 Q 2 groups; each Q 2 are 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, chloroalkyl, aryl, heteroaryl or heterocyclyl; R c is 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 2 is selected as follows: i) R 1 and R 2 are each independently hydrogen, alkyl, or cycloalkyl; teeth ii) R 1 and R 2 are optionally substituted along with the carbon atom on which they are substituted. A saturated or unsaturated ring A is formed, and the substituents on ring A, if present, are 1 to 3 Q 1 Select from to be selected; 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 Replace with It has been; 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 1 1 S(O) t R 16 Each Q is selected from 3 is any 1 to 3 Q 4 are substituted with RenoQ 4 are independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl. is roalkyl; Each R 11 is independently alkylene, alkenylene, or a direct bond; Each R 12 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, a alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl. the law of nature; R 13 And R 14 is selected as follows: i) R 13 and R 14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or hetero is cyclyl; or ii) R 13 and R 14 together with the nitrogen atom on which they are substituted, optionally 1 or 2 of alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl forming a 5- or 6-membered heterocyclyl or heteroaryl ring substituted with Each R 15 are independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, alkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; Each R 16 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, a alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl. the law of nature; J is O or S; t is 0 to 2; and where n is 0 to 3.

17. 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. There; R 10 is alkylene; Each Q 3 is a halo; and 17. The compound of claim 16, wherein n is 0 to 3.

18. A compound according to any one of claims 1 or 16 to 17 having the formula XVII, or an enantiomer thereof. a mixture of said enantiomers, or a pharma- ceutical acceptable salt or solvate thereof , hydrates, cocrystals, clathrates or polymorphs: 【Chemistry 7】 (Wherein, each Q 3 is halo; n is 0 to 2; each Q 7 is a halo, or (x is 0 to 4).

19. Q 3 is chloro; n is 1; each Q 7 is fluoro and x is 4; The compound of claim 17.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and a pharma- ceutical acceptable carrier. Pharmaceutical composition.

21. A therapeutically effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 20. The method for treating a disease, the disease being a digestive disease, a respiratory disease, a cardiac disease, Vascular diseases, skin diseases, rheumatic diseases, renal diseases, autoimmune diseases, CNS diseases, inflammatory diseases, The method, wherein the disease is selected from liver disease, cancer and ophthalmological disease.

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