Caspase inhibitors and methods of use thereof

Abstract

Provided herein are compounds of formula (I), compositions comprising the compounds and method of treating various diseases with the compounds and compositions.

Description

CASPASE INHIBITORS AND METHODS OF USE THEREOF 1. RELATED APPLICATIONS

[0001] This application claims the benefit of the priority of U.S. Provisional Application No. 62 / 815,270, filed March 7, 2019. 2. FIELD

[0002] Provided herein are compounds that are caspase inhibitors, pharmaceutical compositions containing these compounds and methods of using such compounds and pharmaceutical compositions. 3. BACKGROUND

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

[0004] Caspases are a family of cysteine protease enzymes that are key mediators in the signaling pathways for apoptosis and cell disassembly (Thornberry, Chem. Biol., 1998, 5, R97- R103). These signaling pathways vary depending on cell type and stimulus, but all apoptosis pathways appear to converge at a common effector pathway leading to proteolysis of key proteins. Caspases are involved in both the effector phase of the signaling pathway and further upstream at its initiation. The upstream caspases involved in initiation events become activated and in turn activate other caspases that are involved in the later phases of apoptosis.

[0005] The substrate specificity of human ICE has been defined with the use of peptides that span the cleavage site of the enzyme. Two features of peptide substrates are essential for catalytic recognition by the enzyme. First, there is a strong preference for aspartic acid adjacent to the cleavage site, in that any substitution of this residue in the IL-1β precursor and peptide substrates leads to a substantial reduction in the rate of catalysis (Kostura, et al., Proc. Natl. Acad. Sci., 86:5227, 1989; Sleath, et al., J. Biol. Chem., 265:14526, 1990; Howard, et al., J. Immunol., 147:2964, 1991).

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

[0007] In view of the multiple uses for caspase inhibitors, there is a constant need to develop new, more effective compounds that can selectively inhibit certain caspases. 4. SUMMARY

[0008] Provided herein are compounds, pharmaceutical compositions containing the compounds and methods of use thereof in treating diseases modulated by certain caspases, including but not limited to caspase-1, caspase-4 and / or caspase-5. In one embodiment, the compounds for use in the compositions and methods provided herein are of Formula I: [Image disponible dans le document PDF, Image available in the PDF document] I or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y, Y1, Y2 and Z3 are as defined elsewhere herein.

[0009] Also provided herein are pharmaceutical compositions comprising one or more compound(s) of Formula I and a pharmaceutically acceptable carrier.

[0010] In one embodiment, provided herein are methods of treating a disease or condition associated with the inflammatory caspases (i.e. caspase-1, caspae-4 and caspase-5) and / or the modulation of the inflammatory caspases, by administering a therapeutically effective amount of a compound provided herein. Treatment can include amelioration, mitigation and / or prevention. In certain embodiments, the conditions or diseases associated with the inflammatory caspases and / or the modulation of inflammatory caspases are selected from autoimmune diseases, inflammatory diseases, CNS diseases liver diseases, respiratory diseases, cardiovascular diseases, dermatological diseases, rheumatological diseases, kidney diseases, and cancers. In certain embodiments, the conditions or diseases associated with the inflammatory caspases and / or the modulation of inflammatory caspases are selected from autoimmune diseases, inflammatory diseases, CNS diseases liver diseases, respiratory diseases, cardiovascular diseases, dermatological diseases, rheumatological diseases, kidney diseases, ophthalmological diseases and cancers.

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

[0012] In one embodiment, the compositions described herein are useful for the treatment, prevention, or amelioration of autoinflammatory diseases, neuroinflammatory diseases, autoimmune diseases and of other inflammatory conditions. In one embodiment, the compositions described herein are useful for the treatment of liver diseases in particular, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and viral hepatitis. In one embodiment, the compositions described herein are useful for the treatment of gastrointestinal diseases in particular, inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease. In one embodiment, the compositions described herein are useful for the treatment of CNS and neuroinflammatory diseases in particular multiple sclerosis (MS), Alzheimer's disease, Huntington's disease (HD), Parkinson's disease (PD) and epilepsies. The compositions described herein are useful for the treatment of cardiovascular diseases and metabolic diseases in particular myocardial infarction (MI), atherosclerosis, type 2 diabetes, and type 1 diabetes. In one embodiment, the compositions described herein are useful for the treatment of kidney diseases, in particular acute kidney injury (AKI), glomerulonephritis and lupus nephritis. In one embodiment, the compositions described herein are useful for the treatment of dermatological diseases, in particular psoriasis and acne. In one embodiment, the compositions described herein are useful for the treatment of rheumatological diseases, in particular rheumatoid arthritis (RA), osteoarthritis (OA), and gout. Exemplary specific autoimmune diseases for which a compound herein may be employed include systemic lupus erythematosus, polychondritis, scleredoma, Wegener granulomatosis, dermatomyositis, Steven- Johnson syndrome, endocrine ophthalmopathy and Graves disease.

[0013] In one embodiment, the compositions described herein are also useful for the treatment, prevention, or amelioration of asthma, steroid resistant asthma, pulmonary emphysema, and other obstructive or inflammatory diseases of the airways.

[0014] In one embodiment, the compositions described herein are also useful for the treatment, prevention, or amelioration of ophthalmological diseases such as retinal degenerative diseases such as age-related macular degeneration (AMD).

[0015] In one embodiment, the compositions described herein may be used for treatment of cancers.

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

[0017] In one embodiment, the compounds provide a therapy to improve the treatment of cancer having at least a partial inflammatory basis. In one embodiment, the compounds are useful for the treatment and / or prevention of cancer having at least a partial inflammatory basis. In another aspect, provided herein is a particular clinical dosage regimen for the administration of a compound for the treatment and / or prevention of cancer. In another aspect, the compound provided herein is administered with one or more therapeutic agent to a subject in need thereof (e.g., a chemotherapeutic agent), and / or the subject in certain embodiments, have received / will receive debulking procedures in addition to the administration of a compound herein.

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

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

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

[0021] In practicing the methods, effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds are administered to an individual exhibiting the symptoms of the disease or disorder to be treated. The amounts are effective to ameliorate or eliminate one or more symptoms of the disease or disorder.

[0022] Further provided is a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use of sale for human administration. The pack or kit can be labeled with information regarding mode of administration, sequence of drug administration (e.g., separately, sequentially or concurrently), or the like.

[0023] These and other aspects of the subject matter described herein will become evident upon reference to the following detailed description. 5. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

[0026] Figure 3 demonstrates in vivo inhibition of inflammatory cytokines IL-1 β and IL 18 by the compound of Example 6 and reference compound MCC950.

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

[0028] Figure 5 provides the effect of twice daily oral administration of the compound of Example 6 and reference compounds on colon histology parameters in a model of ulcerative colitis. 6. DETAILED DESCRIPTION OF THE EMBODIMENTS 6.1. Definitions

[0029] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0030] As used herein, "halogen" refers to all halogens, that is, a halogen substituent can be chloro (Cl), fluoro (F), bromo (Br) or iodo (I).

[0031] "hydroxyl" or "hydroxy" refer to the group —OH.

[0032] "thio" refers to the group —SH.

[0033] As used herein, "lower alkyl" means an alkane-derived radical containing from 1 to 6 carbon atoms (unless specifically defined) that includes a straight chain alkyl or branched alkyl. As used herein, the term "alkyl" means a straight or branched <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics> to <semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics> carbon chain such as methyl, ethyl, tert-butyl, iso-propyl, n-octyl, and the like. The straight chain or branched alkyl group is chemically feasible and attached at any available point to produce a stable compound. In embodiments, a lower alkyl is a straight or branched alkyl group containing from 1-6, 1-4, or 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like. A "substituted lower alkyl" denotes lower alkyl that is optionally independently substituted, unless indicated otherwise, with one or more, for example, 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of —F, —OH, —NH2, —NO2, —CN, —C(O)—OH, — <semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>OH<annotation encoding="application / x-tex">OH< / annotation>< / semantics>, —<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>— <semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>, —<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^o< / annotation>< / semantics>, —<semantics>S<annotation encoding="application / x-tex">S< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^o< / annotation>< / semantics>, —<semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^o< / annotation>< / semantics>, — <semantics>O−C(S)−Ro,−C(O)−Ro,−C(S)−Ro,−C(O)−O−Ro,−C(S)−O−Ro,−S(O)−Ro,−C(O)−C(O)−C(O)−C(O)−C(O)−C(O)−C(O)−C(O)−C(O)−C(O)−C(O)−C(O)−C(O)−C(O)−C(O)−C(O)−<annotation encoding="application / x-tex">O - C(S) - R^{o}, - C(O) - R^{o}, - C(S) - R^{o}, - C(O) - O - R^{o}, - C(S) - O - R^{o}, - S(O) - R^{o}, - C(O) - C(O) - C(O) - C(O) - C(O) - C(O) - C(O) - C(O) - C(O) - C(O) - C(O) - C(O) - C(O) - C(O) - C(O) - C(O) -< / annotation>< / semantics> <semantics>S(O)2−R∘<annotation encoding="application / x-tex">S(O)_2 - R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−N(H)−R∘<annotation encoding="application / x-tex">-C(O) - N(H) - R^{\circ}< / annotation>< / semantics>, <semantics>−C(S)−N(H)−R∘<annotation encoding="application / x-tex">-C(S) - N(H) - R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−N(R∘)−R∘<annotation encoding="application / x-tex">-C(O) - N(R^{\circ}) - R^{\circ}< / annotation>< / semantics>, <semantics>−C(S)−N(R∘)−R∘<annotation encoding="application / x-tex">-C(S) - N(R^{\circ}) - R^{\circ}< / annotation>< / semantics> <semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, <semantics>−S(O)2−N(H)−Ro<annotation encoding="application / x-tex">-S(O)_{2}-N(H)-R^{o}< / annotation>< / semantics>, <semantics>−S(O)2−N(Ro)−Ro<annotation encoding="application / x-tex">-S(O)_{2}-N(R^{o})-R^{o}< / annotation>< / semantics>, <semantics>−C(NH)−N(H)−Ro<annotation encoding="application / x-tex">-C(NH)-N(H)-R^{o}< / annotation>< / semantics>, <semantics>−C(NH)−N(Rp)−Rc<annotation encoding="application / x-tex">-C(NH)-N(R^{p})-R^{c}< / annotation>< / semantics>, <semantics>−N(H)−C(O)−R∘,−N(H)−C(S)−R∘,−N(R∘)−C(O)−R∘,−N(R∘)−C(S)−R∘,−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-C(O)-R^{\circ}, -N(H)-C(S)-R^{\circ}, -N(R^{\circ})-C(O)-R^{\circ}, -N(R^{\circ})-C(S)-R^{\circ}, -N(H)-R^{\circ}< / annotation>< / semantics> <semantics>S(O)2−R0<annotation encoding="application / x-tex">S(O)_2-R^0< / annotation>< / semantics>, <semantics>−N(R0)−S(O)2−R0<annotation encoding="application / x-tex">-N(R^0)-S(O)_2-R^0< / annotation>< / semantics>, <semantics>−N(H)−C(O)−N(H)−R0<annotation encoding="application / x-tex">-N(H)-C(O)-N(H)-R^0< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(H)−R0<annotation encoding="application / x-tex">-N(H)-C(S)-N(H)-R^0< / annotation>< / semantics>, <semantics>−N(H)−R0<annotation encoding="application / x-tex">-N(H)-R^0< / annotation>< / semantics>, <semantics>−N(H)−R0<annotation encoding="application / x-tex">-N(H)-R^0< / annotation>< / semantics>, <semantics>−N(H)−R0<annotation encoding="application / x-tex">-N(H)-R^0< / annotation>< / semantics>, <semantics>−N(H)−R0<annotation encoding="application / x-tex">-N(H)-R^0< / annotation>< / semantics>, <semantics>−N(H)−R0<annotation encoding="application / x-tex">-N(H)-R^0< / annotation>< / semantics>, <semantics>−N(H)−R0<annotation encoding="application / x-tex">-N(H)-R^0< / annotation>< / semantics>, <semantics>−N(H)−R0<annotation encoding="application / x-tex">-N(H)-R^0< / annotation>< / semantics>, <semantics>−N(H)−R0<annotation encoding="application / x-tex">-N(H)-R^0< / annotation>< / semantics>, <semantics>−N(H)−R0<annotation encoding="application / x-tex">-N(H)-R^0< / annotation>< / semantics>, <semantics>−N(H)−R0<annotation encoding="application / x-tex">-N(H)-R^0< / annotation>< / semantics>, <Formule mathématique disponible dans le document PDF, Math available in the PDF document>$-N(H)-R^$ <semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_{2}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_{2}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>— <semantics>N(H)−Ro,−N(H)−C(O)−N(Ro)−Ro,−N(H)−C(S)−N(Ro)−Ro,−N(Ro)−C(O)−Ro<annotation encoding="application / x-tex">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)-R^{o}< / annotation>< / semantics> <semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_{2}< / annotation>< / semantics>, <Formule mathématique disponible dans le document PDF, Math available in the PDF document>-N(R^{\circ})-S(O)_2-N(H)-R^{\circ}, -N(H)-S(O)_2-N(R^{\circ})-R^{\circ}, -N(R^{\circ})-S(O)_2-N(R^{\circ})-R^{\circ}, -N(R^{\circ})-S(O)_2-N(R^{\circ})-R^{\circ}, -N(R^{\circ})-S(O)_2-N(R^{\circ})-R^{\circ}, -N(R^{\circ})-S(O)_2-N(R^{\circ})-R^{\circ}, -N(R^{\circ})-S(O)_2-N(R^{\circ})-R^{\circ <semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>Rc<annotation encoding="application / x-tex">R^{c}< / annotation>< / semantics>, —<semantics>Rf<annotation encoding="application / x-tex">R^{f}< / annotation>< / semantics>, and —<semantics>Rg<annotation encoding="application / x-tex">R^{g}< / annotation>< / semantics>.

[0034] "Alkylene" refer to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation. "Lower alkylene" refer to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having from one to six carbon atoms, e.g., methylene, ethylene, propylene, n-butylene and the like. In certain embodiment, alkylene and lower alkylene is substituted with one or more substituent described in the definition of alkyl agroup above.

[0035] "Lower alkenyl" alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) and at least one, 1-3, 1-2, or only one, carbon to carbon double bond. The term "alkenyl" means a straight or branched <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics> to <semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics> carbon chain containing at least one, 1-3, 1-2, or only one, carbon to carbon double bond. Carbon to carbon double bonds can either be contained within a straight chain or branched portion. The straight chain or branched lower alkenyl group is chemically feasible and attached at any available point to provide a stable compound. Examples of lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like. A "substituted lower alkenyl" denotes lower alkenyl that is optionally independently substituted, unless indicated otherwise, with one or more, for example, 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of — <semantics>F,−OH,−NH2,−NO2,−CN,−C(O)−OH,−C(S)−OH,−C(O)−NH2,−C(S)−NH2,−C(S)−NH2,−C(S)−NH2,−C(S)−NH2,−C(S)−NH2,−C(S)−NH2,−C(S)−NH2,−C(S)−NH2,−C(S)−NH2,−C(S)−NH2,−C(S)−NH2,−C(S)−NH2,−C<annotation encoding="application / x-tex">F, -OH, -NH_2, -NO_2, -CN, -C(O) -OH, -C(S) -OH, -C(O) -NH_2, -C(S) -NH_2, -C(S) -NH_2, -C(S) -NH_2, -C(S) -NH_2, -C(S) -NH_2, -C(S) -NH_2, -C(S) -NH_2, -C(S) -NH_2, -C(S) -NH_2, -C(S) -NH_2, -C(S) -NH_2, -C(S) -NH_2, -C< / annotation>< / semantics> <semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>— <semantics>NH2,−O−Ro,−S−Ro,−O−C(O)−Ro,−O−C(S)−Ro,−C(O)−Ro,−C(S)−Ro,−C(S)−Ro,−C(S)−Ro,−C(S)−Ro,−C(S)−Ro,−C(S)−Ro,−C(S)−Ro,−C(S)−Ro,−C(S)−Ro,−C(S)−Ro,−C(S)−Ro,−C(S)−Ro,−C(S)−Ro,−C(S)−Ro,−C(S)−R<annotation encoding="application / x-tex">NH_2, -O-R^o, -S-R^o, -O-C(O)-R^o, -O-C(S)-R^o, -C(O)-R^o, -C(S)-R^o, -C(S)-R^o, -C(S)-R^o, -C(S)-R^o, -C(S)-R^o, -C(S)-R^o, -C(S)-R^o, -C(S)-R^o, -C(S)-R^o, -C(S)-R^o, -C(S)-R^o, -C(S)-R^o, -C(S)-R^o, -C(S)-R^o, -C(S)-R< / annotation>< / semantics> <Formule mathématique disponible dans le document PDF, Math available in the PDF document>$C(O) - O - R^{o}, -C(S) - O - R^{o}, -S(O) - R^{o}, -S(O)_{2} - R^{o}, -C(O) - N(H) - R^{o}, -C(S) - C(S)_{2} - R^{o}, -C(O)_{3} - R^{o}, -C(O)_{4} - R^{o}, -C(O)_{5} - R^{o}, -C(O)_{5} - R^{o}, -C(O)_{5} - R^{o}, -C(O)_$ <semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>— <semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>—<semantics>N(Rp)<annotation encoding="application / x-tex">N(R^{p})< / annotation>< / semantics>—<semantics>Rc<annotation encoding="application / x-tex">R^{c}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, — <semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>— <semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, —<semantics>N(R∘)<annotation encoding="application / x-tex">N(R^{\circ})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(R∘)<annotation encoding="application / x-tex">N(R^{\circ})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, <Formule mathématique disponible dans le document PDF, Math available in the PDF document>-N(R^{\circ})-C(O)-N(H)-R^{\circ}, -N(R^{\circ})-C(S)-N(H)-R^{\circ}, -N(H)-C(O)-N(R^{\circ})-R^{\circ}, -N(H)-R^{\circ}, -N(H)-R^{\circ}, -N(H)-R^{\circ}, -N(H)-R^{\circ}, -N(H)-R^{\circ}, -N(H)-R^{\circ}, -N(H)-R^{\circ}, -N(H)-R^{\circ}, -N(H)-R^{\circ}, -N(H)-R^{\circ}, -N(H)-R^{ <semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, — <semantics>N(H)−S(O)2−N(H)−Ro,−N(Ro)−S(O)2−NH2,−N(Ro)−S(O)2−N(H)−Ro,−N(H)−Ro<annotation encoding="application / x-tex">N(H)-S(O)_2-N(H)-R^o, -N(R^o)-S(O)_2-NH_2, -N(R^o)-S(O)_2-N(H)-R^o, -N(H)-R^o< / annotation>< / semantics> <semantics>S(O)2−N(Ro)−Ro<annotation encoding="application / x-tex">S(O)_2-N(R^o)-R^o< / annotation>< / semantics>, <semantics>−N(Ro)−S(O)2−N(Ro)−Ro<annotation encoding="application / x-tex">-N(R^o)-S(O)_2-N(R^o)-R^o< / annotation>< / semantics>, <semantics>−N(H)−Ro<annotation encoding="application / x-tex">-N(H)-R^o< / annotation>< / semantics>, <semantics>−N(Ro)−Ro<annotation encoding="application / x-tex">-N(R^o)-R^o< / annotation>< / semantics>, <semantics>−Rd<annotation encoding="application / x-tex">-R^d< / annotation>< / semantics>, <semantics>−Rf<annotation encoding="application / x-tex">-R^f< / annotation>< / semantics>, and <semantics>−−Rg<annotation encoding="application / x-tex">--R^g< / annotation>< / semantics>.

[0036] "Lower alkynyl" alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) containing at least one, or only one, carbon to carbon triple bond. The term "alkynyl" means a straight or branched <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics> to <semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics> carbon chain containing at least one, or only one, carbon to carbon triple bond. The straight chain or branched lower alkynyl group is chemically feasible and attached at any available point to provide a stable compound. Examples of alkynyl groups include ethynyl, propynyl, butynyl, and the like. A "substituted lower alkynyl" denotes lower alkynyl that is optionally independently substituted, unless indicated otherwise, with one or more, for example, 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of —F, —OH, —NH2, —NO2, <semantics>−CN,−C(O)−OH,−C(S)−OH,−C(O)−NH2,−C(S)−NH2,−S(O)2−NH2,−N(H)−N(H)−N(H)−N(H)−N(H)−N(H)−N(H)−N(H)<annotation encoding="application / x-tex">-CN, -C(O)-OH, -C(S)-OH, -C(O)-NH_2, -C(S)-NH_2, -S(O)_2-NH_2, -N(H)-N(H)-N(H)-N(H)-N(H)-N(H)-N(H)-N(H)< / annotation>< / semantics> <semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^o< / annotation>< / semantics>, —<semantics>S<annotation encoding="application / x-tex">S< / annotation>< / semantics>— <semantics>R0<annotation encoding="application / x-tex">R^{0}< / annotation>< / semantics>, <semantics>−O−C(O)−R0<annotation encoding="application / x-tex">-O-C(O)-R^{0}< / annotation>< / semantics>, <semantics>−O−C(S)−R0<annotation encoding="application / x-tex">-O-C(S)-R^{0}< / annotation>< / semantics>, <semantics>−C(O)−R0<annotation encoding="application / x-tex">-C(O)-R^{0}< / annotation>< / semantics>, <semantics>−C(S)−R0<annotation encoding="application / x-tex">-C(S)-R^{0}< / annotation>< / semantics>, <semantics>−C(O)−O−R0<annotation encoding="application / x-tex">-C(O)-O-R^{0}< / annotation>< / semantics>, <semantics>−C(S)−R0<annotation encoding="application / x-tex">-C(S)-R^{0}< / annotation>< / semantics> <semantics>O−Ro<annotation encoding="application / x-tex">O-R^{o}< / annotation>< / semantics>, <semantics>−S(O)−Ro<annotation encoding="application / x-tex">-S(O)-R^{o}< / annotation>< / semantics>, <semantics>−S(O)2−Ro<annotation encoding="application / x-tex">-S(O)_{2}-R^{o}< / annotation>< / semantics>, <semantics>−C(O)−N(H)−Ro<annotation encoding="application / x-tex">-C(O)-N(H)-R^{o}< / annotation>< / semantics>, <semantics>−C(S)−N(H)−Ro<annotation encoding="application / x-tex">-C(S)-N(H)-R^{o}< / annotation>< / semantics>, <semantics>−C(O)−N(H)−Ro<annotation encoding="application / x-tex">-C(O)-N(H)-R^{o}< / annotation>< / semantics> <semantics>N(R∘)−R∘<annotation encoding="application / x-tex">N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−C(S)−N(R∘)−R∘<annotation encoding="application / x-tex">-C(S)-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−S(O)2−N(H)−R∘<annotation encoding="application / x-tex">-S(O)_2-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−S(O)2−N(R∘)−R∘<annotation encoding="application / x-tex">-S(O)_2-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−C(NH)−R∘<annotation encoding="application / x-tex">-C(NH)-R^{\circ}< / annotation>< / semantics> <semantics>N(H)−Ro,−C(NH)−N(Rp)−Rc,−N(H)−C(O)−Ro,−N(H)−C(S)−Ro,−N(Ro)−C(O)−Ro<annotation encoding="application / x-tex">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}< / annotation>< / semantics> <semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, <semantics>−N(Ro)<annotation encoding="application / x-tex">-N(R^{o})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, <semantics>−N(H)<annotation encoding="application / x-tex">-N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, <semantics>−N(Ro)<annotation encoding="application / x-tex">-N(R^{o})< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, <semantics>−N(H)<annotation encoding="application / x-tex">-N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>— <semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(H)−Ro<annotation encoding="application / x-tex">-N(H)-C(S)-N(H)-R^{o}< / annotation>< / semantics>, <semantics>−N(Ro)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^{o})-C(O)-NH_{2}< / annotation>< / semantics>, <semantics>−N(Ro)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{o})-C(S)-NH_{2}< / annotation>< / semantics>, <semantics>−N(Ro)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{o})-C(S)-NH_{2}< / annotation>< / semantics>, <semantics>−N(Ro)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{o})-C(S)-NH_{2}< / annotation>< / semantics>, <semantics>−N(Ro)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{o})-C(S)-NH_{2}< / annotation>< / semantics>, <semantics>−N(Ro)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{o})-C(S)-NH_{2}< / annotation>< / semantics>, <semantics>−N(Ro)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{o})-C(S)-NH_{2}< / annotation>< / semantics>, <semantics>−N(Ro)−C<annotation encoding="application / x-tex">-N(R^{o})-C< / annotation>< / semantics> <semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>— <semantics>N(R∘)−R∘<annotation encoding="application / x-tex">N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−C(O)−N(R∘)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-C(O)-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−N(R∘)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−R∘<annotation encoding="application / x-tex">-N(H)-S(O)_2-R^{\circ}< / annotation>< / semantics> <semantics>N(H)−R∘<annotation encoding="application / x-tex">N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−S(O)2−N(H)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-S(O)_2-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(R∘)−R∘<annotation encoding="application / x-tex">-N(H)-S(O)_2-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−S(O)2−N(R∘)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-S(O)_2-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−Rd<annotation encoding="application / x-tex">-R^{d}< / annotation>< / semantics>, <semantics>−Re<annotation encoding="application / x-tex">-R^{e}< / annotation>< / semantics>, and <semantics>−Rg<annotation encoding="application / x-tex">-R^{g}< / annotation>< / semantics>.

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

[0038] A "substituted cycloalkyl" is a cycloalkyl that is optionally independently substituted, unless indicated otherwise, with one or more, for example, 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, —OH, —NH2, —NO2, —CN, — <semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>OH<annotation encoding="application / x-tex">OH< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>OH<annotation encoding="application / x-tex">OH< / annotation>< / semantics>, —<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>— <semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, <semantics>−N(H)−C(S)−NH2<annotation encoding="application / x-tex">-N(H)-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−NH2<annotation encoding="application / x-tex">-N(H)-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−C(NH)−NH2<annotation encoding="application / x-tex">-C(NH)-NH_2< / annotation>< / semantics>, <semantics>−O−R∘<annotation encoding="application / x-tex">-O-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^\circ< / annotation>< / semantics> <semantics>O−C(O)−R∘<annotation encoding="application / x-tex">O-C(O)-R^{\circ}< / annotation>< / semantics>, <semantics>−O−C(S)−R∘<annotation encoding="application / x-tex">-O-C(S)-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−R∘<annotation encoding="application / x-tex">-C(O)-R^{\circ}< / annotation>< / semantics>, <semantics>−C(S)−R∘<annotation encoding="application / x-tex">-C(S)-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−O−R∘<annotation encoding="application / x-tex">-C(O)-O-R^{\circ}< / annotation>< / semantics>, <semantics>−C(S)−O−R∘<annotation encoding="application / x-tex">-C(S)-O-R^{\circ}< / annotation>< / semantics>, <semantics>−S(O)−R∘<annotation encoding="application / x-tex">-S(O)-R^{\circ}< / annotation>< / semantics>, <semantics>−S(O)2−R∘<annotation encoding="application / x-tex">-S(O)_2-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−N(H)−R∘<annotation encoding="application / x-tex">-C(O)-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−C(S)−N(H)−R∘<annotation encoding="application / x-tex">-C(S)-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−N(R∘)−R∘<annotation encoding="application / x-tex">-C(O)-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−N(R∘)−R∘<annotation encoding="application / x-tex">-C(O)-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−N(R∘)−R∘<annotation encoding="application / x-tex">-C(O)-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−N(R∘)−R∘<annotation encoding="application / x-tex">-C(O)-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−N(R∘)−R∘<annotation encoding="application / x-tex">-C(O)-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−N(R∘)−R∘<annotation encoding="application / x-tex">-C(O)-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O<annotation encoding="application / x-tex">-C(O< / annotation>< / semantics> <semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, — <semantics>C(NH)−N(Rp)−Rc<annotation encoding="application / x-tex">C(NH)-N(R^p)-R^c< / annotation>< / semantics>, <semantics>−N(H)−C(O)−Ro<annotation encoding="application / x-tex">-N(H)-C(O)-R^o< / annotation>< / semantics>, <semantics>−N(H)−C(S)−Ro<annotation encoding="application / x-tex">-N(H)-C(S)-R^o< / annotation>< / semantics>, <semantics>−N(Ro)−C(O)−Ro<annotation encoding="application / x-tex">-N(R^o)-C(O)-R^o< / annotation>< / semantics>, <semantics>−N(Ro)−C(O)−Ro<annotation encoding="application / x-tex">-N(R^o)-C(O)-R^o< / annotation>< / semantics>, <semantics>−N(Ro)−C(O)−Ro<annotation encoding="application / x-tex">-N(R^o)-C(O)-R^o< / annotation>< / semantics>, <semantics>−N(Ro)−C(O)−Ro<annotation encoding="application / x-tex">-N(R^o)-C(O)-R^o< / annotation>< / semantics>, <semantics>−N(Ro)−C(O)−Ro<annotation encoding="application / x-tex">-N(R^o)-C(O)-R^o< / annotation>< / semantics>, <semantics>−N(Ro)−C(O)−Ro<annotation encoding="application / x-tex">-N(R^o)-C(O)-R^o< / annotation>< / semantics>, <semantics>−N(Ro)−C(O)−Ro<annotation encoding="application / x-tex">-N(R^o)-C(O)-R^o< / annotation>< / semantics>, <semantics>−N(Ro)−C(O)−Ro<annotation encoding="application / x-tex">-N(R^o)-C(O)-R^o< / annotation>< / semantics>, <semantics>−N(R<annotation encoding="application / x-tex">-N(R< / annotation>< / semantics> <semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, — <semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, —<semantics>N(R∘)<annotation encoding="application / x-tex">N(R^{\circ})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(R∘)<annotation encoding="application / x-tex">N(R^{\circ})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(R∘)<annotation encoding="application / x-tex">N(R^{\circ})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>— <semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, —<semantics>N(R∘)<annotation encoding="application / x-tex">N(R^{\circ})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(R∘)<annotation encoding="application / x-tex">N(R^{\circ})< / annotation>< / semantics>—<semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(R∘)<annotation encoding="application / x-tex">N(R^{\circ})< / annotation>< / semantics>— <semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−C(O)−N(R∘)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-C(O)-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−N(R∘)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-S(O)_2-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>N(R∘)−S(O)2−NH2,−N(R∘)−S(O)2−N(H)−R∘,−N(H)−S(O)2−N(R∘)−R∘,−N(R∘)−R∘<annotation encoding="application / x-tex">N(R^{\circ})-S(O)_2-NH_2, -N(R^{\circ})-S(O)_2-N(H)-R^{\circ}, -N(H)-S(O)_2-N(R^{\circ})-R^{\circ}, -N(R^{\circ})-R^{\circ}< / annotation>< / semantics> <semantics>S(O)2−N(Ro)−Ro<annotation encoding="application / x-tex">S(O)_2 - N(R^o) - R^o< / annotation>< / semantics>, <semantics>−N(H)−Ro<annotation encoding="application / x-tex">-N(H) - R^o< / annotation>< / semantics>, <semantics>−N(Ro)−Ro<annotation encoding="application / x-tex">-N(R^o) - R^o< / annotation>< / semantics>, <semantics>−Rd<annotation encoding="application / x-tex">-R^d< / annotation>< / semantics>, <semantics>−Re<annotation encoding="application / x-tex">-R^e< / annotation>< / semantics>, <semantics>−Rf<annotation encoding="application / x-tex">-R^f< / annotation>< / semantics>, and <semantics>−Rg<annotation encoding="application / x-tex">-R^g< / annotation>< / semantics>. For example, "C3-6" cycloalkyl" denotes cycloalkyl containing 3-6 carbon atoms, and "C3-5 cycloalkyl" denotes cycloalkyl containing 3-5 carbon atoms.

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

[0040] A "substituted heterocycloalkyl" is a heterocycloalkyl that is optionally independently substituted, unless indicated otherwise, with one or more, for example, 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, —OH, —NH2, — <semantics>NO2<annotation encoding="application / x-tex">NO_2< / annotation>< / semantics>, —<semantics>CN<annotation encoding="application / x-tex">CN< / annotation>< / semantics>, —<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>OH<annotation encoding="application / x-tex">OH< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>OH<annotation encoding="application / x-tex">OH< / annotation>< / semantics>, —<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, — <semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^o< / annotation>< / semantics>, <semantics>−S−R∘<annotation encoding="application / x-tex">-S-R^{\circ}< / annotation>< / semantics>, <semantics>−O−C(O)−R∘<annotation encoding="application / x-tex">-O-C(O)-R^{\circ}< / annotation>< / semantics>, <semantics>−O−C(S)−R∘<annotation encoding="application / x-tex">-O-C(S)-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−R∘<annotation encoding="application / x-tex">-C(O)-R^{\circ}< / annotation>< / semantics>, <semantics>−C(S)−R∘<annotation encoding="application / x-tex">-C(S)-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−O−R∘<annotation encoding="application / x-tex">-C(O)-O-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−O−R∘<annotation encoding="application / x-tex">-C(O)-O-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−O−R∘<annotation encoding="application / x-tex">-C(O)-O-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−O−R∘<annotation encoding="application / x-tex">-C(O)-O-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−O−R∘<annotation encoding="application / x-tex">-C(O)-O-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−O−R∘<annotation encoding="application / x-tex">-C(O)-O-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−O−R∘<annotation encoding="application / x-tex">-C(O)-O-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−O−R∘<annotation encoding="application / x-tex">-C(O)-O-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−O−<annotation encoding="application / x-tex">-C(O)-O-< / annotation>< / semantics> <semantics>C(S)−O−R0,−S(O)−R0,−S(O)2−R0,−C(O)−N(H)−R0,−C(S)−N(H)−R0,−C(O)−R0<annotation encoding="application / x-tex">C(S) - O - R^{0}, -S(O) - R^{0}, -S(O)_{2} - R^{0}, -C(O) - N(H) - R^{0}, -C(S) - N(H) - R^{0}, -C(O) - R^{0}< / annotation>< / semantics> <semantics>N(R0)<annotation encoding="application / x-tex">N(R^{0})< / annotation>< / semantics>—<semantics>R0<annotation encoding="application / x-tex">R^{0}< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(R0)<annotation encoding="application / x-tex">N(R^{0})< / annotation>< / semantics>—<semantics>R0<annotation encoding="application / x-tex">R^{0}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>R0<annotation encoding="application / x-tex">R^{0}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>N(R0)<annotation encoding="application / x-tex">N(R^{0})< / annotation>< / semantics>—<semantics>R0<annotation encoding="application / x-tex">R^{0}< / annotation>< / semantics>, —<semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>— <semantics>N(H)−R∘<annotation encoding="application / x-tex">N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−C(NH)−N(Rp)−Rc<annotation encoding="application / x-tex">-C(NH)-N(R^{p})-R^{c}< / annotation>< / semantics>, <semantics>−N(H)−C(O)−R∘<annotation encoding="application / x-tex">-N(H)-C(O)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−C(S)−R∘<annotation encoding="application / x-tex">-N(H)-C(S)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−C(O)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-C(O)-R^{\circ}< / annotation>< / semantics> <semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−R∘<annotation encoding="application / x-tex">-N(H)-S(O)_2-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−S(O)2−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-S(O)_2-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−C(O)−N(H)−S(O)2−R∘<annotation encoding="application / x-tex">-N(H)-C(O)-N(H)-S(O)_2-R^{\circ}< / annotation>< / semantics> <semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-C(S)-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(O)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N<annotation encoding="application / x-tex">-N< / annotation>< / semantics> <semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>— <semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>— <semantics>N(H)−R∘<annotation encoding="application / x-tex">N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−S(O)2−N(H)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-S(O)_2-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(R∘)−R∘<annotation encoding="application / x-tex">-N(H)-S(O)_2-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−S(O)2−N(R∘)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-S(O)_2-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−R∘<annotation encoding="application / x-tex">-R^{\circ}< / annotation>< / semantics>, <semantics>−R∘<annotation encoding="application / x-tex">-R^{\circ}< / annotation>< / semantics>, <semantics>−R∘<annotation encoding="application / x-tex">-R^{\circ}< / annotation>< / semantics>, and <semantics>−Rg<annotation encoding="application / x-tex">-R^{g}< / annotation>< / semantics>.

[0041] "Aryl" alone or in combination refers to a monocyclic or bicyclic ring system containing aromatic hydrocarbons such as phenyl or naphthyl, which optionally can be fused with a cycloalkyl of, for example, 5-7, or, for example, 5-6, ring members. A "substituted aryl" is an aryl that optionally is independently substituted, unless indicated otherwise, with one or more, for example, 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>, <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, <semantics>−NO2<annotation encoding="application / x-tex">-NO_2< / annotation>< / semantics>, <semantics>−CN<annotation encoding="application / x-tex">-CN< / annotation>< / semantics>, <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>—<semantics>OH<annotation encoding="application / x-tex">OH< / annotation>< / semantics>, <semantics>−C(S)<annotation encoding="application / x-tex">-C(S)< / annotation>< / semantics>—<semantics>OH<annotation encoding="application / x-tex">OH< / annotation>< / semantics>, <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, <semantics>−C(S)<annotation encoding="application / x-tex">-C(S)< / annotation>< / semantics>— <semantics>NH2,−S(O)2−NH2,−N(H)−C(O)−NH2,−N(H)−C(S)−NH2,−N(H)−S(O)2−NH2,−N(H)−S(O)2−NH2,−N(H)−S(O)2−NH2,−N(H)−S(O)2−NH2,−N(H)−S(O)2−NH2,−N(H)−S(O)2−NH2,−N(H)−S(O)2−NH2,−N(H)−S(O)2<annotation encoding="application / x-tex">NH_2, -S(O)_2 -NH_2, -N(H) -C(O) -NH_2, -N(H) -C(S) -NH_2, -N(H) -S(O)_2 -NH_2, -N(H) -S(O)_2 -NH_2, -N(H) -S(O)_2 -NH_2, -N(H) -S(O)_2 -NH_2, -N(H) -S(O)_2 -NH_2, -N(H) -S(O)_2 -NH_2, -N(H) -S(O)_2 -NH_2, -N(H) -S(O)_2< / annotation>< / semantics> <semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^o< / annotation>< / semantics>, —<semantics>S<annotation encoding="application / x-tex">S< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^o< / annotation>< / semantics>, —<semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^o< / annotation>< / semantics>, —<semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^o< / annotation>< / semantics>, —<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^o< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>— <semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>S(O)<annotation encoding="application / x-tex">S(O)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>S(O)<annotation encoding="application / x-tex">S(O)< / annotation>< / semantics>2—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, — <semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>— <semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>—<semantics>N(Rp)<annotation encoding="application / x-tex">N(R^{p})< / annotation>< / semantics>—<semantics>Rc<annotation encoding="application / x-tex">R^{c}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>— <semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, —<semantics>N(R∘)<annotation encoding="application / x-tex">N(R^{\circ})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, —<semantics>N(R∘)<annotation encoding="application / x-tex">N(R^{\circ})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, —<semantics>N(R∘)<annotation encoding="application / x-tex">N(R^{\circ})< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>— <semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−C(O)−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-C(O)-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-C(S)-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(O)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(O)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(O)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(O)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(O)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(O)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(O)-NH_2< / annotation>< / semantics>, <semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(R0)<annotation encoding="application / x-tex">N(R^0)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>R0<annotation encoding="application / x-tex">R^0< / annotation>< / semantics>, —<semantics>N(R0)<annotation encoding="application / x-tex">N(R^0)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>R0<annotation encoding="application / x-tex">R^0< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>— <semantics>N(Ro)−Ro<annotation encoding="application / x-tex">N(R^{o})-R^{o}< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(Ro)−Ro<annotation encoding="application / x-tex">-N(H)-C(S)-N(R^{o})-R^{o}< / annotation>< / semantics>, <semantics>−N(Ro)−C(O)−N(Ro)−Ro<annotation encoding="application / x-tex">-N(R^{o})-C(O)-N(R^{o})-R^{o}< / annotation>< / semantics>, <semantics>−N(Ro)−C(S)−Ro<annotation encoding="application / x-tex">-N(R^{o})-C(S)-R^{o}< / annotation>< / semantics> <semantics>N(R∘)−R∘<annotation encoding="application / x-tex">N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-S(O)_2-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−S(O)2−N(H)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-S(O)_2-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(R∘)−R∘<annotation encoding="application / x-tex">-N(H)-S(O)_2-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−S(O)2−N(R∘)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-S(O)_2-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−Rd<annotation encoding="application / x-tex">-R^{d}< / annotation>< / semantics>, —Re, —Rf, and —Rg. In some embodiments, the substituents are selected from among one to three halo, trihalomethyl, amino, protected amino, amino salts, mono-substituted amino, di-substituted amino, carboxy, protected carboxy, carboxylate salts, hydroxy, protected hydroxy, salts of a hydroxy group, lower alkoxy, lower alkylthio, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, (cycloalkyl)alkyl, substituted (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, and substituted phenylalkyl groups. In certain embodiments, the substituents are selected from among trifluoromethyl, trichloromethyl, tribromomethyl and triiodomethyl. In some embodiments, the substituents are one or more trifluoromethyl.

[0042] The term "substituted phenyl" specifies a phenyl group substituted with one or more substituents chosen from the above-identified "aryl" substituents. In embodiments, the substituents are selected from among halogen, hydroxy, protected hydroxy, cyano, nitro, trifluoromethyl, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted) amino, carboxamide, protected carboxamide, N-(lower alkyl)carboxamide, protected N-(lower alkyl)carboxamide, N,N-di(lower alkyl)carboxamide, N-((lower alkyl)sulfonyl) amino, N- (phenylsulfonyl)amino or by a substituted or unsubstituted phenyl group, such that in the latter case a biphenyl or naphthyl group results. Examples of the term "substituted phenyl" include a mono-, di-, tri- or tetra(halo)phenyl group such as 2-, 3- or 4-chlorophenyl, 2,6- dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3,5-trichlorophenyl, 2,3,5,6- tetrachlorophenyl, 2-, 3- or 4-bromophenyl, 2,6-dibromophenyl, 2,5-dibromophenyl, 3,4- dibromophenyl, 2,3,5-tribromophenyl, 2,3,5,6-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-fluorophenyland the like; a mono or di(hydroxy)phenyl group such as 2-, 3-, or 4-hydroxyphenyl, 2,4- dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 2-, 3-, or 4-nitrophenyl; a cyanophenyl group, for example, 2-,3- or 4-cyanophenyl; a mono- or di(alkyl)phenyl group such as 2-, 3-, or 4-methylphenyl, 2,4-dimethylphenyl, 2-, 3- or 4-(isopropyl)phenyl, 2-, 3-, or 4-ethylphenyl, 2-, 3- or 4-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group, for example, 2,6-dimethoxyphenyl, 2-, 3- or 4-(isopropoxy)phenyl, 2-, 3- or 4-(t-butoxy)phenyl, 3-ethoxy-4- methoxyphenyl and the like; 2 - , 3- or 4- trifiuoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxyphenyl group such as 2-, 3- or 4-carboxyphenyl or 2,4-di(protected carboxy)phenyl; a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 2-, 3- or 4-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono – or di(a minomethyl)phenyl or (protected aminomethyl)phenyl such as 2-, 3- or 4-(aminomethyl) phenyl or 2,4-(protected aminomethyl)phenyl; or a mono- or di(N- (methylsulfonylamino))phenyl such as 2, 3 or 4-(N (methylsulfonylamino))phenyl. Also, the term "substituted phenyl" represents disubstituted phenyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4- hydroxyphenyl, 2-methoxy-4- bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4- nitrophenyl, 2-hydroxy-4-chlorophenyl, and the like.

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

[0044] "Heteroaryl" alone or in combination refers to a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, e.g., 1-4, 1-3 or 1-2 heteroatoms independently selected from the group consisting of O, S, and N, which optionally can be fused with a cycloalkyl of, for example, 5-7, or, for example, 5-6, ring members. Heteroaryl also is intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced. Examples of heteroaryl groups (whether substituted or unsubstituted) include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinoxalyl, indolizinyl, benzo [b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, pyrrolidinyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, pyridyl, oxazinyl, triazinyl, thiadiazinyl tetrazolo, 1,5-[b]pyridazinyl and purinyl, as well as benzo-fused derivatives, for example, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuryl and indolyl. "Nitrogen containing heteroaryl" refers to heteroaryl wherein at least one heteroatom is N. In some instances, for example when R groups of a nitrogen combine with the nitrogen to form a 5 or 7 membered nitrogen containing heteroaryl, any heteroatoms in such 5 or 7 membered heteroaryl are N. An "optionally substituted heteroaryl" is a heteroaryl that is optionally independently substituted, unless indicated otherwise, with one or more, for example, 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, —CF3,—OH, —NH2, —NO2, — <semantics>CN,−C(O)−OH,−C(S)−OH,−C(O)−NH2,−C(S)−NH2,−S(O)2−NH2,−N(H)−<annotation encoding="application / x-tex">CN, -C(O) -OH, -C(S) -OH, -C(O) -NH_2, -C(S) -NH_2, -S(O)_2 -NH_2, -N(H) -< / annotation>< / semantics> <semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>—<semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, —<semantics>S<annotation encoding="application / x-tex">S< / annotation>< / semantics>— <semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, <semantics>−O−C(O)−R∘<annotation encoding="application / x-tex">-O-C(O)-R^{\circ}< / annotation>< / semantics>, <semantics>−O−C(S)−R∘<annotation encoding="application / x-tex">-O-C(S)-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−R∘<annotation encoding="application / x-tex">-C(O)-R^{\circ}< / annotation>< / semantics>, <semantics>−C(S)−R∘<annotation encoding="application / x-tex">-C(S)-R^{\circ}< / annotation>< / semantics>, <semantics>−C(O)−O−R∘<annotation encoding="application / x-tex">-C(O)-O-R^{\circ}< / annotation>< / semantics>, <semantics>−C(S)−R∘<annotation encoding="application / x-tex">-C(S)-R^{\circ}< / annotation>< / semantics> <semantics>O−Ro<annotation encoding="application / x-tex">O-R^{o}< / annotation>< / semantics>, <semantics>−S(O)−Ro<annotation encoding="application / x-tex">-S(O)-R^{o}< / annotation>< / semantics>, <semantics>−S(O)2−Ro<annotation encoding="application / x-tex">-S(O)_{2}-R^{o}< / annotation>< / semantics>, <semantics>−C(O)−N(H)−Ro<annotation encoding="application / x-tex">-C(O)-N(H)-R^{o}< / annotation>< / semantics>, <semantics>−C(S)−N(H)−Ro<annotation encoding="application / x-tex">-C(S)-N(H)-R^{o}< / annotation>< / semantics>, <semantics>−C(O)−N(H)−Ro<annotation encoding="application / x-tex">-C(O)-N(H)-R^{o}< / annotation>< / semantics> <semantics>N(R∘)−R∘<annotation encoding="application / x-tex">N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−C(S)−N(R∘)−R∘<annotation encoding="application / x-tex">-C(S)-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−S(O)2−N(H)−R∘<annotation encoding="application / x-tex">-S(O)_2-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−S(O)2−N(R∘)−R∘<annotation encoding="application / x-tex">-S(O)_2-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−C(NH)−R∘<annotation encoding="application / x-tex">-C(NH)-R^{\circ}< / annotation>< / semantics> <semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>—<semantics>N(Rp)<annotation encoding="application / x-tex">N(R^{p})< / annotation>< / semantics>—<semantics>Rc<annotation encoding="application / x-tex">R^{c}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>— <semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, <semantics>−N(Ro)<annotation encoding="application / x-tex">-N(R^{o})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, <semantics>−N(H)<annotation encoding="application / x-tex">-N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, <semantics>−N(Ro)<annotation encoding="application / x-tex">-N(R^{o})< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, <semantics>−N(H)<annotation encoding="application / x-tex">-N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>— <semantics>R∘<annotation encoding="application / x-tex">R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(H)−R∘<annotation encoding="application / x-tex">-N(H)-C(S)-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(O)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N<annotation encoding="application / x-tex">-N< / annotation>< / semantics> <semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(Ro)<annotation encoding="application / x-tex">N(R^{o})< / annotation>< / semantics>—<semantics>Ro<annotation encoding="application / x-tex">R^{o}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>— <semantics>N(R∘)−R∘<annotation encoding="application / x-tex">N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−C(O)−N(R∘)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-C(O)-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−C(S)−N(R∘)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-C(S)-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−R∘<annotation encoding="application / x-tex">-N(H)-S(O)_2-R^{\circ}< / annotation>< / semantics> <semantics>N(H)−R∘<annotation encoding="application / x-tex">N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(R∘)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^{\circ})-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−N(R∘)−S(O)2−N(H)−R∘<annotation encoding="application / x-tex">-N(R^{\circ})-S(O)_2-N(H)-R^{\circ}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(R∘)−R∘<annotation encoding="application / x-tex">-N(H)-S(O)_2-N(R^{\circ})-R^{\circ}< / annotation>< / semantics>, <semantics>−N(Ro)−S(O)2−N(Ro)−Ro<annotation encoding="application / x-tex">-N(R^{o})-S(O)_{2}-N(R^{o})-R^{o}< / annotation>< / semantics>, <semantics>−N(H)−Ro<annotation encoding="application / x-tex">-N(H)-R^{o}< / annotation>< / semantics>, <semantics>−N(Ro)−Ro<annotation encoding="application / x-tex">-N(R^{o})-R^{o}< / annotation>< / semantics>, <semantics>−Rd<annotation encoding="application / x-tex">-R^{d}< / annotation>< / semantics>, <semantics>−Re<annotation encoding="application / x-tex">-R^{e}< / annotation>< / semantics>, <semantics>−Rf<annotation encoding="application / x-tex">-R^{f}< / annotation>< / semantics>, and <semantics>−Rg<annotation encoding="application / x-tex">-R^{g}< / annotation>< / semantics>.

[0045] Substituents for the above optionally substituted heteroaryl rings are as denoted above, e.g., for the "aryl," and "phenyl," groups. In certain embodiments, the substituents are selected from among one to three halo, trihalomethyl, amino, protected amino, amino salts, mono-substituted amino, di-substituted amino, carboxy, protected carboxy, carboxy late salts, hydroxy, protected hydroxy, salts of a hydroxy group, lower alkoxy, lower alkylthio, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, (cycloalkyl)alkyl, substituted (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, and substituted phenylalkyl groups.

[0046] "Pyridyl," as used herein, refers to a 6-membered aromatic ring with one "N" atom. As used herein, "pyridazinyl" refers to a 6-membered aromatic ring with two "N" atoms in the 1 and 2 positions, "pyrimidyl" refers to a 6-membered aromatic ring with two "N" atoms in the 1 and 3 positions and "pyrazinyl" refers to a 6-membered aromatic ring with two "N" atoms in the 1 and 4 positions.

[0047] Substituents for the above defined "pyridyl," "pyridazinyl," "pyrimidyl" and "pyrazinyl" groups are as denoted above, e.g., for the "aryl," "phenyl," and "heteroaryl" groups. In some embodiments, the substituents are selected from among one to three halo, trihalomethyl, amino, protected amino, amino salts, mono-substituted amino, di-substituted amino, carboxy, protected carboxy, carboxylate salts, hydroxy, protected hydroxy, salts of a hydroxy group, lower alkoxy, lower alkylthio, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, (cycloalkyl)alkyl, substituted (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, and substituted phenylalkyl groups. In certain embodiments, the substituents are selected from among trifluoromethyl, trichloromethyl, tribromomethyl and triiodomethyl. In some embodiments, the substituents are one or more trifluoromethyl.

[0048] The variables Ro, Rp, Rc, Rd, Re, Rf and Rg as used in the description of optional substituents for alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, phenyl, napthyl and heteroaryl are defined as follows: • each Ro, Rp, and Rc are independently selected from the group consisting of Rd, Re, Rf, and Rg, or Rp and Rc combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, —NO2, —CN, —OH, <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, <semantics>−O−Ru<annotation encoding="application / x-tex">-O-R^u< / annotation>< / semantics>, <semantics>−S−Ru<annotation encoding="application / x-tex">-S-R^u< / annotation>< / semantics>, <semantics>−N(H)−Ru<annotation encoding="application / x-tex">-N(H)-R^u< / annotation>< / semantics>, <semantics>−N(Ru)−Ru<annotation encoding="application / x-tex">-N(R^u)-R^u< / annotation>< / semantics>, <semantics>−Rx<annotation encoding="application / x-tex">-R^x< / annotation>< / semantics>, and <semantics>−Ry<annotation encoding="application / x-tex">-R^y< / annotation>< / semantics>; • each Rd is independently lower alkyl, wherein lower alkyl is optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of fluoro, —OH, —NH2, —NO2, —CN, —C(O)—OH, —C(S)—OH, <semantics>−C(O)−NH2,−C(S)−NH2,−S(O)2−NH2,−N(H)−C(O)−NH2,−N(H)−C(S)−NH2<annotation encoding="application / x-tex">-C(O)-NH_2, -C(S)-NH_2, -S(O)_2-NH_2, -N(H)-C(O)-NH_2, -N(H)-C(S)-NH_2< / annotation>< / semantics> <semantics>NH2,−N(H)−S(O)2−NH2,−C(NH)−NH2,−O−Rk,−S−Rk,−O−C(O)−Rk,−<annotation encoding="application / x-tex">NH_2, -N(H)-S(O)_2-NH_2, -C(NH)-NH_2, -O-R^k, -S-R^k, -O-C(O)-R^k, -< / annotation>< / semantics> <semantics>O−C(S)−Rk<annotation encoding="application / x-tex">O - C(S) - R^k< / annotation>< / semantics>, <semantics>−C(O)−Rk<annotation encoding="application / x-tex">-C(O) - R^k< / annotation>< / semantics>, <semantics>−C(S)−Rk<annotation encoding="application / x-tex">-C(S) - R^k< / annotation>< / semantics>, <semantics>−C(O)−O−Rk<annotation encoding="application / x-tex">-C(O) - O - R^k< / annotation>< / semantics>, <semantics>−C(S)−O−Rk<annotation encoding="application / x-tex">-C(S) - O - R^k< / annotation>< / semantics>, <semantics>−S(O)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−<annotation encoding="application / x-tex">-S(O) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) -< / annotation>< / semantics> <semantics>Rk<annotation encoding="application / x-tex">R^{k}< / annotation>< / semantics>, <semantics>−S(O)2−Rk<annotation encoding="application / x-tex">-S(O)_{2}-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(H)−Rk<annotation encoding="application / x-tex">-C(O)-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−C(S)−N(H)−Rk<annotation encoding="application / x-tex">-C(S)-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(O)-N(R^{k})-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(O)-N(R^{k})-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(O)-N(R^{k})-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(O)-N(R^{k})-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(O)-N(R^{k})-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(O)-N(R^{k})-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(<annotation encoding="application / x-tex">-C(O)-N(< / annotation>< / semantics> <semantics>C(S)−N(Rk)−Rk<annotation encoding="application / x-tex">C(S)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−S(O)2−N(H)−Rk<annotation encoding="application / x-tex">-S(O)_2-N(H)-R^k< / annotation>< / semantics>, <semantics>−S(O)2−N(Rk)−Rk<annotation encoding="application / x-tex">-S(O)_2-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−C(NH)−N(H)−Rk<annotation encoding="application / x-tex">-C(NH)-N(H)-R^k< / annotation>< / semantics>, <semantics>−C(NH)−N(Rm)−Rn<annotation encoding="application / x-tex">-C(NH)-N(R^m)-R^n< / annotation>< / semantics>, <semantics>−N(H)−C(O)−Rk<annotation encoding="application / x-tex">-N(H)-C(O)-R^k< / annotation>< / semantics>, <semantics>−N(H)−C(S)−Rk<annotation encoding="application / x-tex">-N(H)-C(S)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(O)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(O)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(S)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(S)-R^k< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−Rk<annotation encoding="application / x-tex">-N(H)-S(O)_2-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−Rk<annotation encoding="application / x-tex">-N(R^k)-S(O)_2-R^k< / annotation>< / semantics>, <semantics>−N(H)−C(O)−Rk<annotation encoding="application / x-tex">-N(H)-C(O)-R^k< / annotation>< / semantics> <semantics>N(H)−Rk<annotation encoding="application / x-tex">N(H) - R^{k}< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(H)−Rk<annotation encoding="application / x-tex">-N(H) - C(S) - N(H) - R^{k}< / annotation>< / semantics>, <semantics>−N(Rk)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^{k}) - C(O) - NH_{2}< / annotation>< / semantics>, <semantics>−N(Rk)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{k}) - C(S) - NH_{2}< / annotation>< / semantics>, <semantics>−N(Rk)−C(O)−N(H)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(O)-N(H)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(S)−N(H)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(S)-N(H)-R^k< / annotation>< / semantics>, <semantics>−N(H)−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-N(H)-C(O)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(Rk)−Rk<annotation encoding="application / x-tex">-N(H)-C(S)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(O)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(S)−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(S)-N(R^k)-R^k< / annotation>< / semantics> <semantics>Rk<annotation encoding="application / x-tex">R^{k}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(H)−Rk<annotation encoding="application / x-tex">-N(H)-S(O)_{2}-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^{k})-S(O)_{2}-NH_{2}< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−N(H)−Rk<annotation encoding="application / x-tex">-N(R^{k})-S(O)_{2}-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(Rk)−Rk<annotation encoding="application / x-tex">-N(H)-S(O)_2-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^k)-S(O)_2-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(H)−Rk<annotation encoding="application / x-tex">-N(H)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^k)-R^k< / annotation>< / semantics> <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics>, <semantics>−Ri<annotation encoding="application / x-tex">-R^i< / annotation>< / semantics>, and <semantics>−Rj<annotation encoding="application / x-tex">-R^j< / annotation>< / semantics>; • each Re is independently lower alkenyl, wherein lower alkenyl is optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of fluoro, —OH, —NH2, —NO2, —CN, —C(O)—OH, —C(S)—OH, <semantics>−C(O)−NH2,−C(S)−NH2,−S(O)2−NH2,−N(H)−C(O)−NH2,−N(H)−C(S)−NH2<annotation encoding="application / x-tex">-C(O)-NH_2, -C(S)-NH_2, -S(O)_2-NH_2, -N(H)-C(O)-NH_2, -N(H)-C(S)-NH_2< / annotation>< / semantics> <semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−NH2<annotation encoding="application / x-tex">-N(H)-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−C(NH)−NH2<annotation encoding="application / x-tex">-C(NH)-NH_2< / annotation>< / semantics>, <semantics>−O−Rk<annotation encoding="application / x-tex">-O-R^k< / annotation>< / semantics>, <semantics>−S−Rk<annotation encoding="application / x-tex">-S-R^k< / annotation>< / semantics>, <semantics>−O−C(O)−Rk<annotation encoding="application / x-tex">-O-C(O)-R^k< / annotation>< / semantics>, <semantics>−S−Rk<annotation encoding="application / x-tex">-S-R^k< / annotation>< / semantics> <semantics>O−C(S)−Rk<annotation encoding="application / x-tex">O-C(S)-R^k< / annotation>< / semantics>, <semantics>−C(O)−Rk<annotation encoding="application / x-tex">-C(O)-R^k< / annotation>< / semantics>, <semantics>−C(S)−Rk<annotation encoding="application / x-tex">-C(S)-R^k< / annotation>< / semantics>, <semantics>−C(O)−O−Rk<annotation encoding="application / x-tex">-C(O)-O-R^k< / annotation>< / semantics>, <semantics>−C(S)−O−Rk<annotation encoding="application / x-tex">-C(S)-O-R^k< / annotation>< / semantics>, <semantics>−S(O)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S<annotation encoding="application / x-tex">-S(O)-C(S)-C(S)-C(S)-C(S)-C(S)-C(S)-C(S)-C(S< / annotation>< / semantics> <semantics>Rk<annotation encoding="application / x-tex">R^{k}< / annotation>< / semantics>, <semantics>−S(O)2−Rk<annotation encoding="application / x-tex">-S(O)_{2}-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(H)−Rk<annotation encoding="application / x-tex">-C(O)-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−C(S)−N(H)−Rk<annotation encoding="application / x-tex">-C(S)-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(O)-N(R^{k})-R^{k}< / annotation>< / semantics>, <semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics> <semantics>C(S)−N(Rk)−Rk<annotation encoding="application / x-tex">C(S)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−S(O)2−N(H)−Rk<annotation encoding="application / x-tex">-S(O)_2-N(H)-R^k< / annotation>< / semantics>, <semantics>−S(O)2−N(Rk)−Rk<annotation encoding="application / x-tex">-S(O)_2-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−C(NH)−N(H)−Rk<annotation encoding="application / x-tex">-C(NH)-N(H)-R^k< / annotation>< / semantics>, <semantics>−C(NH)−N(Rm)−Rn<annotation encoding="application / x-tex">-C(NH)-N(R^m)-R^n< / annotation>< / semantics>, <semantics>−N(H)−C(O)−Rk<annotation encoding="application / x-tex">-N(H)-C(O)-R^k< / annotation>< / semantics>, <semantics>−N(H)−C(S)−Rk<annotation encoding="application / x-tex">-N(H)-C(S)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(O)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(O)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(S)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(S)-R^k< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−Rk<annotation encoding="application / x-tex">-N(H)-S(O)_2-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−Rk<annotation encoding="application / x-tex">-N(R^k)-S(O)_2-R^k< / annotation>< / semantics>, <semantics>−N(H)−C(O)−Rk<annotation encoding="application / x-tex">-N(H)-C(O)-R^k< / annotation>< / semantics> <semantics>N(H)−Rk<annotation encoding="application / x-tex">N(H) - R^{k}< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(H)−Rk<annotation encoding="application / x-tex">-N(H) - C(S) - N(H) - R^{k}< / annotation>< / semantics>, <semantics>−N(Rk)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^{k}) - C(O) - NH_{2}< / annotation>< / semantics>, <semantics>−N(Rk)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^{k}) - C(S) - NH_{2}< / annotation>< / semantics>, <semantics>−N(Rk)−C(O)−N(H)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(O)-N(H)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(S)−N(H)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(S)-N(H)-R^k< / annotation>< / semantics>, <semantics>−N(H)−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-N(H)-C(O)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(Rk)−Rk<annotation encoding="application / x-tex">-N(H)-C(S)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(O)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(S)−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(S)-N(R^k)-R^k< / annotation>< / semantics> <semantics>Rk<annotation encoding="application / x-tex">R^{k}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(H)−Rk<annotation encoding="application / x-tex">-N(H)-S(O)_{2}-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^{k})-S(O)_{2}-NH_{2}< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−N(H)−Rk<annotation encoding="application / x-tex">-N(R^{k})-S(O)_{2}-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(Rk)−Rk<annotation encoding="application / x-tex">-N(H)-S(O)_2-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^k)-S(O)_2-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(H)−Rk<annotation encoding="application / x-tex">-N(H)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^k)-R^k< / annotation>< / semantics> <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics>, <semantics>−Rh<annotation encoding="application / x-tex">-R^h< / annotation>< / semantics>, and <semantics>−Rj<annotation encoding="application / x-tex">-R^j< / annotation>< / semantics>. each Rt is independently lower alkynyl, wherein lower alkynyl is optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of fluoro, —OH, —NH2, —NO2, —CN, —C(O)—OH, —C(S)—OH, <semantics>−C(O)−NH2,−C(S)−NH2,−S(O)2−NH2,−N(H)−C(O)−NH2,−N(H)−C(S)−NH2<annotation encoding="application / x-tex">-C(O)-NH_2, -C(S)-NH_2, -S(O)_2-NH_2, -N(H)-C(O)-NH_2, -N(H)-C(S)-NH_2< / annotation>< / semantics> <semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−NH2<annotation encoding="application / x-tex">-N(H)-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−C(NH)−NH2<annotation encoding="application / x-tex">-C(NH)-NH_2< / annotation>< / semantics>, <semantics>−O−Rk<annotation encoding="application / x-tex">-O-R^k< / annotation>< / semantics>, <semantics>−S−Rk<annotation encoding="application / x-tex">-S-R^k< / annotation>< / semantics>, <semantics>−O−C(O)−Rk<annotation encoding="application / x-tex">-O-C(O)-R^k< / annotation>< / semantics>, <semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics> <semantics>O−C(S)−Rk<annotation encoding="application / x-tex">O - C(S) - R^k< / annotation>< / semantics>, <semantics>−C(O)−Rk<annotation encoding="application / x-tex">-C(O) - R^k< / annotation>< / semantics>, <semantics>−C(S)−Rk<annotation encoding="application / x-tex">-C(S) - R^k< / annotation>< / semantics>, <semantics>−C(O)−O−Rk<annotation encoding="application / x-tex">-C(O) - O - R^k< / annotation>< / semantics>, <semantics>−C(S)−O−Rk<annotation encoding="application / x-tex">-C(S) - O - R^k< / annotation>< / semantics>, <semantics>−S(O)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−C(S)−<annotation encoding="application / x-tex">-S(O) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) - C(S) -< / annotation>< / semantics> <semantics>Rk<annotation encoding="application / x-tex">R^{k}< / annotation>< / semantics>, <semantics>−S(O)2−Rk<annotation encoding="application / x-tex">-S(O)_{2}-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(H)−Rk<annotation encoding="application / x-tex">-C(O)-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−C(S)−N(H)−Rk<annotation encoding="application / x-tex">-C(S)-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(O)-N(R^{k})-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(O)-N(R^{k})-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(O)-N(R^{k})-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(O)-N(R^{k})-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(O)-N(R^{k})-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(O)-N(R^{k})-R^{k}< / annotation>< / semantics>, <semantics>−C(O)−N(<annotation encoding="application / x-tex">-C(O)-N(< / annotation>< / semantics> <semantics>C(S)−N(Rk)−Rk<annotation encoding="application / x-tex">C(S)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−S(O)2−N(H)−Rk<annotation encoding="application / x-tex">-S(O)_2-N(H)-R^k< / annotation>< / semantics>, <semantics>−S(O)2−N(Rk)−Rk<annotation encoding="application / x-tex">-S(O)_2-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−C(NH)−N(H)−Rk<annotation encoding="application / x-tex">-C(NH)-N(H)-R^k< / annotation>< / semantics>, <semantics>−C(NH)−N(Rm)−Rn<annotation encoding="application / x-tex">-C(NH)-N(R^m)-R^n< / annotation>< / semantics>, <semantics>−N(H)−C(O)−Rk<annotation encoding="application / x-tex">-N(H)-C(O)-R^k< / annotation>< / semantics>, <semantics>−N(H)−C(S)−Rk<annotation encoding="application / x-tex">-N(H)-C(S)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(O)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(O)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(S)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(S)-R^k< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−Rk<annotation encoding="application / x-tex">-N(H)-S(O)_2-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−Rk<annotation encoding="application / x-tex">-N(R^k)-S(O)_2-R^k< / annotation>< / semantics>, <semantics>−N(H)−C(O)−Rk<annotation encoding="application / x-tex">-N(H)-C(O)-R^k< / annotation>< / semantics> <semantics>N(H)−Rk<annotation encoding="application / x-tex">N(H) - R^k< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(H)−Rk<annotation encoding="application / x-tex">-N(H) - C(S) - N(H) - R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^k) - C(O) - NH_2< / annotation>< / semantics>, <semantics>−N(Rk)−C(S)−NH2<annotation encoding="application / x-tex">-N(R^k) - C(S) - NH_2< / annotation>< / semantics>, <semantics>−N(Rk)−C(O)−N(H)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(O)-N(H)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(S)−N(H)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(S)-N(H)-R^k< / annotation>< / semantics>, <semantics>−N(H)−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-N(H)-C(O)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(Rk)−Rk<annotation encoding="application / x-tex">-N(H)-C(S)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(O)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(S)−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(S)-N(R^k)-R^k< / annotation>< / semantics> <semantics>Rk<annotation encoding="application / x-tex">R^{k}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(H)−Rk<annotation encoding="application / x-tex">-N(H)-S(O)_{2}-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^{k})-S(O)_{2}-NH_{2}< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−N(H)−Rk<annotation encoding="application / x-tex">-N(R^{k})-S(O)_{2}-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(Rk)−Rk<annotation encoding="application / x-tex">-N(H)-S(O)_2-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^k)-S(O)_2-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(H)−Rk<annotation encoding="application / x-tex">-N(H)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^k)-R^k< / annotation>< / semantics> <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics>, <semantics>−−−−−−−−<annotation encoding="application / x-tex">-\!\!\!-\!\!\!\!-\!\!\!\!-\!\!\!\!-\!\!\!\!-\!\!\!\!\!-\!\!\!\!\!-\!\!\!\!< / annotation>< / semantics> each Rg is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of halogen, —OH, —NH2, —NO2, <semantics>−CN,−C(O)−OH,−C(S)−OH,−C(O)−NH2,−C(S)−NH2,−S(O)2−NH2,−<annotation encoding="application / x-tex">-CN, -C(O)-OH, -C(S)-OH, -C(O)-NH_2, -C(S)-NH_2, -S(O)_2-NH_2, -< / annotation>< / semantics> <semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, — <semantics>O−Rk<annotation encoding="application / x-tex">O-R^k< / annotation>< / semantics>, <semantics>−O−C(O)−Rk<annotation encoding="application / x-tex">-O-C(O)-R^k< / annotation>< / semantics>, <semantics>−O−C(S)−Rk<annotation encoding="application / x-tex">-O-C(S)-R^k< / annotation>< / semantics>, <semantics>−C(O)−Rk<annotation encoding="application / x-tex">-C(O)-R^k< / annotation>< / semantics>, <semantics>−C(S)−Rk<annotation encoding="application / x-tex">-C(S)-R^k< / annotation>< / semantics>, <semantics>−C(O)−O−Rk<annotation encoding="application / x-tex">-C(O)-O-R^k< / annotation>< / semantics>, <semantics>−C(S)−O−Rk<annotation encoding="application / x-tex">-C(S)-O-R^k< / annotation>< / semantics>, <semantics>−S(O)−Rk<annotation encoding="application / x-tex">-S(O)-R^k< / annotation>< / semantics>, <semantics>−S(O)2−Rk<annotation encoding="application / x-tex">-S(O)_2-R^k< / annotation>< / semantics>, <semantics>−C(O)−N(H)−Rk<annotation encoding="application / x-tex">-C(O)-N(H)-R^k< / annotation>< / semantics>, <semantics>−C(S)−N(H)−Rk<annotation encoding="application / x-tex">-C(S)-N(H)-R^k< / annotation>< / semantics>, <semantics>−C(O)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(O)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−C(S)−N(Rk)−Rk<annotation encoding="application / x-tex">-C(S)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−S(O)2−N(H)−Rk<annotation encoding="application / x-tex">-S(O)_2-N(H)-R^k< / annotation>< / semantics>, <semantics>−S(O)2−N(Rk)−Rk<annotation encoding="application / x-tex">-S(O)_2-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−C(NH)−N(H)−Rk<annotation encoding="application / x-tex">-C(NH)-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−C(NH)−N(Rm)−Rn<annotation encoding="application / x-tex">-C(NH)-N(R^{m})-R^{n}< / annotation>< / semantics>, <semantics>−N(H)−C(O)−Rk<annotation encoding="application / x-tex">-N(H)-C(O)-R^{k}< / annotation>< / semantics>, <semantics>−N(H)−C(S)−Rm<annotation encoding="application / x-tex">-N(H)-C(S)-R^{m}< / annotation>< / semantics> <semantics>Rk<annotation encoding="application / x-tex">R^{k}< / annotation>< / semantics>, <semantics>−N(Rk)<annotation encoding="application / x-tex">-N(R^{k})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>Rk<annotation encoding="application / x-tex">R^{k}< / annotation>< / semantics>, <semantics>−N(Rk)<annotation encoding="application / x-tex">-N(R^{k})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>Rk<annotation encoding="application / x-tex">R^{k}< / annotation>< / semantics>, <semantics>−N(H)<annotation encoding="application / x-tex">-N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>Rk<annotation encoding="application / x-tex">R^{k}< / annotation>< / semantics>, <semantics>−N(Rk)<annotation encoding="application / x-tex">-N(R^{k})< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>— <semantics>Rk<annotation encoding="application / x-tex">R^{k}< / annotation>< / semantics>, <semantics>−N(H)−C(O)−N(H)−Rk<annotation encoding="application / x-tex">-N(H)-C(O)-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(H)−Rk<annotation encoding="application / x-tex">-N(H)-C(S)-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−N(Rk)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^{k})-C(O)-NH_{2}< / annotation>< / semantics>, <semantics>−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^{k})-R^{k}< / annotation>< / semantics> <semantics>N(Rk)<annotation encoding="application / x-tex">N(R^k)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(Rk)<annotation encoding="application / x-tex">N(R^k)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics>, —<semantics>N(Rk)<annotation encoding="application / x-tex">N(R^k)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics>, — <semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(Rk)<annotation encoding="application / x-tex">N(R^k)< / annotation>< / semantics>—<semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(Rk)<annotation encoding="application / x-tex">N(R^k)< / annotation>< / semantics>—<semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics>, —<semantics>N(Rk)<annotation encoding="application / x-tex">N(R^k)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(Rk)<annotation encoding="application / x-tex">N(R^k)< / annotation>< / semantics>—<semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics>, <semantics>−N(Rk)−C(S)−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^k)-C(S)-N(R^k)-R^k< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(H)−Rk<annotation encoding="application / x-tex">-N(H)-S(O)_2-N(H)-R^k< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^k)-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^k)-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^k)-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^k)-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^k)-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^k)-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−N(Rk)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^k)-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−N(Rk)<annotation encoding="application / x-tex">-N(R^k)< / annotation>< / semantics> <semantics>N(Rk)<annotation encoding="application / x-tex">N(R^k)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>N(Rk)<annotation encoding="application / x-tex">N(R^k)< / annotation>< / semantics>—<semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics>, —<semantics>N(Rk)<annotation encoding="application / x-tex">N(R^k)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>N(Rk)<annotation encoding="application / x-tex">N(R^k)< / annotation>< / semantics>—<semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics>, <semantics>−N(H)−Rk<annotation encoding="application / x-tex">-N(H)-R^{k}< / annotation>< / semantics>, <semantics>−N(Rk)−Rk<annotation encoding="application / x-tex">-N(R^{k})-R^{k}< / annotation>< / semantics>, <semantics>−Rh<annotation encoding="application / x-tex">-R^{h}< / annotation>< / semantics>, <semantics>−Ri<annotation encoding="application / x-tex">-R^{i}< / annotation>< / semantics>, and <semantics>−Rj<annotation encoding="application / x-tex">-R^{j}< / annotation>< / semantics>; o wherein Rk, Rm, and Rn at each occurrence are independently selected from the group consisting of Rh, Ri, and Rj, or Rm and Rn combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, —NO2, —CN, —OH, <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, <semantics>−O−Ru<annotation encoding="application / x-tex">-O-R^u< / annotation>< / semantics>, <semantics>−S−Ru<annotation encoding="application / x-tex">-S-R^u< / annotation>< / semantics>, <semantics>−N(H)−Ru<annotation encoding="application / x-tex">-N(H)-R^u< / annotation>< / semantics>, <semantics>−NRuRu<annotation encoding="application / x-tex">-NR^uR^u< / annotation>< / semantics>, <semantics>−Rx<annotation encoding="application / x-tex">-R^x< / annotation>< / semantics>, and <semantics>−Ry<annotation encoding="application / x-tex">-R^y< / annotation>< / semantics>; o wherein each Rh is independently lower alkyl optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of fluoro, —OH, —NH2, —NO2, —CN, —C(O)—OH, — <semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>OH<annotation encoding="application / x-tex">OH< / annotation>< / semantics>, —<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>— <semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, <semantics>−N(H)−C(S)−NH2<annotation encoding="application / x-tex">-N(H)-C(S)-NH_2< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−NH2<annotation encoding="application / x-tex">-N(H)-S(O)_2-NH_2< / annotation>< / semantics>, <semantics>−C(NH)−NH2<annotation encoding="application / x-tex">-C(NH)-NH_2< / annotation>< / semantics>, <semantics>−O−Rr<annotation encoding="application / x-tex">-O-R^r< / annotation>< / semantics>, <semantics>−S−Rr<annotation encoding="application / x-tex">-S-R^{r}< / annotation>< / semantics>, <semantics>−O−C(O)−Rr<annotation encoding="application / x-tex">-O-C(O)-R^{r}< / annotation>< / semantics>, <semantics>−O−C(S)−Rr<annotation encoding="application / x-tex">-O-C(S)-R^{r}< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^{r}< / annotation>< / semantics>, <semantics>−C(S)−Rr<annotation encoding="application / x-tex">-C(S)-R^{r}< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^{r}< / annotation>< / semantics> <semantics>O−Rr<annotation encoding="application / x-tex">O-R^r< / annotation>< / semantics>, <semantics>−C(S)−O−Rr<annotation encoding="application / x-tex">-C(S)-O-R^r< / annotation>< / semantics>, <semantics>−S(O)−Rr<annotation encoding="application / x-tex">-S(O)-R^r< / annotation>< / semantics>, <semantics>−S(O)2−Rr<annotation encoding="application / x-tex">-S(O)_2-R^r< / annotation>< / semantics>, <semantics>−C(O)−N(H)−Rr<annotation encoding="application / x-tex">-C(O)-N(H)-R^r< / annotation>< / semantics>, <semantics>−C(O)−N(H)−Rr<annotation encoding="application / x-tex">-C(O)-N(H)-R^r< / annotation>< / semantics> <semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>— <semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, <semantics>−S(O)2<annotation encoding="application / x-tex">-S(O)_{2}< / annotation>< / semantics> <semantics>−N(Rr)<annotation encoding="application / x-tex">-N(R^{r})< / annotation>< / semantics> <semantics>−Rr<annotation encoding="application / x-tex">-R^{r}< / annotation>< / semantics>, <semantics>−C(NH)<annotation encoding="application / x-tex">-C(NH)< / annotation>< / semantics> <semantics>−N(H)<annotation encoding="application / x-tex">-N(H)< / annotation>< / semantics> <semantics>−Rr<annotation encoding="application / x-tex">-R^{r}< / annotation>< / semantics>, <semantics>−C(NH)<annotation encoding="application / x-tex">-C(NH)< / annotation>< / semantics> <semantics>−N(Rs)<annotation encoding="application / x-tex">-N(R^{s})< / annotation>< / semantics> <semantics>−Rt<annotation encoding="application / x-tex">-R^{t}< / annotation>< / semantics>, <semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics> <semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, —<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^r)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, —<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^r)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−Rr<annotation encoding="application / x-tex">-N(H)-S(O)_2-R^r< / annotation>< / semantics>, <semantics>−N(Rr)−S(O)2−Rr<annotation encoding="application / x-tex">-N(R^r)-S(O)_2-R^r< / annotation>< / semantics>, <semantics>−N(H)−C(O)−N(H)−Rr<annotation encoding="application / x-tex">-N(H)-C(O)-N(H)-R^r< / annotation>< / semantics>, <semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics> <semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, —<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^r)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^r)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, — <semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>— <semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(Rr)−Rr<annotation encoding="application / x-tex">-N(H)-C(S)-N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−N(Rr)−C(O)−N(Rr)−Rr<annotation encoding="application / x-tex">-N(R^{r})-C(O)-N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−N(Rr)−C(S)−Rr<annotation encoding="application / x-tex">-N(R^{r})-C(S)-R^{r}< / annotation>< / semantics> <semantics>N(Rr)−Rr<annotation encoding="application / x-tex">N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(H)−Rr<annotation encoding="application / x-tex">-N(H)-S(O)_{2}-N(H)-R^{r}< / annotation>< / semantics>, <semantics>−N(Rr)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^{r})-S(O)_{2}-NH_{2}< / annotation>< / semantics>, <semantics>−N(Rr)−S(O)2−NH2<annotation encoding="application / x-tex">-N(R^{r})-S(O)_{2}-NH_{2}< / annotation>< / semantics> <semantics>S(O)2−N(H)−Rr<annotation encoding="application / x-tex">S(O)_2-N(H)-R^r< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−N(Rr)−Rr<annotation encoding="application / x-tex">-N(H)-S(O)_2-N(R^r)-R^r< / annotation>< / semantics>, <semantics>−N(Rr)−S(O)2−N(Rr)−Rr<annotation encoding="application / x-tex">-N(R^r)-S(O)_2-N(R^r)-R^r< / annotation>< / semantics>, <semantics>−N(H)−Rr<annotation encoding="application / x-tex">-N(H)-R^{r}< / annotation>< / semantics>, <semantics>−N(Rr)−Rr<annotation encoding="application / x-tex">-N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−Ri<annotation encoding="application / x-tex">-R^{i}< / annotation>< / semantics>, and <semantics>−Rj<annotation encoding="application / x-tex">-R^{j}< / annotation>< / semantics>. o wherein each R1 is independently selected from the group consisting of lower alkenyl and lower alkynyl, wherein lower alkenyl or lower alkynyl are optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of fluoro, —OH, —NH2, —NO2, —CN, — <semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>OH<annotation encoding="application / x-tex">OH< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>OH<annotation encoding="application / x-tex">OH< / annotation>< / semantics>, —<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, — <semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>C(NH)<annotation encoding="application / x-tex">C(NH)< / annotation>< / semantics>— <semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, <semantics>−O−Rr<annotation encoding="application / x-tex">-O-R^r< / annotation>< / semantics>, <semantics>−S−Rr<annotation encoding="application / x-tex">-S-R^r< / annotation>< / semantics>, <semantics>−O−C(O)−Rr<annotation encoding="application / x-tex">-O-C(O)-R^r< / annotation>< / semantics>, <semantics>−O−C(S)−Rr<annotation encoding="application / x-tex">-O-C(S)-R^r< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^r< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^r< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^r< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^r< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^r< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^r< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^r< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^r< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^r< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^r< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^r< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^r< / annotation>< / semantics>, <semantics>−C(O)−<annotation encoding="application / x-tex">-C(O)-< / annotation>< / semantics> <Formule mathématique disponible dans le document PDF, Math available in the PDF document>$C(S)-R^{r}, -C(O)-O-R^{r}, -C(S)-O-R^{r}, -S(O)-R^{r}, -S(O)_{2}-R^{r}, -S(O)_{3}-R^{r}, -S(O)_{4}-R^{r}, -S(O)_{5}-R^{r}, -S(O)_{5}-R^{r}, -S(O)_{5}-R^{r}, -S(O)_{5}-R^{r}, -S(O)_{5}-R^{r}, -S(O)_{5}-R^{r}, -S(O)_{5}-R^$ <semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, <semantics>−S(O)2−N(H)−Rr<annotation encoding="application / x-tex">-S(O)_2-N(H)-R^r< / annotation>< / semantics>, <semantics>−S(O)2−N(Rr)−Rr<annotation encoding="application / x-tex">-S(O)_2-N(R^r)-R^r< / annotation>< / semantics>, <semantics>−C(NH)−N(H)−Rr<annotation encoding="application / x-tex">-C(NH)-N(H)-R^r< / annotation>< / semantics>, <semantics>−C(NH)−N(H)−Rr<annotation encoding="application / x-tex">-C(NH)-N(H)-R^r< / annotation>< / semantics> <semantics>N(Rs)<annotation encoding="application / x-tex">N(R^s)< / annotation>< / semantics>—<semantics>Rt<annotation encoding="application / x-tex">R^t< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, —<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^r)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, — <semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>— <semantics>N(H)−Rr<annotation encoding="application / x-tex">N(H)-R^{r}< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(H)−Rr<annotation encoding="application / x-tex">-N(H)-C(S)-N(H)-R^{r}< / annotation>< / semantics>, <semantics>−N(Rr)−C(O)−NH2<annotation encoding="application / x-tex">-N(R^{r})-C(O)-NH_{2}< / annotation>< / semantics>, <semantics>−N(Rr)−C(S)−Rr<annotation encoding="application / x-tex">-N(R^{r})-C(S)-R^{r}< / annotation>< / semantics> <semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, <semantics>−N(Rr)<annotation encoding="application / x-tex">-N(R^r)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, <semantics>−N(Rr)<annotation encoding="application / x-tex">-N(R^r)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, <semantics>−N(H)<annotation encoding="application / x-tex">-N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>— <semantics>N(Rr)−Rr<annotation encoding="application / x-tex">N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−N(H)−C(S)−N(Rr)−Rr<annotation encoding="application / x-tex">-N(H)-C(S)-N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−N(Rr)−C(O)−N(Rr)−Rr<annotation encoding="application / x-tex">-N(R^{r})-C(O)-N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−N(Rr)−Rr<annotation encoding="application / x-tex">-N(R^{r})-R^{r}< / annotation>< / semantics> <semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^r)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, —<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^r)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, — <semantics>N(Rr)−S(O)2−N(H)−Rr,−N(H)−S(O)2−N(Rr)−Rr,−N(Rr)−S(O)2−N(Rr)<annotation encoding="application / x-tex">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})< / annotation>< / semantics> <semantics>N(Rr)−Rr<annotation encoding="application / x-tex">N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−N(H)−Rr<annotation encoding="application / x-tex">-N(H)-R^{r}< / annotation>< / semantics>, <semantics>−N(Rr)−Rr<annotation encoding="application / x-tex">-N(R^{r})-R^{r}< / annotation>< / semantics>, and <semantics>−RJ<annotation encoding="application / x-tex">-R^{J}< / annotation>< / semantics>; 0 wherein each RJ is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents selected from the group consisting of halogen, — <semantics>OH,−NH2,−NO2,−CN,−C(O)−OH,−C(S)−OH,−C(O)−NH2,−<annotation encoding="application / x-tex">OH, -NH_2, -NO_2, -CN, -C(O) -OH, -C(S) -OH, -C(O) -NH_2, -< / annotation>< / semantics> <semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>, — <semantics>N(H)−S(O)2−NH2,−C(NH)−NH2,−O−Rr,−S−Rr,−O−C(O)−Rr,−<annotation encoding="application / x-tex">N(H)-S(O)_2-NH_2, -C(NH)-NH_2, -O-R^r, -S-R^r, -O-C(O)-R^r, -< / annotation>< / semantics> <semantics>O−C(S)−Rr<annotation encoding="application / x-tex">O-C(S)-R^{r}< / annotation>< / semantics>, <semantics>−C(O)−Rr<annotation encoding="application / x-tex">-C(O)-R^{r}< / annotation>< / semantics>, <semantics>−C(S)−Rr<annotation encoding="application / x-tex">-C(S)-R^{r}< / annotation>< / semantics>, <semantics>−C(O)−O−Rr<annotation encoding="application / x-tex">-C(O)-O-R^{r}< / annotation>< / semantics>, <semantics>−C(S)−O−Rr<annotation encoding="application / x-tex">-C(S)-O-R^{r}< / annotation>< / semantics>, <semantics>−C(S)−O−Rr<annotation encoding="application / x-tex">-C(S)-O-R^{r}< / annotation>< / semantics>, <semantics>−C(S)−O−Rr<annotation encoding="application / x-tex">-C(S)-O-R^{r}< / annotation>< / semantics>, <semantics>−C(S)−O−Rr<annotation encoding="application / x-tex">-C(S)-O-R^{r}< / annotation>< / semantics>, <semantics>−C(S)−O−Rr<annotation encoding="application / x-tex">-C(S)-O-R^{r}< / annotation>< / semantics>, <semantics>−C(S)−O−Rr<annotation encoding="application / x-tex">-C(S)-O-R^{r}< / annotation>< / semantics>, <semantics>−C(S)−O−Rr<annotation encoding="application / x-tex">-C(S)-O-R^{r}< / annotation>< / semantics>, <semantics>−C(S)−O−Rr<annotation encoding="application / x-tex">-C(S)-O-R^{r}< / annotation>< / semantics>, <semantics>−C(S)−O−Rr<annotation encoding="application / x-tex">-C(S)-O-R^{r}< / annotation>< / semantics>, <semantics>−C(S<annotation encoding="application / x-tex">-C(S< / annotation>< / semantics> <semantics>S(O)−Rr,−S(O)2−Rr,−C(O)−N(H)−Rr,−C(S)−N(H)−Rr,−C(O)−Rr<annotation encoding="application / x-tex">S(O)-R^{r}, -S(O)_{2}-R^{r}, -C(O)-N(H)-R^{r}, -C(S)-N(H)-R^{r}, -C(O)-R^{r}< / annotation>< / semantics> <semantics>N(Rr)−Rr<annotation encoding="application / x-tex">N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−C(S)−N(Rr)−Rr<annotation encoding="application / x-tex">-C(S)-N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−S(O)2−N(H)−Rr<annotation encoding="application / x-tex">-S(O)_{2}-N(H)-R^{r}< / annotation>< / semantics>, <semantics>−S(O)2−N(Rr)−Rr<annotation encoding="application / x-tex">-S(O)_{2}-N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−S(O)2−N(Rr)−Rr<annotation encoding="application / x-tex">-S(O)_{2}-N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−S(O)2−N(Rr)−Rr<annotation encoding="application / x-tex">-S(O)_{2}-N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−S(O)2−N(Rr)−Rr<annotation encoding="application / x-tex">-S(O)_{2}-N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−S(O)2−N(Rr)−Rr<annotation encoding="application / x-tex">-S(O)_{2}-N(R^{r})-R^{r}< / annotation>< / semantics>, <Formule mathématique disponible dans le document PDF, Math available in the PDF document>$-S(O)_{2}-N(R^$ <semantics>C(NH)−N(H)−Rr<annotation encoding="application / x-tex">C(NH)-N(H)-R^{r}< / annotation>< / semantics>, <semantics>−C(NH)−N(Rs)−Rt<annotation encoding="application / x-tex">-C(NH)-N(R^{s})-R^{t}< / annotation>< / semantics>, <semantics>−N(H)−C(O)−Rr<annotation encoding="application / x-tex">-N(H)-C(O)-R^{r}< / annotation>< / semantics>, <semantics>−N(H)−Rr<annotation encoding="application / x-tex">-N(H)-R^{r}< / annotation>< / semantics> <semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, — <semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_{2}< / annotation>< / semantics>-le, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, — <semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_{2}< / annotation>< / semantics>, —<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>NH2<annotation encoding="application / x-tex">NH_{2}< / annotation>< / semantics>, —<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, — <semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, —<semantics>N(H)<annotation encoding="application / x-tex">N(H)< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^{r})< / annotation>< / semantics>— <semantics>Rr<annotation encoding="application / x-tex">R^{r}< / annotation>< / semantics>, <semantics>−N(Rr)−C(O)−N(Rr)−Rr<annotation encoding="application / x-tex">-N(R^{r})-C(O)-N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−N(Rr)−C(S)−N(Rr)−Rr<annotation encoding="application / x-tex">-N(R^{r})-C(S)-N(R^{r})-R^{r}< / annotation>< / semantics>, <semantics>−N(H)−S(O)2−Rr<annotation encoding="application / x-tex">-N(H)-S(O)_{2}-R^{r}< / annotation>< / semantics> <semantics>N(H)−Rr,−N(Rr)−S(O)2−NH2,−N(Rr)−S(O)2−N(H)−Rr,−N(H)−Rr<annotation encoding="application / x-tex">N(H)-R^{r}, -N(R^{r})-S(O)_{2}-NH_{2}, -N(R^{r})-S(O)_{2}-N(H)-R^{r}, -N(H)-R^{r}< / annotation>< / semantics> <semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^r)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, —<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^r)< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^r)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, —<semantics>N(Rr)<annotation encoding="application / x-tex">N(R^r)< / annotation>< / semantics>—<semantics>Rr<annotation encoding="application / x-tex">R^r< / annotation>< / semantics>, cycloalkylamino, and <semantics>−Rx<annotation encoding="application / x-tex">-R^x< / annotation>< / semantics>; 0 wherein each Rr, Rs, and Rt at each occurrence are independently selected from the group consisting of lower alkyl, C3-6 alkenyl, C3-6alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of —Ry, fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> alkenyl or <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> alkynyl are optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of —Ry, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, —OH, —NH2, —NO2, —CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, or Rs and Rt combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, —NO2, —CN, —OH, —NH2, —O—Ru, —S—Ru, <semantics>−N(H)−Ru<annotation encoding="application / x-tex">-N(H)-R^{u}< / annotation>< / semantics>, <semantics>−N(Ru)−Ru<annotation encoding="application / x-tex">-N(R^{u})-R^{u}< / annotation>< / semantics>, <semantics>−Rx<annotation encoding="application / x-tex">-R^{x}< / annotation>< / semantics>, and <semantics>−Ry<annotation encoding="application / x-tex">-R^{y}< / annotation>< / semantics>; 0 wherein each Ru is independently selected from the group consisting of lower alkyl, C3-6 alkenyl, C3-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of —Ry, fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> alkenyl or <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> alkynyl are optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of —Ry, fluoro, —OH, —NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di- alkylamino, and cycloalkylamino, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, — OH, —NH2, —NO2, —CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 0 wherein each Rx is selected from the group consisting of lower alkyl, lower alkenyl and lower alkynyl, wherein lower alkyl is optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of —Ry, fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, and cycloalkylamino, and wherein lower alkenyl or lower alkynyl are optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of —Ry, fluoro, —OH, —NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; 0 wherein each Ry is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, for example 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, — OH, —NH2, —NO2, —CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.

[0049] In some embodiments, all occurrences of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted C3-6 alkenyl, optionally substituted lower alkynyl, or optionally substituted <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> alkynyl are optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of fluoro, —NO2, —CN, <semantics>−O−R1a<annotation encoding="application / x-tex">-O-R^{1a}< / annotation>< / semantics>, <semantics>−S−R1a<annotation encoding="application / x-tex">-S-R^{1a}< / annotation>< / semantics>, <semantics>−N(R1a)−R1a<annotation encoding="application / x-tex">-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−O−C(O)−R1a<annotation encoding="application / x-tex">-O-C(O)-R^{1a}< / annotation>< / semantics>, <semantics>−O−C(S)−R1a<annotation encoding="application / x-tex">-O-C(S)-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−R1a<annotation encoding="application / x-tex">-C(O)-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−R1a<annotation encoding="application / x-tex">-C(O)-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−R1a<annotation encoding="application / x-tex">-C(O)-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−R1a<annotation encoding="application / x-tex">-C(O)-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−R1a<annotation encoding="application / x-tex">-C(O)-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−R1a<annotation encoding="application / x-tex">-C(O)-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−R1a<annotation encoding="application / x-tex">-C(O)-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−R1a<annotation encoding="application / x-tex">-C(O)-R^{1a}< / annotation>< / semantics>, <Formule mathématique disponible dans le document PDF, Math available in the PDF document>-C(O)-R^{ <semantics>C(S)−R1a<annotation encoding="application / x-tex">C(S)-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−O−R1a<annotation encoding="application / x-tex">-C(O)-O-R^{1a}< / annotation>< / semantics>, <semantics>−C(S)−O−R1a<annotation encoding="application / x-tex">-C(S)-O-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−N(R1a)−R1a<annotation encoding="application / x-tex">-C(O)-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−C(S)−N(R1a)−R1a<annotation encoding="application / x-tex">-C(S)-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−S(O)2−N(R1a)−R1a<annotation encoding="application / x-tex">-S(O)_2-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−C(NH)−N(R1a)−R1a<annotation encoding="application / x-tex">-C(NH)-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−N(R1a)−C(O)−R1a<annotation encoding="application / x-tex">-N(R^{1a})-C(O)-R^{1a}< / annotation>< / semantics>, <semantics>−N(R1a)−C(S)−R1a<annotation encoding="application / x-tex">-N(R^{1a})-C(S)-R^{1a}< / annotation>< / semantics>, [Image disponible dans le document PDF, Image available in the PDF document] <semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>S(O)<annotation encoding="application / x-tex">S(O)< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group [Image disponible dans le document PDF, Image available in the PDF document] <semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>, and lower alkyl optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and —R1b; and all occurrences of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted 5-7 membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, also 1, 2, or 3 groups or substituents selected from the group consisting of halogen, —NO2, —CN, —O—R1a, —S— <semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, <semantics>−N(R1a)−R1a<annotation encoding="application / x-tex">-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−O−C(O)−R1a<annotation encoding="application / x-tex">-O-C(O)-R^{1a}< / annotation>< / semantics>, <semantics>−O−C(S)−R1a<annotation encoding="application / x-tex">-O-C(S)-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−R1a<annotation encoding="application / x-tex">-C(O)-R^{1a}< / annotation>< / semantics>, <semantics>−C(S)−R1a<annotation encoding="application / x-tex">-C(S)-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−R1a<annotation encoding="application / x-tex">-C(O)-R^{1a}< / annotation>< / semantics> <semantics>O−R1a<annotation encoding="application / x-tex">O-R^{1a}< / annotation>< / semantics>, <semantics>−C(S)−O−R1a<annotation encoding="application / x-tex">-C(S)-O-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−N(R1a)−R1a<annotation encoding="application / x-tex">-C(O)-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−C(S)−N(R1a)−R1a<annotation encoding="application / x-tex">-C(S)-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−S(O)2−N(R1a)−R1a<annotation encoding="application / x-tex">-S(O)_2-N(R^{1a})-R^{1a}< / annotation>< / semantics> <semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, <semantics>−C(NH)−N(R1a)−R1a<annotation encoding="application / x-tex">-C(NH)-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−N(R1a)−C(O)−R1a<annotation encoding="application / x-tex">-N(R^{1a})-C(O)-R^{1a}< / annotation>< / semantics>, <semantics>−N(R1a)−C(S)−R1a<annotation encoding="application / x-tex">-N(R^{1a})-C(S)-R^{1a}< / annotation>< / semantics>, <semantics>−N(R1a)−S(O)2−R1a<annotation encoding="application / x-tex">-N(R^{1a})-S(O)_2-R^{1a}< / annotation>< / semantics> <semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, <semantics>−N(R1a)<annotation encoding="application / x-tex">-N(R^{1a})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, <semantics>−N(R1a)<annotation encoding="application / x-tex">-N(R^{1a})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, <semantics>−N(R1a)<annotation encoding="application / x-tex">-N(R^{1a})< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>— <semantics>N(R1a)−R1a<annotation encoding="application / x-tex">N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−S(O)−R1a<annotation encoding="application / x-tex">-S(O)-R^{1a}< / annotation>< / semantics>, <semantics>−S(O)2−R1a<annotation encoding="application / x-tex">-S(O)_2-R^{1a}< / annotation>< / semantics>, <semantics>−R1b<annotation encoding="application / x-tex">-R^{1b}< / annotation>< / semantics>, and lower alkyl optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and —R1b; wherein R1a is selected from the group consisting of hydrogen, —R1b, and lower alkyl optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and —R1b, and wherein —R1b is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of halogen, —CN, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.

[0050] In some embodiments, all occurrences of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted C3-6 alkenyl, optionally substituted lower alkynyl, or optionally substituted <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> alkynyl are optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of fluoro, —CN, —O— <semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, <semantics>−S−R1a<annotation encoding="application / x-tex">-S-R^{1a}< / annotation>< / semantics>, <semantics>−N(R1a)−R1a<annotation encoding="application / x-tex">-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−R1a<annotation encoding="application / x-tex">-C(O)-R^{1a}< / annotation>< / semantics>, <semantics>−C(S)−R1a<annotation encoding="application / x-tex">-C(S)-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−O−R1a<annotation encoding="application / x-tex">-C(O)-O-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−C(O)−C(O)−C(O)<annotation encoding="application / x-tex">-C(O)-C(O)-C(O)-C(O)< / annotation>< / semantics> <semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>,—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>,—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>,—<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>,—<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>— <semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>S(O)<annotation encoding="application / x-tex">S(O)< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of halogen, <semantics>−CN<annotation encoding="application / x-tex">-CN< / annotation>< / semantics>, <semantics>−O−R1a<annotation encoding="application / x-tex">-O-R^{1a}< / annotation>< / semantics>, <semantics>−S−R1a<annotation encoding="application / x-tex">-S-R^{1a}< / annotation>< / semantics>, <semantics>−N(R1a)−R1a<annotation encoding="application / x-tex">-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−R1a<annotation encoding="application / x-tex">-C(O)-R^{1a}< / annotation>< / semantics>, <semantics>−C(S)−R1a<annotation encoding="application / x-tex">-C(S)-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−O−R1a<annotation encoding="application / x-tex">-C(O)-O-R^{1a}< / annotation>< / semantics>, <semantics>−C(O)−N(R1a)−R1a<annotation encoding="application / x-tex">-C(O)-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−C(S)−N(R1a)−R1a<annotation encoding="application / x-tex">-C(S)-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−S(O)2−N(R1a)−R1a<annotation encoding="application / x-tex">-S(O)_2-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−S(O)2−N(R1a)−R1a<annotation encoding="application / x-tex">-S(O)_2-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−S(O)2−N(R1a)−R1a<annotation encoding="application / x-tex">-S(O)_2-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−S(O)2−N(R1a)−R1a<annotation encoding="application / x-tex">-S(O)_2-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−S(O)2−N(R1a)−R1a<annotation encoding="application / x-tex">-S(O)_2-N(R^{1a})-R^{1a}< / annotation>< / semantics>, <semantics>−S(O)2−N(<annotation encoding="application / x-tex">-S(O)_2-N(< / annotation>< / semantics> <semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>S(O)<annotation encoding="application / x-tex">S(O)< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>, —<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>R<annotation encoding="application / x-tex">R< / annotation>< / semantics> R1a, —R1b, and lower alkyl optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and —R1b; and all occurrences of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted 5-7 membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, also 1, 2, or 3 groups or substituents selected from the group consisting of halogen, —CN, —O—R1a, —S—R1a, — <semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>,—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>,—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>,—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>,—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>,—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>— <semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>,—<semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>—<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>,—<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>,—<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>—<semantics>C(S)<annotation encoding="application / x-tex">C(S)< / annotation>< / semantics>—<semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>,—<semantics>N(R1a)<annotation encoding="application / x-tex">N(R^{1a})< / annotation>< / semantics>— <semantics>S(O)2−R1a<annotation encoding="application / x-tex">S(O)_2 - R^{1a}< / annotation>< / semantics>, <semantics>−S(O)−R1a<annotation encoding="application / x-tex">-S(O) - R^{1a}< / annotation>< / semantics>, <semantics>−S(O)2−R1a<annotation encoding="application / x-tex">-S(O)_2 - R^{1a}< / annotation>< / semantics>, <semantics>−R1b<annotation encoding="application / x-tex">-R^{1b}< / annotation>< / semantics>, and lower alkyl optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and —R1b; wherein R1a is selected from the group consisting of hydrogen, —R1b, and lower alkyl optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and —R1b, and wherein —R1b is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more, also 1, 2 or 3 groups or substituents selected from the group consisting of halogen, —CN, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.

[0051] As used herein, "lower alkoxy" denotes the group —ORz, where Rz is lower alkyl. "Substituted lower alkoxy" denotes lower alkoxy in which Rz is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I, including descriptions of substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl, attached at any available atom to provide a stable compound. In some embodiments, substitution of lower alkoxy is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents. For example, "fluoro substituted lower alkoxy" denotes lower alkoxy in which the lower alkyl is substituted with one or more fluoro atoms, where in some embodiments, the lower alkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that substitutions on alkoxy are chemically feasible and attached at any available atom to provide a stable compound.

[0052] It is understood that all possible substitutions as defined above include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Formula I, attached at any available atom to produce a stable compound. For example, "fluoro substituted phenyl" denotes a phenyl group substituted with one or more fluoro atoms where, for example, the phenyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, e.g., 2,3,5,6- tetrafluorophenyl. It also is understood that any of the substitutions made according to the definitions above are chemically feasible and attached at any available atom to provide a stable compound.

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

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

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

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

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

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

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

[0060] As used herein, "treatment" means any manner in which a disease or disorder, or one or more of the symptoms of a disease or disorder, are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein, such as use for treating cancer. Reference to "treatment," herein also includes prevention, amelioration or mitigation.

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

[0062] As used herein, "amelioration" or "mitigation" of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition are used interchangeably and refers to any lessening of the symptoms, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.

[0063] As used herein, "complication" refers to a condition that develops in association with a condition or disease. The complication can be as a direct result caused by the condition or disease, or can be associated with the existence of the primary condition or disease. In some embodiments, the complications of a disease can be manifested as a symptom and, in those instances, the two terms are used interchangeably herein.

[0064] As used herein, and unless otherwise indicated, the terms "manage," "managing" and "management" encompass preventing the recurrence of the specified disease or disorder in a patient who has already suffered from the disease or disorder, and / or lengthening the time that a patient who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development and / or duration of the disease or disorder, or changing the way that a patient responds to the disease or disorder.

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

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

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

[0068] The term "about," as used herein, unless otherwise indicated, refers to a value that is no more than 10% above or below the value being modified by the term. For example, the term "about 10 mg" means a range of from 9 mg to 11 mg.

[0069] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC IUB Commission on Biochemical Nomenclature (see, Biochem. 1972, 11:942 944). 6.2. Caspase Inhibitor Compounds

[0070] In one embodiment, provided herein is a compound of Formula I: [Image disponible dans le document PDF, Image available in the PDF document] I or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -RaORb, or -RaN(Rc)(Rd), each of which is optionally substituted; or ii) X is -O-, or -N(Rc)-; Y is hydrogen, -C(O)Rd, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>, <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> and <semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics> are selected as follows: i) Y1 together with R3 forms an optionally substituted saturated or unsaturated bicyclic ring B; Y2 is absent, hydrogen or optionally substituted alkyl; and Y3 is absent, hydrogen or optionally substituted alkyl; or ii) <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is hydrogen or optionally substituted alkyl; <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> and <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> together are <semantics>=0<annotation encoding="application / x-tex">=0< / annotation>< / semantics>; and <semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics> is <semantics>−N(Z1)(Z2)<annotation encoding="application / x-tex">-N(Z^1)(Z^2)< / annotation>< / semantics>; X, Y, <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> and <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> are selected such that when X is O, then <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> cannot form ring B; each Ra is independently alkylene or a direct bond; Rb is hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted hydroxyalkyl, optionally substituted alkoxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; each Rc is independently hydrogen or optionally substituted alkyl; each Rd is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -RaORb, each of which is optionally substituted; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A; <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>, <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> and <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> are each independently hydrogen or optionally substituted alkyl; R9 is aryl or heteroaryl, each optionally substituted; R10 is alkylene; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> and <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> are selected as follows: i) <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or optionally substituted alkyl; and <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionally substituted; or ii) <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> and <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> together with the nitrogen atom on which they are substituted form an optionally substituted saturated or unsaturated ring C.

[0071] In one embodiment, provided herein is a compound of Formula I or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co- crystal, clathrate, or polymorph thereof; wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -RaORb, or <semantics>−RaN(Rc)(Rd)<annotation encoding="application / x-tex">-R^aN(R^c)(R^d)< / annotation>< / semantics>; or ii) X is -O-, or -N(Rc)-; Y is hydrogen, -C(O)Rd, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; Y is optionally substituted with one to three groups Q1; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>, <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> and <semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics> are selected as follows: i) Y1 together with R3 forms an optionally substituted saturated or unsaturated bicyclic ring B, where substituents on ring B, when present, are selected from one to three groups Q1; Y2 is absent, hydrogen or alkyl; and Y3 is absent, hydrogen or alkyl; or ii) <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> and <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> together are <semantics>=0<annotation encoding="application / x-tex">=0< / annotation>< / semantics>; and <semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics> is <semantics>−N(Z1)(Z2)<annotation encoding="application / x-tex">-N(Z^1)(Z^2)< / annotation>< / semantics>; X, Y, <semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics> and Y1 are selected such that when X is O, then Y1 and <semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics> cannot form ring B; each Q1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; each <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics> is optionally substituted with one to three groups <semantics>Q2<annotation encoding="application / x-tex">Q^2< / annotation>< / semantics>; each Q2 is independently alkyl, halo, haloalkyl, aryl or haloaryl; each Ra is independently alkylene or a direct bond; Rb is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; each Rc is independently hydrogen or alkyl; each Rd is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -RaORb; each Rd is optionally substituted with one to three groups Q1; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen, alkyl or cycloalkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, where the substituents on ring A, when present, are selected from one to three groups Q1; <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>, <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> and <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> are each independently hydrogen or alkyl; <semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics> is anylor heteroaryl, each optionally substituted with one to four substituents <semantics>ℚ1<annotation encoding="application / x-tex">\mathbb{Q}^1< / annotation>< / semantics>; R10 is alkylene; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> and <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> are selected as follows: i) <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; and <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; or ii) <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> and <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> together with the nitrogen atom on which they are substituted form an optionally substituted saturated or unsaturated ring C, where the substituents on ring C, when present, are selected from one to three groups <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11OR11OR12<annotation encoding="application / x-tex">-R^{11}OR^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11SR12<annotation encoding="application / x-tex">-R^{11}SR^{12}< / annotation>< / semantics>, <semantics>−R11OR11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11OR11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−C(J)R15<annotation encoding="application / x-tex">-C(J)R^{15}< / annotation>< / semantics> and <semantics>R11S(O)tR16<annotation encoding="application / x-tex">R^{11}S(O)_tR^{16}< / annotation>< / semantics>; where each <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics> is optionally substituted with one to three groups Q4, where each Q4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R11 is independently alkylene, alkenylene or a direct bond; each R12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; <semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics> and <semantics>R14<annotation encoding="application / x-tex">R^{14}< / annotation>< / semantics> are selected as follows: i) R13 and R14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; or ii) R13 and R14 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; each R16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; J is O or S; and t is 0-2.

[0072] In one embodiment, provided herein is a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co- crystal, clathrate, or polymorph thereof, wherein X and Y are selected as follows: i) X is C=O; and Y is <semantics>−RaORb<annotation encoding="application / x-tex">-R^aOR^b< / annotation>< / semantics>; or ii) X is -O-; Y is hydrogen, -C(O)Rd, alkyl or aryl; Y is optionally substituted with one to three groups Q1; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>, <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> and <semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics> are selected as follows: i) Y1 together with R3 forms an optionally substituted saturated or unsaturated ring B, where substituents on ring B, when present, are selected from one to three groups <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; Y2 is absent, hydrogen or alkyl; and Y3 is absent, hydrogen or alkyl; or ii) <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> and <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> together are <semantics>=0<annotation encoding="application / x-tex">=0< / annotation>< / semantics>; and <semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics> is <semantics>−N(Z1)(Z2)<annotation encoding="application / x-tex">-N(Z^1)(Z^2)< / annotation>< / semantics>; X, Y, <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> and <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> are selected such that when X is O, then <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> cannot form ring B; each Q1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q1 is optionally substituted with one to three groups Q2; each <semantics>Q2<annotation encoding="application / x-tex">Q^2< / annotation>< / semantics> is independently alkyl, halo, haloalkyl, aryl or haloaryl; Ra is alkylene or a direct bond; Rb is hydrogen, alkyl or aryl; Rd is aryl or -RaORb; each Rd is optionally substituted with one to three groups Q1; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen or alkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form a cycloalkyl ring; <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>, <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> and <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> are each independently hydrogen or alkyl; <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is anylor heteroaryl, each optionally substituted with one to four substituents <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics>; R10 is alkylene; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is aryl or heteroaryl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−C(O)R15<annotation encoding="application / x-tex">-C(O)R^{15}< / annotation>< / semantics> and <semantics>−R11C(O)NH2<annotation encoding="application / x-tex">-R^{11}C(O)NH_2< / annotation>< / semantics>; each R11 is independently alkylene or a direct bond; R12 is hydrogen, alkyl or haloalkyl; and R15 is hydroxyl or alkyl.

[0073] In one embodiment, provided herein is a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co- crystal, clathrate, or polymorph thereof, wherein X and Y are selected as follows: i) X is C=O; and Y is <semantics>−RaORb<annotation encoding="application / x-tex">-R^aOR^b< / annotation>< / semantics>; or ii) X is -O-; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or -C(O)Rd; where the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>, <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> and <semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics> are selected as follows: i) <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> together with <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> forms an optionally substituted saturated or unsaturated ring B, where substituents on ring B, when present, are selected from one to three groups <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; Y2 is absent, hydrogen or alkyl; and Y3 is absent, hydrogen or alkyl; or ii) <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> and <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> together are <semantics>=0<annotation encoding="application / x-tex">=0< / annotation>< / semantics>; and <semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics> is <semantics>−N(Z1)(Z2)<annotation encoding="application / x-tex">-N(Z^1)(Z^2)< / annotation>< / semantics>; X, Y, <semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics> and Y1 are selected such that when X is O, then Y1 and <semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics> cannot form ring B; Ra is alkylene or a direct bond; Rb is hydrogen, alkyl or aryl; Rd is aryl or aryloxy; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen or alkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form a cycloalkyl ring; <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>, <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> and <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> are each independently hydrogen or alkyl; R9 is anyl or heteroaryl, each optionally substituted with one to four substituents selected from halo, alkyl and haloalkyl; R10 is alkylene; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is anylor heteroaryl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−C(O)R15<annotation encoding="application / x-tex">-C(O)R^{15}< / annotation>< / semantics> and <semantics>−C(O)NH2<annotation encoding="application / x-tex">-C(O)NH_2< / annotation>< / semantics>; R11 is alkylene or a direct bond; R12 is hydrogen, alkyl or haloalkyl; and R15 is hydroxyl or alkyl.

[0074] In one embodiment, provided herein is a compound of Formula II: [Image disponible dans le document PDF, Image available in the PDF document] <semantics>∏<annotation encoding="application / x-tex">\prod< / annotation>< / semantics> or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -RaORb, or <semantics>−RaN(Rc)(Rd)<annotation encoding="application / x-tex">-R^aN(R^c)(R^d)< / annotation>< / semantics>; or ii) X is -O-, or -N(Rc)-; Y is hydrogen, -C(O)Rd, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is optionally substituted with one to three groups Q1; each Q1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q1 is optionally substituted with one to three groups Q2; each Q2 is independently alkyl, halo, haloalkyl, aryl or haloaryl; each Ra is independently alkylene or a direct bond; Rb is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; each Rc is independently hydrogen or alkyl; each Rd is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -RaORb; each Rd is optionally substituted with one to three groups Q1; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen, alkyl or cycloalkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, where substituents on ring A, when present, are selected from one to three groups <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics>; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>, <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> and <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> are each independently hydrogen or alkyl; <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is anylor heteroaryl, each optionally substituted with one to four substituents <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics>; R10 is alkylene; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> and <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> are selected as follows: i) <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; and <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; or ii) <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> and <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> together with the nitrogen atom on which they are substituted form an optionally substituted saturated or unsaturated ring C, where the substituents on ring C, when present, are selected from one to three groups <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11OR11OR12<annotation encoding="application / x-tex">-R^{11}OR^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11SR12<annotation encoding="application / x-tex">-R^{11}SR^{12}< / annotation>< / semantics>, <semantics>−R11OR11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11OR11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−C(J)R15<annotation encoding="application / x-tex">-C(J)R^{15}< / annotation>< / semantics> and <semantics>R11S(O)tR16<annotation encoding="application / x-tex">R^{11}S(O)_tR^{16}< / annotation>< / semantics>; where each <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics> is optionally substituted with one to three groups Q4, where each Q4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R11 is independently alkylene, alkenylene or a direct bond; each R12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; <semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics> and <semantics>R14<annotation encoding="application / x-tex">R^{14}< / annotation>< / semantics> are selected as follows: i) R13 and R14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; or ii) R13 and R14 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; each R16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; J is O or S; and t is 0-2.

[0075] In one embodiment, provided herein is a compound of Formula II or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co- crystal, clathrate, or polymorph thereof; wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -RaORb, or <semantics>−RaN(Rc)(Rd)<annotation encoding="application / x-tex">-R^aN(R^c)(R^d)< / annotation>< / semantics>; or ii) X is -O-, or -N(Rc)-; Y is hydrogen, -C(O)Rd, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is optionally substituted with one to three groups Q1; each Q1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; each <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics> is optionally substituted with one to three groups <semantics>Q2<annotation encoding="application / x-tex">Q^2< / annotation>< / semantics>; each Q2 is independently alkyl, halo, haloalkyl, aryl or haloaryl; each Ra is independently alkylene or a direct bond; Rb is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; each Rc is independently hydrogen or alkyl; each Rd is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -RaORb; each Rd is optionally substituted with one to three groups Q1; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen, alkyl or cycloalkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, where substituents on ring A, when present, are selected from one to three groups <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics>; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>, <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> and <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> are each independently hydrogen or alkyl; <semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics> is anylor heteroaryl, each optionally substituted with one to four substituents <semantics>ℚ1<annotation encoding="application / x-tex">\mathbb{Q}^1< / annotation>< / semantics>; R10 is alkylene; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11OR11OR12<annotation encoding="application / x-tex">-R^{11}OR^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11SR12<annotation encoding="application / x-tex">-R^{11}SR^{12}< / annotation>< / semantics>, <semantics>−R11OR11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11OR11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−C(J)R15<annotation encoding="application / x-tex">-C(J)R^{15}< / annotation>< / semantics> and <semantics>R11S(O)tR16<annotation encoding="application / x-tex">R^{11}S(O)_tR^{16}< / annotation>< / semantics>; where each <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics> is optionally substituted with one to three groups Q4, where each Q4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R11 is independently alkylene, alkenylene or a direct bond; each R12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; <semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics> and <semantics>R14<annotation encoding="application / x-tex">R^{14}< / annotation>< / semantics> are selected as follows: i) R13 and R14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; or ii) R13 and R14 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; each R16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; J is O or S; and t is 0-2.

[0076] In one embodiment, provided herein is a compound of Formula II, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co- crystal, clathrate, or polymorph thereof, wherein X and Y are selected as follows: i) X is <semantics>C=O<annotation encoding="application / x-tex">C=O< / annotation>< / semantics>; and Y is <semantics>−RaORb<annotation encoding="application / x-tex">-R^aOR^b< / annotation>< / semantics>; or ii) X is -O-; Y is hydrogen, -C(O)Rd, alkyl or aryl; Y is optionally substituted with one to three groups Q1; each Q1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; each <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics> is optionally substituted with one to three groups <semantics>Q2<annotation encoding="application / x-tex">Q^2< / annotation>< / semantics>; each Q2 is independently alkyl, halo, haloalkyl, aryl or haloaryl; each Ra is independently alkylene or a direct bond; each Rb is independently hydrogen, alkyl or aryl; Rd is aryl or -RaORb; each Rd is optionally substituted with one to three groups Q1; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen or alkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form a cycloalkyl ring; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>, <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> and <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> are each independently hydrogen or alkyl; <semantics>ℝ9<annotation encoding="application / x-tex">\mathbb{R}^9< / annotation>< / semantics> is anylor heteroaryl, each optionally substituted with one to four substituents <semantics>ℚ1<annotation encoding="application / x-tex">\mathbb{Q}^1< / annotation>< / semantics>; R10 is alkylene; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is aryl or heteroaryl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−C(O)R15<annotation encoding="application / x-tex">-C(O)R^{15}< / annotation>< / semantics> and <semantics>−R11C(O)NH2<annotation encoding="application / x-tex">-R^{11}C(O)NH_2< / annotation>< / semantics>; each R11 is independently alkylene or a direct bond; R12 is hydrogen, alkyl or haloalkyl; and R15 is hydroxyl or alkyl.

[0077] In one embodiment, provided herein is a compound of Formula II, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co- crystal, clathrate, or polymorph thereof, wherein X and Y are selected as follows: i) X is C=O; and Y is -RaORb; or ii) X is -O-; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or -C(O)Rd; where the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; Ra is alkylene or a direct bond; Rb is hydrogen, alkyl or aryl; Rd is aryl or aryloxy; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen or alkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form a cycloalkyl ring; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>, <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> and <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> are each independently hydrogen or alkyl; R9 is aryl or heteroaryl, each optionally substituted with one to four substituents selected from halo, alkyl and haloalkyl; R10 is alkylene; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; <semantics>ℤ2<annotation encoding="application / x-tex">\mathbb{Z}^2< / annotation>< / semantics> is anylor heteroaryl, each optionally substituted with one to four substituents <semantics>ℚ3<annotation encoding="application / x-tex">\mathbb{Q}^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−C(O)R15<annotation encoding="application / x-tex">-C(O)R^{15}< / annotation>< / semantics> and <semantics>−C(O)NH2<annotation encoding="application / x-tex">-C(O)NH_2< / annotation>< / semantics>; each R11 is independently alkylene or a direct bond; R12 is hydrogen, alkyl or haloalkyl; and R15 is hydroxyl or alkyl.

[0078] In one embodiment, provided herein is a compound of Formula III [Image disponible dans le document PDF, Image available in the PDF document] III or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -RaORb, or <semantics>−RaN(Rc)(Rd)<annotation encoding="application / x-tex">-R^aN(R^c)(R^d)< / annotation>< / semantics>; or ii) X is -O-, or -N(Rc)-; Y is hydrogen, -C(O)Rd, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is optionally substituted with one to three groups Q1; each Q1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; each <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics> is optionally substituted with one to three groups <semantics>Q2<annotation encoding="application / x-tex">Q^2< / annotation>< / semantics>; each Q2 is independently alkyl, halo, haloalkyl, aryl or haloaryl; each Ra is independently alkylene or a direct bond; Rb is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; each Rc is independently hydrogen or alkyl; each Rd is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -RaORb; each Rd is optionally substituted with one to three groups Q1; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen, alkyl or cycloalkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, where substituents on ring A, when present, are selected from one to three groups <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics>; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>, <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> and <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> are each independently hydrogen or alkyl; R10 is alkylene; each Q5 is independently alkyl, halo or haloalkyl; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11OR11OR12<annotation encoding="application / x-tex">-R^{11}OR^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11SR12<annotation encoding="application / x-tex">-R^{11}SR^{12}< / annotation>< / semantics>, <semantics>−R11OR11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11OR11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−C(J)R15<annotation encoding="application / x-tex">-C(J)R^{15}< / annotation>< / semantics> and <semantics>R11S(O)tR16<annotation encoding="application / x-tex">R^{11}S(O)_tR^{16}< / annotation>< / semantics>; where each <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics> is optionally substituted with one to three groups Q4, where each Q4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R11 is independently alkylene, alkenylene or a direct bond; each R12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; <semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics> and <semantics>R14<annotation encoding="application / x-tex">R^{14}< / annotation>< / semantics> are selected as follows: i) R13 and R14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; or ii) R13 and R14 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl; each R16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; J is O or S; t is 0-2; and m is 0-4.

[0079] In one embodiment, provided herein is a compound of Formula III, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co- crystal, clathrate, or polymorph thereof, wherein X and Y are selected as follows: i) X is <semantics>C=O<annotation encoding="application / x-tex">C=O< / annotation>< / semantics>; and Y is <semantics>−RaORb<annotation encoding="application / x-tex">-R^aOR^b< / annotation>< / semantics>; or ii) X is -O-; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or -C(O)Rd; where the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; Ra is alkylene or a direct bond; Rb is hydrogen, alkyl or aryl; each Rd is independently aryl or aryloxy; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen or alkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form a cycloalkyl ring; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>, <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> and <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> are each independently hydrogen or alkyl; Q1 is selected from halo, alkyl and haloalkyl; m is 0-4; R10 is alkylene; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is aryl or heteroaryl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−C(O)R15<annotation encoding="application / x-tex">-C(O)R^{15}< / annotation>< / semantics> and <semantics>−C(O)NH2<annotation encoding="application / x-tex">-C(O)NH_2< / annotation>< / semantics>; R11 is alkylene or a direct bond; R12 is hydrogen, alkyl or haloalkyl; and R15 is hydroxyl or alkyl.

[0080] In one embodiment, provided herein is a compound of Formula III, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co- crystal, clathrate, or polymorph thereof, wherein X and Y are selected as follows: i) X is C=O; and Y is -RaORb; or ii) X is -O-; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or -C(O)Rd; where the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; Ra is alkylene or a direct bond; Rb is hydrogen, alkyl or aryl; Rd is aryl or aryloxy; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen or alkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form a cycloalkyl ring; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>, <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> and <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> are hydrogen; Q1 is selected from halo, alkyl and haloalkyl; m is 0-4; R10 is alkylene; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>, <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> and <semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics> are selected as follows: i) Y1 together with R3 forms an optionally substituted saturated or unsaturated ring B, where substituents on ring B, when present, are selected from one to three groups Q1; Y2 is absent, hydrogen or alkyl; and Y3 is absent, hydrogen or alkyl; or ii) <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> and <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> together are <semantics>=0<annotation encoding="application / x-tex">=0< / annotation>< / semantics>; and <semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics> is <semantics>−N(Z1)(Z2)<annotation encoding="application / x-tex">-N(Z^1)(Z^2)< / annotation>< / semantics>; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is anylor heteroaryl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−C(O)R15<annotation encoding="application / x-tex">-C(O)R^{15}< / annotation>< / semantics> and <semantics>−C(O)NH2<annotation encoding="application / x-tex">-C(O)NH_2< / annotation>< / semantics>; R11 is alkylene or a direct bond; R12 is hydrogen, alkyl or haloalkyl; and R15 is hydroxyl or alkyl.

[0081] In one embodiment, provided herein is a compound of Formula IV [Image disponible dans le document PDF, Image available in the PDF document] or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein X and Y are selected as follows: i) X is C=O; and Y is -RaORb; or ii) X is -O-; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or -C(O)Rd; where the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; Ra is alkylene or a direct bond; Rb is hydrogen, alkyl or aryl; Rd is aryl or aryloxy; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen or alkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form a cycloalkyl ring; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>, <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> and <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> are hydrogen; Q5 is selected from halo, alkyl and haloalkyl; p is 0-3; R10 is alkylene; Z1 is hydrogen or alkyl; <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is anylor heteroaryl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−C(O)R15<annotation encoding="application / x-tex">-C(O)R^{15}< / annotation>< / semantics> and <semantics>−C(O)NH2<annotation encoding="application / x-tex">-C(O)NH_2< / annotation>< / semantics>; R11 is alkylene or a direct bond; R12 is hydrogen, alkyl or haloalkyl; and R15 is hydroxyl or alkyl.

[0082] In one embodiment, provided herein is a compound of Formula V: [Image disponible dans le document PDF, Image available in the PDF document] V or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -RaORb, or <semantics>−RaN(Rc)(Rd)<annotation encoding="application / x-tex">-R^aN(R^c)(R^d)< / annotation>< / semantics>; or ii) X is -O-, or -N(Rc)-; Y is hydrogen, -C(O)Rd, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is optionally substituted with one to three groups Q1; each Q1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; each Q1 is optionally substituted with one to three groups Q2; each Q2 is independently alkyl, halo, haloalkyl, aryl or haloaryl; each Ra is independently alkylene or a direct bond; Rb is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; each Rc is independently hydrogen or alkyl; each Rd is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -RaORb; each Rd is optionally substituted with one to three groups Q1; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen, alkyl or cycloalkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, where the substituents on ring A, when present, are selected from one to three groups Q1; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>, <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> and <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> are each independently hydrogen or alkyl; R10 is alkylene; each Q3 is independently selected from alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11OR11OR12<annotation encoding="application / x-tex">-R^{11}OR^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11SR12<annotation encoding="application / x-tex">-R^{11}SR^{12}< / annotation>< / semantics>, <semantics>−R11OR11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11OR11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−C(J)R15<annotation encoding="application / x-tex">-C(J)R^{15}< / annotation>< / semantics> and <semantics>R11S(O)tR16<annotation encoding="application / x-tex">R^{11}S(O)_tR^{16}< / annotation>< / semantics>; where each <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics> is optionally substituted with one to three groups Q4, where each Q4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R11 is independently alkylene, alkenylene or a direct bond; each R12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; <semantics>R13<annotation encoding="appli...

Claims

<pat:ClaimStatement>The embodiments of the present invention for which an exclusive property or privilege is claimed are defined as follows:< / pat:ClaimStatement> <pat:Claims com:id="claims"> <pat:Claim com:id="CLM-00001"> <pat:ClaimNumber>1< / pat:ClaimNumber> <pat:ClaimText>1. A compound having formula I: [Image disponible dans le document PDF, Image available in the PDF document] or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -RaORb, or -RaN(Rc)(Rd); or ii) X is -O-, or -N(Rc)-; Y is hydrogen, -C(O)Rd, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Y is optionally substituted with one to three groups Q1; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>, <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> and <semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics> are selected as follows: i) Y1 together with R3 forms an optionally substituted saturated or unsaturated bicyclic ring B, where substituents on ring B, when present, are selected from one to three groups Q1; <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> is absent, hydrogen or alkyl; and Y3 is absent, hydrogen or alkyl; or ii) <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> and <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> together are <semantics>=0<annotation encoding="application / x-tex">=0< / annotation>< / semantics>; and <semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics> is <semantics>−N(Z1)(Z2)<annotation encoding="application / x-tex">-N(Z^1)(Z^2)< / annotation>< / semantics>; <semantics>X,Y,R3<annotation encoding="application / x-tex">X, Y, R^3< / annotation>< / semantics> and <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> are selected such that when X is O, then <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> cannot form ring B; each Q1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; each <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics> is optionally substituted with one to three groups <semantics>Q2<annotation encoding="application / x-tex">Q^2< / annotation>< / semantics>; each Q2 is independently alkyl, halo, haloalkyl, aryl or haloaryl; each Ra is independently alkylene or a direct bond; Rb is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; each Rc is independently hydrogen or alkyl; each Rd is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -RaORb; each Rd is optionally substituted with one to three groups Q1; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen, alkyl or cycloalkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, where the substituents on ring A, when present, are selected from one to three groups Q1; R4, R5, R6, R7 and R8 are each independently hydrogen or alkyl; <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is anylor heteroaryl, each optionally substituted with one to four substituents <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics>; R10 is alkylene; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> and <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> are selected as follows: i) <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; and <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; or ii) <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> and <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> together with the nitrogen atom on which they are substituted form an optionally substituted saturated or unsaturated ring C, where the substituents on ring C, when present, are selected from one to three groups <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11OR11OR12<annotation encoding="application / x-tex">-R^{11}OR^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11SR12<annotation encoding="application / x-tex">-R^{11}SR^{12}< / annotation>< / semantics>, <semantics>−R11OR11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11OR11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−C(J)R15<annotation encoding="application / x-tex">-C(J)R^{15}< / annotation>< / semantics> and <semantics>R11S(O)tR16<annotation encoding="application / x-tex">R^{11}S(O)_tR^{16}< / annotation>< / semantics>; where each <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics> is optionally substituted with one to three groups Q4, where each Q4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R11 is independently alkylene, alkenylene or a direct bond; each R12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; <semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics> and <semantics>R14<annotation encoding="application / x-tex">R^{14}< / annotation>< / semantics> are selected as follows: i) R13 and R14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; or ii) R13 and R14 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl; each R16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; J is O or S; and t is 0-2. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00002"> <pat:ClaimNumber>2< / pat:ClaimNumber> <pat:ClaimText>2. The compound of claim 1, wherein X and Y are selected as follows: i) X is C=O; and Y is -RaORb; or ii) X is -O-; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or -C(O)Rd; where the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>, <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> and <semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics> are selected as follows: i) Y1 together with R3 forms an optionally substituted saturated or unsaturated ring B, where substituents on ring B, when present, are selected from one to three groups <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> is absent, hydrogen or alkyl; and Y3 is absent, hydrogen or alkyl; or ii) <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> and <semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics> together are <semantics>=0<annotation encoding="application / x-tex">=0< / annotation>< / semantics>; and <semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics> is <semantics>−N(Z1)(Z2)<annotation encoding="application / x-tex">-N(Z^1)(Z^2)< / annotation>< / semantics>; <semantics>X,Y,R3<annotation encoding="application / x-tex">X, Y, R^3< / annotation>< / semantics> and <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> are selected such that when X is O, then <semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> cannot form ring B; Ra is alkylene or a direct bond; Rb is hydrogen, alkyl or aryl; Rd is aryl or aryloxy; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are each independently hydrogen or alkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form a cycloalkyl ring; R4, R5, R6, R7 and R8 are each independently hydrogen or alkyl; R9 is aryl or heteroaryl, each optionally substituted with one to four substituents selected from halo, alkyl and haloalkyl; R10 is alkylene; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is aryl or heteroaryl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−C(O)R15<annotation encoding="application / x-tex">-C(O)R^{15}< / annotation>< / semantics> and <semantics>−C(O)NH2<annotation encoding="application / x-tex">-C(O)NH_2< / annotation>< / semantics>; R11 is alkylene or a direct bond; R12 is hydrogen, alkyl or haloalkyl; and R15 is hydroxyl or alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00003"> <pat:ClaimNumber>3< / pat:ClaimNumber> <pat:ClaimText>3. The compound of claim 1 or claim 2, having formula II [Image disponible dans le document PDF, Image available in the PDF document] II or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00004"> <pat:ClaimNumber>4< / pat:ClaimNumber> <pat:ClaimText>4. The compound of any one of claims 1 to 3, wherein X and Y are selected as follows: i) X is C=O; and Y is -RaORb; or ii) X is -O-; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or -C(O)Rd; where the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; Ra is alkylene or a direct bond; Rb is hydrogen, alkyl or aryl; Rd is aryl or aryloxy; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen or alkyl; or ii) <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> together with the carbon atom on which they are substituted form a cycloalkyl ring; R3, R4, R5, R6, R7 and R8 are each independently hydrogen or alkyl; R9 is aryl or heteroaryl, each optionally substituted with one to four substituents selected from halo, alkyl and haloalkyl; R10 is alkylene; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is aryl or heteroaryl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−C(O)R15<annotation encoding="application / x-tex">-C(O)R^{15}< / annotation>< / semantics> and <semantics>−C(O)NH2<annotation encoding="application / x-tex">-C(O)NH_2< / annotation>< / semantics>; each R11 is independently alkylene or a direct bond; R12 is hydrogen, alkyl or haloalkyl; and R15 is hydroxyl or alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00005"> <pat:ClaimNumber>5< / pat:ClaimNumber> <pat:ClaimText>5. The compound of any one of claims 1 to 4, wherein R9 is phenyl or pyrimidinyl, each optionally substituted with one to four substituents selected from halo, alkyl and haloalkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00006"> <pat:ClaimNumber>6< / pat:ClaimNumber> <pat:ClaimText>6. The compound of any one of claims 1 to 3, having formula III [Image disponible dans le document PDF, Image available in the PDF document] III or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein X and Y are selected as follows: i) X is C=O; and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, <semantics>−RaORb<annotation encoding="application / x-tex">-R^aOR^b< / annotation>< / semantics>, or <semantics>−RaN(Rc)(Rd)<annotation encoding="application / x-tex">-R^aN(R^c)(R^d)< / annotation>< / semantics>; or ii) X is -O-, or -N(Rc)-; Y is hydrogen, -C(O)Rd, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Y is optionally substituted with one to three groups Q1; each Q1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; each <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics> is optionally substituted with one to three groups <semantics>Q2<annotation encoding="application / x-tex">Q^2< / annotation>< / semantics>; each Q2 is independently alkyl, halo, haloalkyl, aryl or haloaryl; each Ra is independently alkylene or a direct bond; Rb is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; each Rc is independently hydrogen or alkyl; each Rd is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -RaORb; each Rd is optionally substituted with one to three groups Q1; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen, alkyl or cycloalkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, where substituents on ring A, when present, are selected from one to three groups Q1; R3, R4, R5, R6, R7 and R8 are each independently hydrogen or alkyl; R10 is alkylene; each Q5 is independently alkyl, halo or haloalkyl; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11OR11OR12<annotation encoding="application / x-tex">-R^{11}OR^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11SR12<annotation encoding="application / x-tex">-R^{11}SR^{12}< / annotation>< / semantics>, <semantics>−R11OR11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11OR11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−C(J)R15<annotation encoding="application / x-tex">-C(J)R^{15}< / annotation>< / semantics> and <semantics>R11S(O)tR16<annotation encoding="application / x-tex">R^{11}S(O)_tR^{16}< / annotation>< / semantics>; where each <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics> is optionally substituted with one to three groups Q4, where each Q4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R11 is independently alkylene, alkenylene or a direct bond; each R12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; <semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics> and <semantics>R14<annotation encoding="application / x-tex">R^{14}< / annotation>< / semantics> are selected as follows: i) R13 and R14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; or ii) R13 and R14 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl; each R16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; J is O or S; t is 0-2; and m is 0-4. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00007"> <pat:ClaimNumber>7< / pat:ClaimNumber> <pat:ClaimText>7. The compound of claim 6, having formula V [Image disponible dans le document PDF, Image available in the PDF document] V or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00008"> <pat:ClaimNumber>8< / pat:ClaimNumber> <pat:ClaimText>8. The compound of claim 7, wherein X and Y are selected as follows: i) X is C=O; and Y is -RaORb; or ii) X is -O-; Y is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or -C(O)Rd; where the alkyl and aryl groups are optionally substituted with one or two groups selected from alkyl and halo; Ra is alkylene or a direct bond; Rb is hydrogen, alkyl or aryl; Rd is aryl or aryloxy; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen or alkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form a cycloalkyl ring; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> and <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> are each independently hydrogen or alkyl; R10 is alkylene; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; each Q3 is independently selected from alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−C(O)R15<annotation encoding="application / x-tex">-C(O)R^{15}< / annotation>< / semantics> and <semantics>−C(O)NH2<annotation encoding="application / x-tex">-C(O)NH_2< / annotation>< / semantics>; each R11 is independently alkylene or a direct bond; R12 is hydrogen, alkyl or haloalkyl; R15 is hydroxyl or alkyl; each Q5 is independently alkyl, halo or haloalkyl; m is 0-4; and n is 0-2. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00009"> <pat:ClaimNumber>9< / pat:ClaimNumber> <pat:ClaimText>9. The compound of any one of claims 1 to 4, having formula VIII [Image disponible dans le document PDF, Image available in the PDF document] VIII or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein each Q6 is independently alkyl, halo or haloalkyl; and m is 0-4. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00010"> <pat:ClaimNumber>10< / pat:ClaimNumber> <pat:ClaimText>10. The compound of claim 9, wherein Rb is hydrogen; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen or alkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form a 3-5 membered cycloalkyl ring; <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> and <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> are each independently hydrogen or alkyl; <semantics>Z1<annotation encoding="application / x-tex">Z^1< / annotation>< / semantics> is hydrogen or alkyl; <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is aryl or heteroaryl, each optionally substituted with one to four substituents <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics>; each Q3 is independently selected from alkyl, haloalkyl, haloalkoxy, halo, cyano, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−C(O)R15<annotation encoding="application / x-tex">-C(O)R^{15}< / annotation>< / semantics> and <semantics>−C(O)NH2<annotation encoding="application / x-tex">-C(O)NH_2< / annotation>< / semantics>; <semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics> is <semantics>−CH2−<annotation encoding="application / x-tex">-CH_2-< / annotation>< / semantics> or <semantics>−CH2−CH2−<annotation encoding="application / x-tex">-CH_2-CH_2-< / annotation>< / semantics>; R11 is alkylene or a direct bond; R12 is hydrogen, alkyl or haloalkyl; R15 is hydroxyl or alkyl; Q6 is independently alkyl, halo or haloalkyl; and m is 0-4. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00011"> <pat:ClaimNumber>11< / pat:ClaimNumber> <pat:ClaimText>11. The compound of any of claims 1 to 10, wherein R10 is lower alkylene. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00012"> <pat:ClaimNumber>12< / pat:ClaimNumber> <pat:ClaimText>12. The compound of claim 11, wherein R10 is methylene or ethylene. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00013"> <pat:ClaimNumber>13< / pat:ClaimNumber> <pat:ClaimText>13. The compound of any one of claims 1 to 12, wherein i) R1 and R2 are each independently hydrogen or methyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form a cyclopentyl ring. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00014"> <pat:ClaimNumber>14< / pat:ClaimNumber> <pat:ClaimText>14. The compound of any one of claims 1 to 6 or 9, wherein <semantics>Z2<annotation encoding="application / x-tex">Z^2< / annotation>< / semantics> is selected from phenyl, pyridinyl, pyrimidyl, naphthyl, indazolyl, quinolinyl, isoquinolynyl and benzoisothiazolyl; each optionally substituted with one or two Q3 groups, and each Q3 is independently selected from halo, alkyl, haloalkyl, arylalkyl, alkoxy, alkylcarbonyl, haloalkoxy, cyano, aryl, heteroaryl and aminocarbonyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00015"> <pat:ClaimNumber>15< / pat:ClaimNumber> <pat:ClaimText>15. The compound of any one of claims 1 to 4, having formula XIV [Image disponible dans le document PDF, Image available in the PDF document] XIV or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; wherein X is C=O; Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -RaORb, or -RaN(Rc)(Rd); each optionally substituted with one to three groups Q1; each Q1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; each <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics> is optionally substituted with one to three groups <semantics>Q2<annotation encoding="application / x-tex">Q^2< / annotation>< / semantics>; each Q2 is independently alkyl, halo, haloalkyl, aryl or haloaryl; each Ra is independently alkylene or a direct bond; Rb is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; Rc is hydrogen or alkyl; Rd is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or -RaORb; each Rd is optionally substituted with one to three groups Q1; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are selected as follows: i) R1 and R2 are each independently hydrogen, alkyl or cycloalkyl; or ii) R1 and R2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, where the substituents on ring A, when present, are selected from one to three groups <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics>; R4, R5, R6, R7 and R8 are each independently hydrogen or alkyl; <semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics> is anylor heteroaryl, each optionally substituted with one to four substituents <semantics>Q1<annotation encoding="application / x-tex">Q^1< / annotation>< / semantics>; R10 is alkylene; each Q3 is independently selected from alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, <semantics>−R11OR12<annotation encoding="application / x-tex">-R^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11OR11OR12<annotation encoding="application / x-tex">-R^{11}OR^{11}OR^{12}< / annotation>< / semantics>, <semantics>−R11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11SR12<annotation encoding="application / x-tex">-R^{11}SR^{12}< / annotation>< / semantics>, <semantics>−R11OR11N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−R11OR11C(J)N(R13)(R14)<annotation encoding="application / x-tex">-R^{11}OR^{11}C(J)N(R^{13})(R^{14})< / annotation>< / semantics>, <semantics>−C(J)R15<annotation encoding="application / x-tex">-C(J)R^{15}< / annotation>< / semantics> and <semantics>R11S(O)tR16<annotation encoding="application / x-tex">R^{11}S(O)_tR^{16}< / annotation>< / semantics>; where each <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics> is optionally substituted with one to three groups Q4, where each Q4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R11 is independently alkylene, alkenylene or a direct bond; each R12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; <semantics>R13<annotation encoding="application / x-tex">R^{13}< / annotation>< / semantics> and <semantics>R14<annotation encoding="application / x-tex">R^{14}< / annotation>< / semantics> are selected as follows: i) R13 and R14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; or ii) R13 and R14 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl; each R15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl; each R16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; J is O or S; t is 0-2; and n is 0-3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00016"> <pat:ClaimNumber>16< / pat:ClaimNumber> <pat:ClaimText>16. The compound of claim 15, wherein X is <semantics>C=O<annotation encoding="application / x-tex">C=O< / annotation>< / semantics>; and Y is <semantics>−RaORb<annotation encoding="application / x-tex">-R^aOR^b< / annotation>< / semantics>; Ra is alkylene or a direct bond; Rb is hydrogen or alkyl; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are each hydrogen; R4, R5, R6, R7 and R8 are each independently hydrogen or alkyl; R9 is aryl or heteroaryl, each optionally substituted with one to four halo; R10 is alkylene; each <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics> is halo; and n is 0-3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00017"> <pat:ClaimNumber>17< / pat:ClaimNumber> <pat:ClaimText>17. The compound of any one of claims 1, 15 or 16, having formula XVII [Image disponible dans le document PDF, Image available in the PDF document] or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein each <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics> is halo; n is 0-2; each <semantics>Q7<annotation encoding="application / x-tex">Q^7< / annotation>< / semantics> is halo, and x is 0-4. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00018"> <pat:ClaimNumber>18< / pat:ClaimNumber> <pat:ClaimText>18. The compound of claim 16, wherein <semantics>Q3<annotation encoding="application / x-tex">Q^3< / annotation>< / semantics> is chloro; n is 1; each <semantics>Q7<annotation encoding="application / x-tex">Q^7< / annotation>< / semantics> is fluoro and x is 4. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00019"> <pat:ClaimNumber>19< / pat:ClaimNumber> <pat:ClaimText>19. A pharmaceutical composition, comprising the compound of any one of claims 1 to 18 and a pharmaceutically acceptable carrier. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00020"> <pat:ClaimNumber>20< / pat:ClaimNumber> <pat:ClaimText>20. Use of a therapeutically effective amount of the compound of any one of claims 1 to 18 or the pharmaceutical composition of claim 19, for treating a disease wherein the disease is selected from the group consisting of gastrointestinal disease, respiratory disease, cardiovascular disease, dermatological disease, rheumatological diseases, kidney disease, autoimmune disease, CNS disease, inflammatory disease, liver disease, cancer and ophthalmological disease. < / pat:ClaimText> < / pat:Claim> < / pat:Claims>