WO2017156074A1 - Modulateurs de calpaïne et leurs méthodes de production et d'utilisation - Google Patents

Modulateurs de calpaïne et leurs méthodes de production et d'utilisation Download PDF

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Publication number
WO2017156074A1
WO2017156074A1 PCT/US2017/021288 US2017021288W WO2017156074A1 WO 2017156074 A1 WO2017156074 A1 WO 2017156074A1 US 2017021288 W US2017021288 W US 2017021288W WO 2017156074 A1 WO2017156074 A1 WO 2017156074A1
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substituted
heteroaryl
group
aryl
ring structure
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PCT/US2017/021288
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English (en)
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Brad Owen BUCKMAN
Shendong Yuan
John Beamond NICHOLAS
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Blade Therapeutics, Inc.
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Priority to AU2017229591A priority Critical patent/AU2017229591B2/en
Publication of WO2017156074A1 publication Critical patent/WO2017156074A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
    • C07D245/02—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
    • C07D245/04—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom

Definitions

  • the present disclosure relates to small molecule calpain modulatory compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions to modulate calpain activity, including methods to treat diseases and conditions mediated at least in part by the physiologic effects of CAPN1, CAPN2 or CAPN9, or combinations thereof.
  • Fibrotic disease accounts for an estimated 45% of deaths in the developed world but the development of therapies for such diseases is still in its infancy.
  • the current treatments for fibrotic diseases such as for idiopathic lung fibrosis, renal fibrosis, systemic sclerosis, and liver cirrhosis, are few in number and only alleviate some of the symptoms of fibrosis while failing to treat the underlying cause.
  • myofibroblasts these transformed cells can secrete large amounts of extracellular matrix proteins and matrix degrading enzymes, resulting in the formation of scar tissue and eventual organ failure.
  • This cellular process is transformative and termed “myofibroblast differentiation” (which includes Epithelial-to-Mesenchymal Transition (EpMT) and its variations like Endothelial-to-Mesenchymal Transition (EnMT) and
  • Fibroblast-to-Myofibroblast Transition This process is a major target for the treatment of fibrotic diseases.
  • Myofibroblast differentiation has also been shown to occur within cancer cells that have been chronically exposed to high ⁇ , causing stationary epithelial cells to become motile, invasive, and metastasize.
  • the signaling has been documented to associate with the acquisition of drug resistance, immune system evasion, and development of stem cell properties,
  • ⁇ is a pleiotropic cytokine with many physiological functions such that global suppression of TGF signaling was also associated with severe side effects. Additionally, current data suggests that such proximal inhibition may be vulnerable to pathologic workaround strategies (i.e., due to redundancy or compensation), that would limit the utility of such drags. Further complicating matters is that, in cancer, ⁇ signaling early on functions as an anti -turn ori genie growth inhibitor but later becomes tumor promoting and is another reason why selective inhibiti on of pathogenic el ements of signaling is so strongly desired. In light of these inherent limitations, current treatment strategies have refocused on identification and inhibition of critical distal events in ⁇ signaling, which in theory would preferentially target the pathologic, but not physiological functions of ⁇ signaling.
  • compounds are inhibitors ciapains.
  • compounds are selective and/or specific calpain inhibitors.
  • compounds are specific inhibitors of one of: CAPNl, CAPN2 or CAPN9.
  • compounds are selective inhibitors of one of: CAPNl , CAPN2 or CAPN9.
  • compounds are selective inhibitors of: CAPNl and CAPN2, or CAPNl and CAPN9, or CAPN2 and CAPN9.
  • compounds are effective inhibitors of CAPN1 , CAPN2 and/or CAPN9.
  • Keto-amide compounds of the present invention are broadly effective in treating a host of conditions arising from fibrosis or inflammation, and specifically including those associated with myofibroblast differentiation.
  • compounds of the invention are active therapeutics for a diverse set of diseases or disorders that include or that produces a symptom which include, but are not limited to; liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemi c scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic- reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post- vasectomy pain syndrome, and rheumatoid arthritis diseases or disorders.
  • Certain embodiments of the present invention are directed toward using these keto- amide compounds to treat diseases or conditions or that produces a symptom in a subject which include, but not limited to: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases.
  • methods for alleviating or ameliorating a condition or disorder, affected at least in part by the enzymatic activity of CAPN1 , CAPN2, and/or CAPN9, or mediated at least in part by the enzymatic activity of CAPN1, CAPN2, and/or CAPNl wherein the condition includes or produces a symptom which includes: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic- reperfusion
  • the methods, compounds, and/or compositions of the present invention are used for prophylactic therapy.
  • the CAPNl, CAPN2, and/or CAPN9 inhibiting compounds demonstrate efficacy in animal models of human disease. Specifically, in-vivo treatment of mice, rabbits, and other mammalian subjects with compounds of the present invention establish the utility of these compounds as therapeutic agents to modulate CAPNl, CAPN2, and/or CAPN9 activities in humans and thereby ameliorate corresponding medical conditions.
  • Some embodiments provide compounds, pharmaceutical compositions, and methods of use to inhibit myofibroblast differentiation. Some embodiments provide compounds, pharmaceutical compositions, and methods of use for inhibiting CAPNl, CAPN2, and/or CAPN9 or combinations of these enzyme activities such as CAPNl and CAPN2, or CAPNl and CAPN9, or CAPN2 and CAPN9. Some embodiments provide methods for treatment of diseases and disorders by inhibiting CAPNl , CAPN2, and/or CAPN9 or combinations of these enzymatic activities.
  • Certain embodiments provide novel small molecules that are specific or selective inhibitors of CAPNl, CAPN2, and/or CAPN9 activity, or selective inhibitors of combinations of CAPNl , CAPN2 and CAPN9 activities, e.g., selective inhibitors of CAPNl and CAPN2, or CAPNl and CAPN9, or CAPN2 and CAPN9.
  • the compound has a structure represented by Formula I:
  • each R 4 is independently selected from the group consisting of: H and each R x and R J is independently selected from the group consisting of: hydrogen, Ci-Cg alkyl, substituted Ci-Cg alkyl, Ci-Cg aikenyl, substituted Ci-Cg alkenyl, Ci-Cg alkynyl, substituted Ci-Cg alkynyl, C 3 -C 7 aiyl, substituted C 3 -C 7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloal kyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocvcloalkvl, C 3 - C 9 heteroaryl , substituted C3-C9 heteroaryl, Ci-Cg alkoxy, substituted Ci-Cg al koxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR 2 , NH 2 ,
  • L is selected from the group consisting of: R ? , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethyiene glycol, -CO- polyethylene glycol, substituted sulfonyl, substituted sulfmyl, thioacyl, aminoacyl, phthaiimido, and formyl; and wherein any two or more W groups can be bonded together to form a C 3 -C 12 cycloalkyl ring structure, a C Ci 2 fused cycloalkyl ring structure, a C 3 -C 12 aryl ring structure, a C3-C 12 fused aryl ring structure, a C 3 -C 12 heteroaryi ring structure, a C 3 -C 12 fused heteroaryl ring structure, a C 3 -C 12 heterocyclic ring structure, and a C
  • Some embodiments include a compound selected from the group consisting of:
  • compositions that include an effective amount of one or more compounds of Formula I-XVIII described herein and a
  • methods for inhibiting CAPNl, CAPN2 or CAPN9 that includes contacting (in vivo or in vitro) cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds of Formula I- XVIII described herein.
  • methods are provided for selectively inhibiting one of:
  • CAPNl, CAPN2, or CAPN9 that includes contacting (in vivo or in vitro) ceils (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds of Formula I-X VIII described herein.
  • methods are provided for selectively inhibiting two of: CAPNI, CAPN2, or CAPN9 (e.g., CAP I and CAPN2, or CAPNI and CAPN9 or CAPN2 and CAPN9) that includes contacting (in vivo or in vitro) ceils (including neurons/mi croglia /invading macrophages) with an effective amount of one or more compounds of Formula I- XVIII described herein.
  • CAPNI, CAPN2, or CAPN9 that includes contacting (in vivo or in vitro) cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds of Formula I-XVIH described herein.
  • CAPNI , CAPN2, or CAPN9 e.g., CAPNI and CAPN2, or CAPNI and CAPN9 or CAPN2 and CAPN9 that includes contacting (in vivo or in vitro) (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds of Formula I- XVIII described herein.
  • a method for treating a disease or disorder affected at least in part by CAPNI, CAPN2, and/or CAPN9, where the method comprises administering to a subject in need of treatment an effective amount of one or more compounds of Formula I- XVIII, or a pharmaceutical composition comprising a phannaceuticaliy acceptable excipient and an effective amount of one or more compounds of Formula I-XVDI described herein.
  • an article of manufacture for use in inhibiting CAPNI, CAPN2, and/or CAPN9 and treating a disease or disorder affected at least in part by CAPNI, CAPN2, and/or CAPN9, wherein the article comprises a a compound of Formula I-XVDI as provided herein.
  • the diseases affected at least in part by CAPNI, CAPN2, and/or CAPN9 are as provided herein.
  • the article of manufacture further includes a label with instructions for using the composition to treat a disease or disorder affected at least in part by C APNI, CAPN2, and/or CAPN9,
  • Compounds of the present invention inhibit calpain. Specifically, these compounds of Formula I-XVUI inhibit CAPN 1, 2, and/or 9. Such compounds are useful for the treatment or therapy of fibrotic and other diseases.
  • references to a certain element such as hydrogen or H is meant to include all isotopes of that element.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • Compounds comprising radioisotopes such as tritium, C 14 , P 3 and S 35 are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.
  • a fibrotic disease includes, for example, liver fibrosis (alcoholic, viral, autoimmune, metabolic and hereditary chronic disease), renal fibrosis (e.g., resulting from chronic inflammation, infections or type II diabetes), lung fibrosis (idiopathic or resulting from environmental insults including toxic particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, bacterial infections including tuberculosis, medicines, etc.), interstitial fibrosis, systemic scleroderma (autoimmune disease in which many organs become fibrotic), macular degeneration (fibrotic disease of the eye), pancreatic fibrosis (resulting from, for example, alcohol abuse and chronic inflammatory disease of the pancreas), fibrosis of the spleen (from sickle cell anemia, other blood disorders) cardiac fibrosis (resulting from infection, inflammation and hypertrophy), mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retro
  • ameliorating refers to any therapeutically beneficial result in the treatment of a disease state, e.g., an inflammatory disease state, including lessening in the severity or progression, remission, or cure thereof.
  • ameliorating includes prophylaxis of a disease state
  • in vitro refers to processes that occur in a living cell growing separate from a living organism, e.g., growing in tissue culture.
  • / / vivo refers to processes that occur in a living organism.
  • mammal as used herein includes both humans and non-humans and include but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines.
  • sufficient amount means an amount sufficient to produce a desired effect, e.g., an amount sufficient to modulate protein aggregation in a cell
  • terapéuticaally effective amount is an amount that is effective to ameliorate a symptom of a disease.
  • a therapeutically effective amount can, in some embodiments, be a "prophylactically effective amount” as prophylaxis can be considered therapy.
  • Stereoisomers of compounds also known as optical isomers
  • compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions.
  • the compounds of the present technology can exist as solvates, especially hydrates. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds.
  • Compounds of the present technology can exist as organic solvates as well, including DMF, ether, and alcohol solvates among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry, [0037] "Subject” refers to a mammalian organism treated using a compound of the present invention. The “subject” can be a human or non-human mammalian organism.
  • Treating" or “treatment” of a disease or disorder in a subject refers to 1) preventing the disease or disorder from occurring in a subject that is predisposed or does not yet display symptoms of the disease or disorder; 2) inhibiting the disease or disorder or arresting its development; or 3) ameliorating or alleviating the cause of the regression of the disease or disorder.
  • Naturally occurring amino acid side chain will be understood to be the substituent of a natural amino acid.
  • Naturally occurring amino acids have a substituent attached to the a-carbon.
  • Naturally occurring amino acids include the list shown below. Charged:
  • non-naturally occurring amino acid side chain will be understood to be the substituent of a non-naturally occurring amino acid.
  • Non-naturally occurring amino acids have a substituent attached to the a-carbon.
  • Non-naturally occurring amino acids include the list described below.
  • Non-natural amino acids include ⁇ -amino acids ( ⁇ 3 and ⁇ 2 ), Homo-ami no acids, Proline and Pyruvic acid derivatives, 3-substituted Alanine derivatives, Glycine derivatives. Ring-substituted Phenylalanine and Tyrosine Derivatives, Linear core amino acids and N- methyl amino acids.
  • Exemplary non-natural amino acids are available from Sigma-Aldridge, listed under "unnatural amino acids & derivatives.” See also, Travis S. Young and Peter G. Schultz, "Beyond the Canonical 20 Amino Acids: Expanding the Genetic Lexicon,” J. Biol. Chem. 2010 285: 11039-1 1044.
  • the phrase “modulating or inhibiting (the activity of) CAPNl, CAPN2, and/or CAPN9” refers to use of any agent capable of altering the cellular expression levels and/or biological activity of the CAPNl, CAPN2, and/or CAPN9 gene, messenger RNA, or protein.
  • an agent that modulates or inhibits the biological activity of CAPNl, CAPN2, and/or CAPN9 directly interferes with the expression (such as transcription, splicing, transport, etc.) of the gene encoding the CAPNl , CAPN2, and/or CAPN9 mRNA.
  • an agent that modulates or inhibits the activity of CAPNl, CAPN2, and/or CAPN9 directly interferes with the biological activity or production of the CAPNl , CAPN2, and/or CAPN9 proteins (such as though inhibition of translation, post-translational modifications, intracellular transport, disruption of interactions between one or more proteins, etc.).
  • an agent that modulates or inhibits the activity of CAPNl, CAPN2, and/or CAPN9 does not directly affect the expression level or activity of CAPNl, CAPN2, and/or CAPN9 but, instead, alters the activity or expression levels of a protein whose function directly impacts the expression or activity of CAPNl, CAPN2, and/or CAPN9 (such as, for example, calpastatin).
  • an agent may specifically inhibit one or more CAPN l, CAPN2, and/or CAPN9 enzymes. In yet other embodiments, an agent may selectively inhibit CAPNl, CAPN2, and/or CAPN9 enzymes. In yet other embodiments, an agent may both specifically and selectively inhibit one or more CAPNl, CAPN2, and/or CAPN9 enzymes. In yet other embodiments, an agent is neither a specific nor selective inhibitor for one or more CAPNl, CAPN2, and/or CAPN9 enzymes, but is still active for the inhibition of one or more of the CAPN l, CAPN2, and/or CAPN9 enzymes. Calpains are also expressed in cells other than neurons, microglia and invading macrophages. In particular, they are important in skeletal muscle and herein inhibition of calpains also refers to inhibition in these cells as well.
  • an agent is said to be "specific” if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular target (for example, a protein, such as CAPN9, CAPN2, or CAPNl as well as a nucleic acid encoding the same) than it does with alternative substances, especially as compared to substances that are structurally related to the target, e.g., an isoform of the target.
  • a target protein such as CAPN9, CAPN2, or CAPNl if it binds with greater affinity, avidity, more readily, and/or with greater duration than it binds to other substances
  • an agent is "specifi c" for a target if a concentration of the agent that produces a maximal effect in an in vitro or in vivo target assay (e.g., a binding assay or an enzyme activity assay) produces no measurable effect in a comparable assay carried out using another substance, especially one or more substances that are structurally related to the target.
  • an in vitro or in vivo target assay e.g., a binding assay or an enzyme activity assay
  • an agent is said to be a "specific inhibitor" of CAPNl , CAPN2 or CAPN9 if it inhibits the biological activity and/or expression level of CAPNl, CAPN2 or CAPN9 without inhibiting the biological activity and/or expression level of other members of the calpain family of proteases or other members of the TRP family of calcium channels.
  • an agent is an agent is said to be "selective" if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular target or a small set of structurally-related targets (for example, a protein, such as CAPN9, CAPN2, or CAPNl as well as a nucleic acid encoding the same) than it does with alternative substances, especially as compared to other substances that are structurally related to the target or small set of structurally-related targets, e.g., an isoform of the target.
  • a protein such as CAPN9, CAPN2, or CAPNl
  • alternative substances especially as compared to other substances that are structurally related to the target or small set of structurally-related targets, e.g., an isoform of the target.
  • a "selective" agent reacts similarly with multiple related targets, whereas a “specific” agent reacts with its target in a manner that is markedly differently from the way it interacts with other biological molecules.
  • an antibody "selectively binds" to a target protein (such as CAPN9, CAPN2, or CAPNl if it binds with greater affinity, avidity, more readily, and/or with greater duration to two related targets (e.g., CAPN9, CAPN2) than it binds to other substances.
  • an agent is "selective" for a set of targets if a concentration of the agent that produces a maximal effect in an in vitro or in vivo assay (e.g., a binding assay or an enzyme activity assay) with a first target molecule produces a measurable effect in a comparable assay carried out using a second target molecule.
  • an agent is selective if it binds to two or more targets (especially structurally-related targets) with Kd or IC50 (or other related measures) ratios of first to second target that are within a range of 1 : 1 to about 1 :500.
  • an agent is said to be a "selective inhibitor" of CAPNl , CAPN2 or CAPN9 if it can be shown to inhibit the biological activity and/or expression level of two or three of CAPNl, CAPN2 or CAPN9 (e.g., CAPNl and CAPN2, or CAPNl and CAPN9, or CAPN2 and CAPN9 or CAPNl, CAPN2 and CAPN9) without inhibiting the biological activity and/or expression level of level of other members of the calpain family of proteases or other members of the TRP family of calcium channels.
  • the term "contacting,” as used herein, includes both directly contacting cells, for example, in vivo, in vitro, or ex vivo, or indirectly contacting cells, such as, for example, by administering an agent to a subject. Further, "contacting" a cell with an agent includes administering or applying a prodrug version of the agent. In some embodiments, the cell is in a fibrotic tissue, a cancerous tissue, and/or tissue with high TGFP signaling.
  • the term “fibrosis” refers to the increased extracellular matrix protein synthesis and deposition that results in the accumulation of scar tissue.
  • fibrotic tissue refers to tissue that has high levels of extracellular matrix proteins ⁇ i.e., collagen), undergone extensive remodeling (though activity of matrix metalloproteinases) and exhibits progressively diminished physiological function, due to the activity of ceils that have undergone myofibroblast differentiation (such as, EMT and/or FMT).
  • the cell is in a cancerous tissue, such as in tissue that comprises at least one cancer cell.
  • the cell is in a tissue with high ⁇ signaling.
  • the term “inhibit,” “decrease” and grammatical derivations thereof, refers to the ability of an agent to block, partially block, interfere, reduce or deactivate a pathway or mechanism of action.
  • the term “inhibit” or “decrease” encompasses a complete and/or partial loss of activity, e.g., a loss in activity by at least 10%, in some embodiments, a loss in activity by at least 20%, 30%, 50%, 75%, 95%, 98%, and up to and including 100%.
  • the term "expression level and/or activity of a calpain” refers to the amount of a calpain found in a ceil, tissue and/or subject, and/or a function of a calpain. Such functions can include, without limitation, its protease ability, its function in modulating ⁇ signaling, its function in myofibroblast transition (such as EMT and/or FMT).
  • the expression level of a calpain refers to mRNA expression level.
  • the expression level of a calpain refers to protein expression level.
  • the myofibroblast transition i s EMT (such as a TGFp-mediated EMT).
  • at least one agent inhibits Fibroblast-to-Myofibroblast Transition (FMT).
  • the calpain is CAPN9, CAPN1, and/or CAPN2.
  • the terms "prevent,” “preventing,” “prevention,” “prophylactic treatment” and the like refer to reducing the probability of developing a disease, disorder, or condition in a subject, who does not have, but is at risk of or susceptible to developing a disease, disorder, or condition.
  • an agent can be administered prophylactically to prevent the onset of a disease, disorder, or condition, or to prevent the recurrence of a disease, disorder, or condition.
  • the term "about,” when referring to a value can be meant to encompass variations of, in some aspects, ⁇ 100% in some aspects ⁇ 50%, in some aspects ⁇ 20%, in some aspects ⁇ 10%, in some aspects ⁇ 5%, in some aspects ⁇ 1%, in some aspects ⁇ 0.5%, and in some aspects ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.
  • Alkyi refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 ⁇ ), ethyl (CH 3 CH 2 -), «-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), w-butyl (CH 3 CH 2 CH 2 CH 2 ⁇ ), isobutyl
  • ( ⁇ alkyi refers to an a k ] group having x number of carbon atoms.
  • C x alkenyl refers to an alkenyl group having x number of carbon atoms.
  • Alkynyi refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetyl enic (-C ⁇ C-) unsaturation. Examples of such alkynyi groups include acetyl enyl (-C ⁇ CH), and propargyl (-CH 2 C ⁇ CH). C x alkynyi refers to an alkynyi group having x number of carbon atoms.
  • Substituted alkyi refers to an alkyi group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acyiamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl , aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aiyloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloaikyl, cycloalkyloxy, substituted
  • the substituted alkyi groups include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyi, fluorom ethyl and the like.
  • Cycloalkyl or “Cyclyl alkyl” refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms and no heteroatoms. Cycloalkyl encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems. In fused ring systems, one or more of the rings can be cycloalkyl, aryl,
  • heterocycloalkyl or heteroaryl provided that the point of attachment is through the original non-aromatic cycloalkyl ring.
  • Substituted alkenyl refers to alkenyl groups having from J to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aiyloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cyclo
  • Substituted alkynyl refers to aikynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonyl amino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl esterjoxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyl oxy, substituted substituted
  • Ar refers to any group which is aromatic. This group must be cyclic; however, it may contain heteroatoms or may not.
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, «-propoxy, isopropoxy, w-butoxy, t-butoxy, sec-butoxy, and w-pentoxy.
  • Substituted alkoxy refers to the group -0-(substituted alkyl) wherein substituted alkyl is defined herein.
  • Preferred substituted alkyl groups in -0-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, diflurom ethyl, fluoromethyl and the like.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloaikyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl -C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyi, substituted alkenyi, alkoxy, substituted alkoxy, aikynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, substituted
  • Acylamino refers to the groups -NR 0 C(G)aikyl, - R 30 C(O)substituted alkyl, - R 30 C(O)cycloaikyl, -NR 30 C(O)substituted cycloalkyl -N R 30 C(O)alkenyl,
  • R 3 ° is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyi, substituted alkenyi, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaiyl, substituted heteroaiyl, heterocyclic and substituted heterocyclic are as defined herein.
  • Aminoacyi refers to the groups H-C(N)-, alkyl-C(N)-, substituted alkyl-C(N)-, alkenyl-C( )-, substituted alkenyl-C(N)-, alkynyl -C(N)-, substituted alkynyl-C(N)-, cycloalkyl -C(N)-, substituted cycloalkyl-C(N)-, aryl-C(N)-, substituted aryl-C(N)-, heteroaiyl -C(N)-, substituted heieroaiyl-C(N)-, heterocyclic-C(N)-, and substituted heterocyclic-C(N)-, wherein alkyl, substituted alkyl, alkenyi, substituted alkenyi, alkoxy, substituted alkoxy, aikynyl, substituted alkynyl, cycloalkyl-C(
  • Acyloxy refers to the groups alkyi-C(())0-, substituted alkyl-C(0)0-, aikenyl-C(0)0-, substituted alkenyl-C(0)0-, alkynyl-C(0)0-, substituted alkynyl -C(0)0-, aryl-C(0)0-, substituted aryl-C(0)0-, cycloalkyl-C(0)0 ⁇ , substituted cycloalkyl -C(0)0-, heteroaryl -C(0)0-, substituted heteroaryl-C(0)0-, heterocyclic-C(0)0-, and substituted heterocyclic-C(0)0- wherein alkyl, substituted alkyl, alkenyi, substituted alkenyi, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein,
  • Amino refers to the group -NH 2 .
  • Substituted amino refers to the group -NR l R 32 where R 31 and I 1 are
  • alkyl, substituted alkyl independently selected from the group consisting of hydrogen, alkyl, substituted alkyl , alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and substituted sulfonyl and wherein R 3 i and R j2 are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R 3 ' and R 3i are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl
  • R i is hydrogen and R 32 is alkyl
  • the substituted amino group is sometimes referred to herein as alkylamino.
  • R 31 and R 3 are alkyl
  • the substituted amino group is sometimes referred to herein as dialkylamino.
  • a rnonosubstituted amino it is meant that either R 31 or R 32 is hydrogen but not both.
  • a disubstituted amino it is meant that neither R 31 nor R 32 are hydrogen.
  • Aminocarbonyl refers to the group -C(0)NR 3 R 3 " where R 33 and R' 4 are
  • alkyl, substituted alkyl independently selected from the group consisting of hydrogen, alkyl, substituted alkyl , alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Aminoacyl carbonyloxy refers to the group -C(NR 33 )OR 34 where R 33 and R 4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R j3 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted hetero
  • Arninothiocarbonyi refers to the group -C(S)NR j3 R 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R' 3 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
  • Aminocarbonylamino refers to the group -NR 3J C(0)NR 3 R 34 where R 30 is hydrogen or alkyl and R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl
  • Arninothiocarbonyi amino refers to the group -NR " C(S)NR “ R” where R " is hydrogen or alkyl and R 33 and R j4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R j3 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, substituted cycloalky
  • Aminocarbonyloxy refers to the group -0-C(0)NR 33 R 34 where R 33 and R j4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R' 3 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroary
  • Aminosuifonyi refers to the group -S0 2 R 3 R 3it where R 3 and R' 4 are
  • Aminosuifonyi oxy refers to the group where R 33 and R "' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R j3 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein aikyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycl
  • Aminosulfonylamino refers to the group -NR J J -S0 2 NR :> R ⁇ " where R ⁇ is hydrogen or alkyl and R JJ and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted aikyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 3 ' and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substitute
  • Substituted aryl refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably J to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl , aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)amino
  • Aryloxy refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.
  • Substituted aryloxy refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.
  • Arylthio refers to the group -S-aryl, where aryl is as defined herein.
  • Substituted arylthio refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
  • Carboxy or “carboxyl” refers to -COOH or salts thereof.
  • Carboxyl ester or “carboxy ester” refers to the groups -C(0)0-alkyl
  • -C(0)0-substituted alkyl -C(0)0-alkenyl, -C(0)0-substituted alkenyl, -C(0)0-alkynyl, -C(0)0-substituted alkynyl, -C(0)0-aryl, -C(0)0-substituted aryl, -C(0)0-cycloalkyl, -C(0)0-substituted cycloalkyi, -C(0)0-heteroaryl, -C(0)0-substituted heteroaryl,
  • R 30 is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cvcloalkyl, substituted cvcloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • (Carboxyl ester)oxy refers to the group -0-C(0)0-alkyl, -0-C(0)0-substituted alkyl, -0-C(0)0-alkenyl, -0-C(0)0-substituted alkenyl, -0-C(0)0-alkynyl,
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cvcloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Cyano refers to the group -C ⁇ N.
  • Cycloalkyl refers to a saturated or unsaturated but nonaromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems.
  • C x cvcloalkyl refers to a cycloalkyl group having x number of ring carbon atoms.
  • suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
  • One or more the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring saturated carbocyclic ring
  • "Substituted cycloalkyl” refers to a cycloalkyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl amino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl
  • Cycloalkyloxy refers to -O-cycloalkyl.
  • Substituted cycloalkyloxy ' refers to -0-(substituted cycloalkyl).
  • Cycloalkylthio refers to -S-cycloalkyl.
  • Substituted cycloalkylthio refers to -S-(substituted cycloalkyl).
  • Ethylene glycol refers to the group -0-CH 2 CH 2 -0-E, wherein E is either H or
  • Halo or "halogen” refers to fluoro, chloro, bromo and iodo and preferably is iluoro or chloro,
  • Heteroaryl refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring.
  • Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings ma or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ 0), sulfinyl, or sulfonyl moieties.
  • Preferred heteroaryl s include 5 or 6 membered heteroaryl s such as pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
  • Substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
  • Heteroaryl oxy refers to -O-heteroaryl.
  • Substituted heteroaryl oxy refers to the group -0-(substituted heteroaryl).
  • Heteroarylthio refers to the group -S-heteroaryl.
  • Substituted heteroarylthio refers to the group -S-(substituted heteroaryl).
  • Heterocycle or “heterocyclic” or “heterocycloalkyl” or “heterocyclvl” refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms and from I to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen.
  • C x cycloalkyl refers to a heterocycloalkyl group having x number of ring atoms including the ring heteroatoms.
  • Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems.
  • one or more the rings can be cycloalkyl, aryl or heteroaryl provided that the point of attachment is through the non-aromatic ring.
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, sulfonyl moieties,
  • Substituted heterocyclic or “substituted heterocycloalkyl” or “substituted heterocyclvl” refers to heterocyclvl groups that are substitiited with from 1 to 5 or preferably I to 3 of the same substituents as defined for substituted cycloalkyl.
  • Heterocyclyloxy refers to the group -O-heterocycyl.
  • Substituted heterocyclyloxy refers to the group -0-(substituted heterocycyl).
  • Heterocyclvl thio refers to the group -S-heterocycyl.
  • Substituted heterocyclylthio refers to the group -S-(substituted heterocycyl).
  • heterocycle and heteroaryl include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothl zole, phenazine, isoxazole, phenoxazine, phenothl zine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline
  • Neitro refers to the group -N0 2 .
  • Phthalimido refers to the group . Phthalimide functional groups are well known in the art and can be generated by covalentiy bonding a nitrogen atom to a C 6 H 4 (CO) 2 group,
  • Polyethylene glycol refers to the group -0-(CH 2 CH 2 -0) n -E, wherein E is either H or CH 3 , where n is between 2-20,000.
  • Spirocyciic ring system refers to a ring system with two rings that has a single ring carbon atom in common to both rings.
  • bi cyclic can incorporate up to four heteroatoms in either ring.
  • Bicyclic ring system refers to a ring system with two rings that has two ring carbon atoms in common, and which can located at any position along either ring.
  • bicyclic ring system can incorporate up to four heteroatoms in either ring.
  • Substituted sulfonyl refers to the group -S0 2 -alkyl, -S0 2 - substituted alkyl, -SO 2 -OH, -SO 2 -alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cvlcoalkyl, -S0 2 -aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -S0 2 -substituted heteroarvl, -S0 2 - eterocycIic, -S0 2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycl
  • Substituted sulfonyl includes groups such as m ethyl -S0 2 -, phenyl-S0 2 -, and 4-methylphenyl-S0 2 -.
  • Preferred substituted alky] groups on the substituted alkyl-S0 2 - include halogenated alkyl groups and particularly halogenated methyl groups such as tnfluoromethyl, difluromethyl, fluoromethyl and the like.
  • Substituted sulfmyl refers to the group -SO-alkyl, -SO-substituted alkyl, -SO-alkenyl, -SO-substituted alkenyl, -SO-cycloalkyl, -SO-substituted cyicoalkyl, -SO-aryl, -SO-substituted aryl, -SO-heteroaryl, -SO-substituted heteroaryl, -SO-heterocyclic,
  • Substituted heterocyclic includes groups such as methyl-SO-, phenyl-SO-, and
  • substituted alkyl groups on the substituted alkyl-SO- include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
  • Sulfonyloxy or “substituted sulfonyl oxy” refers to the group -OS0 2 -alkyl, -OS0 2 -substituted alkyl, -OS0 2 -OH, -OS0 2 -alkenyl, -OS0 2 -substituted alkenyl,
  • -OS0 2 -cycioalkyl -OS0 2 -substituted cyicoalkyl, -OS0 2 -aryl, -OS0 2 -substituted aryi, -OS0 2 -heteroaryl, -OS0 2 -substituted heteroaryl, -OS0 2 -heterocyclic, -OS0 2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • substitution or “substitution” generally refers groups which are covalently bonded to an atom to replace a hydrogen atom.
  • the atom in this general context can be a carbon atom or a heteroatom, for example a nitrogen atom.
  • Thioacyl refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl -C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-,
  • heteroaryl-C(S)- substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted
  • heterocyclic-C(S)- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Forml refers to the group -C(0)H.
  • Alkylthio refers to the group -S-alkyl wherein alkyl is as defined herein.
  • Substituted alkylthio refers to the group -S ⁇ (substituted alkyl) wherein substituted alkyl is as defined herein.
  • Preferred substituted alkyl groups on -S-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluorom ethyl and the like.
  • Stereoisomers of compounds include all chiral, diastereomeric, and raeemic forms of a structure, unless the specific stereochemistry is expressly indicated.
  • compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions.
  • Both raeemic and d or 1 enriched stereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.
  • the compounds of the present technology may exist as solvates, especially hydrates. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds.
  • Compounds of the present technology may exist as organic solvates as well, including DMF, ether, and alcohol solvates among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry.
  • any substituted functional group is substituted at from one to three different positions, and those one to three substituting groups are capable of each independently being substituted at one to three positions, wherein any and each substituting group is independently selected from the group consisting of: halogen, hydroxyl, Cj -Cg alkyl, substituted Ci-Cg alkyl, Ci-Cg alkenyl, substituted Ci-Cg alkenyl, Ci-Cg aikynyl, substituted Ci-Cg alkynyl, acyl, acylamino, aminocarbonylamino, aminoacyl, acyloxy, amino, substituted amino,
  • any and ail heteroaryl and heterocycloalkyi substituents may contain up to four heteroatoms selected from the group consisting of: O, N, and S.
  • impermissible substitution patterns e.g., methyl substituted with 5 fiuoro groups. Such impermissible substitution patterns are well known to the skilled artisan.
  • impermissible substitution patterns are well known to the skilled artisan.
  • the text refers to various embodiments of the present compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather, it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present technology.
  • the present technology is directed to compounds, compositions, and methods of using said compounds or compositions to inhibit CAPN1, CAPN2, and/or CAPN9. Also provided are methods useful in order treating diseases or disorders which are affected at least in part by CAPN1, CAPN2, and/or CAPN9.
  • the present technology provides for one or more compounds of a core structure of a mono- or di- amino acid or tri -amino acid wherein the compounds may be substituted by one or more organic functional groups at the C-terminus, N-terminus, and/or the side-chain.
  • the invention is a compound comprising Formula II:
  • n is from 1 -1 1 ; each R ! and R 3 is independently selected from the group consisting of: hydrogen, Ci-C 8 alkyl, substituted Ci-Cg alkyl, Ci-Cg alkenyl, substituted C Cg alkenyl, Ci-Cg alkynyl, substituted Ci-Cg alkynyl, C3-C7 aryl, substituted C3-C7 aryl, cyano, C3-C 10 cyeloalkyl, substituted C 3 -C 10 cyeloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C 3 - C9 heteroaryl, substituted C3-C9 heteroaryl, Ci-Cg alkoxy, substituted Ci-Cg alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR 2 , H 2 , NHR 2 , SR 2 ,
  • L 4 is selected from the group consisting of: R ⁇ , acy!, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosu!fony!, amidino, carboxy ester, -CO-ethylene glycol, -C0- polyethylene glycol, substituted sulfonyl, substituted sulfmyl, thioacyl, aminoacyl,
  • any two or more W groups can be bonded together to form a C 3 -C 12 cyeloalkyl ring structure, a C3-C 12 fused cyeloalkyl ring structure, a C3-C 12 aryl ring structure, a C3-C 12 fused aryl ring structure, a C 3 -C 12 heteroaryl ring structure, a C3-C 12 fused heteroaryl ring structure, a C3-C 12 heterocyclic ring structure, and a C3-C 12 fused heterocyclic ring structure; and wherein W n does not form an (S) * 2 2 ' group in the ring starting from the carbon attached to R 2 which is adjacent to the keto-amide functional group; or a tautomer and/or a pharmaceutically acceptable salt thereof.
  • the invention is a compound comprising Formula IH:
  • each R x and R 3 is independently selected from the group consisting of: hydrogen, Ci-Cg alkyl, substituted Cj -Cg alkyl, C ⁇ -C % alkenyl, substituted Cj-C 8 alkenyl, Ci ⁇ C 8 alkynyl, substituted Ci-Cg alkynyl, C 3 -C 7 aryl, substituted C 3 -C 7 aryl, cyano, C -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, C3-C 9 heterocycloalkvl, substituted C3-C9 heterocycloalkvl, C 3 - C 9 heteroaryl, substituted C3-C 9 heteroaryl, Ci-Cg alkoxy, substituted Ci-Cg alkoxy, amino, substituted amino
  • each R" is independently selected from the group consisting of: hydrogen, Ci -Cg alkyl, substituted Ci-Cg alkyl, Ci -Cg alkenyl, substituted Ci-Cg alkenyl, Ci-Cg alkynyl, substituted Ci-Cg alkynyl, C3-C7 aryl, substituted C 3 -C 7 aryl, cyano, OH, Ci-C 8 alkoxy, substituted Ci-Cg alkoxy, amino, substituted amino, C 3 -C 10 cycloal kyl, substituted C3-C10 cycloalkyl, C
  • L 4 is selected from the group consisting of: R 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO- polyethylene glycol , substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl,
  • the invention is a compound comprising Formula IV:
  • each R and R 3 is independently selected from the group consisting of: hydrogen, C C 8 alkyl, substituted Ci-Cg alkyl, Ci-Cs alkenyl, substituted Ci-Cx alkenyl, Ci-Cg alkynyl, substituted Ci-C 8 alkynyl, C 3 -C 7 aryl, substituted C 3 -C 7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C 3 - C9 heteroaryl, substituted C3-C9 heteroaryl, C ⁇ -C & alkoxy, substituted Ci-C 8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR 2 ,
  • each 2 is independently selected from the group consisting of: hydrogen, Ci-C 3 alkyl, substituted Ci-C% alkyl, C .
  • any R 2 substituent may be covalently bonded to or share another R 2 substituent to form a C 3 -C 12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;
  • L 4 is selected from the group consisting of: R 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl , amidino, carboxy ester, -CO-ethylene glycol, -CO- polyethyiene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl; and wherein any two or more Z groups can be bonded together to form a C 3 -C 12 cycloalkyl ring structure, a C 3 -C 12 fused cycloalkyl ring structure, a C 3 -C 12 aiyl ring structure, a C 3 -C 12 fused aiyl ring staicture, a C 3 -C 12 heteroaryl ring structure, a C 3 -C 12 fused heteroaryl ring structure, a C 3 -C 12 heterocyclic
  • the invention is a compound comprising Formula V :
  • Z 1 , Z 2 , and Z 3 are each independently selected from the group consisting of: CH 2 ,
  • each R and R is independently selected from the group consisting of: hydrogen, Ci-Cg alkyl, substituted Ci ⁇ C 8 alkyl, C C 8 alkenyl, substituted C Cg alkenyl, Cj-C 8 alkynyl, substituted Cj-C 8 alkynyl, C 3 -C7 aryl, substituted C 3 -C7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, C 3 -C9 heterocycloalkyl, substituted C 3 -C9 heterocycloaikyl, C 3 - C9 heteroaryl, substituted C 3 -C9 heteroaryl, Ci-C 8 alkoxy, substituted Ci-C 8 alkoxy, amino, substituted amino, alkylthio, substituted alkyithio, OH, OR 2 , NH 2 , NHR 2 , SR 2 , substituted sulfony
  • L 4 is selected from the group consisting of: R 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO- polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl,
  • any and all Z groups do not form an (S) ⁇ ⁇ " ⁇ ( ⁇ ) 1 ⁇ group in the ring starting from the carbon attached to R 2 which is adjacent to the keto-amide functional group, and wherein any two or more Z groups can be bonded together to form a C 3 -C 12 cycloalkyl ring structure, a C3-C 12 fused cycloalkyl ring structure, a C3-C12 aryl ring structure, a C3-C12 fused aryl ring structure, a C3-C12 heteroaryl ring structure, a C3-C12 fused heteroaryl ring structure, a C 3 -C 12 heterocyclic ring structure, and a C3-C . fused heterocyclic ring structure; or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • the invention is a compound comprising Formula VI:
  • L 4 is selected from the group consisting of: R 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO- polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl; and wherein any and all Z groups do not form an (S) ⁇ C ⁇ ⁇ C 0 ) ⁇ group in the ring starting from the carbon attached to R 2 which is adjacent to the keto-amide functional group, and wherein any two or more Z groups can be bonded together to form a C 3 -C 12 cycloalkyl ring structure, a C 3 -C 12 fused cycioalkyl ring structure, a C 3 -C .
  • aryl ring structure a C 3 -C 12 fused aryl ring staicture, a C 3 -C 12 heteroaryl ring structure, a C 3 -C 12 fused heteroaryl ring structure, a C 3 -C 12 heterocyclic ring structure, and a C 3 -C 12 fused heterocyclic ring structure; or a tautomer and/or a pharmaceutically acceptable salt thereof.
  • the invention is a compound comprising Formula VII:
  • each R and R 3 is independently selected from the group consisting of: hydrogen, Ci ⁇ C 8 alky], substituted Ci-C 8 alkyl, Ci-C 8 alkenyl, substituted C]-C 8 alkenyl, Ci ⁇ C 8 al kynyl, substituted Ci ⁇ C 8 alkynyl, C 3 -C 7 aryl, substituted C 3 -C7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C -C 10 cycloalkyl, C 3 -C9 heterocycloalkyl, substituted C 3 -C9 heterocycloalkyl, C - C9 heteroaryl, substituted C 3 -C9 heteroaryl, Cj -C 8 alkoxy, substituted Cj -C 8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR 2 , NH 2 , HR 2 , SR 2 , substituted
  • L 4 is selected from the group consisting of: R 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethyiene glycol, -CO- polyethylene glycol, substituted sulfonyl, substituted suifmyl, thioacyl, aminoacyl,
  • any and all Z groups do not form an (S) ⁇ CH2CH2C (°) NH group in the ring starting from the carbon attached to R 2 which is adjacent to the keto-amide functional group; and wherein any two or more Z groups can be bonded together to form a C 3 -C 12 cycloalkyi ring structure, a C 3 -C 12 fused cycioalkyi ring structure, a C 3 -C 12 aryl ring structure, a C 3 -C 12 fused aryl ring structure, a C3-C 12 heteroaryl ring structure, a C3-C 12 fused heteroaryl ring structure, a C3-C 12 heterocyclic ring structure, and a C 3 -C 12 fused heterocyclic ring structure; or a tautomer and/or a pharmaceutically acceptable salt thereof.
  • the invention is a compound comprising Formula VIH:
  • each R x and R J is independently selected from the group consisting of: hydrogen, Ci-Cg alkyl, substituted Ci-Cg alkyl, Ci-Cg aikenyl, substituted Ci-Cg alkenyl, Ci-Cg alkynyl, substituted Ci-Cg alkynyl, C 3 -C 7 aryl, substituted C 3 -C 7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloal kyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C 3 - C 9 heteroaryl, substituted C3-C9 heteroaryl, Ci-Cg alkoxy, substituted Ci-Cg alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR 2 , NH 2 , NHR 2 , SR 2 , substituted
  • L 4 is selected from the group consisting of: R ⁇ , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonvloxv, aminosuifonyi, amidino, carboxy ester, -CO-ethylene glycol, ⁇ CO- polyethylene glycol, substituted sulfonyl, substituted sulfmyl, thioacyl, aminoacyl,
  • any and all Z groups do not form an (S) ⁇ CH CH2c (°) NH group in the ring starting from the carbon attached to R 2 which is adjacent to the keto-amide functional group; and wherein any two or more Z groups can be bonded together to form a C 3 -C 12 cycloalkyl ring structure, a C3-C 12 fused cycloalkyl ring structure, a C3-C 12 aryl ring structure, a C3-C12 fused aryl ring structure, a C 3 -C 12 heteroaryl ring structure, a C3-C 12 fused heteroaryl ring structure, a C 3 -C 12 heterocyclic ring structure, and a C 3 -C 12 fused heterocyclic ring structure; or a tautomer and/or a pharmaceutically acceptable salt thereof.
  • the invention is a compound comprising Formula IX:
  • ⁇ .7. ⁇ . ⁇ Z 4 , ⁇ Z 6 , and Z ' are each independently selected from the group consisting of: Ci k C(R 2 ) 2 , CH 2 , O, Nil, NR 2 , C( O). ⁇ S), S, S( ()). S( ()),, -C-, -CH-, a C 3 ⁇ C !2 spirocyclic group of where m is 1-19, wherein any two adjacent Z atoms may form
  • each R and R 3 is independently selected from the group consisting of: hydrogen, Ci-Cg alkyl, substituted Ci-Cg alkyl, Ci-Cg alkenyl, substituted Cj-Cg alkenyl, Ci-Cg alkynyl, substituted Ci-C 8 alkynyl, C 3 -C 7 aryl, substituted C3-C7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C3-C 10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3- C 9 heteroaryl, substituted C3-C9 heteroaryl, Cj -Cg alkoxy, substituted Cj -Cg alkoxy, amino, substituted amino, alkyl thio, substituted alkyithio, OH, OR 2 , M k NHR 2 , SR 2 , substituted substituted
  • L 4 is selected from the group consisting of: R 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO- polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl; and wherein any and all Z groups do not form an (S) ⁇ C ⁇ ⁇ C 0 ) ⁇ group in the ring starting from the carbon attached to R 2 which is adjacent to the keto-amide functional group, and wherein any two or more Z groups can be bonded together to form a C 3 -C 12 cycloalkyl ring structure, a C 3 -C 12 fused cycioalkyl ring structure, a C 3 -C .
  • aryl ring structure a C 3 -C 12 fused aryl ring staicture, a C 3 -C 12 heteroaryl ring structure, a C 3 -C 12 fused heteroaryl ring structure, a C 3 -C 12 heterocyclic ring structure, and a C 3 -C 12 fused heterocyclic ring structure; or a tautomer and/or a pharmaceutically acceptable salt thereof.
  • the invention is a compound comprising Formula X:
  • each R and R 3 is independently selected from the group consisting of: hydrogen, Ci-C 8 alkyl, substituted Ci-C 8 alkyl, Ci-Cs aikenyl, substituted Ci-Cx alkenyl, Ci-Cg alkynyl, substituted Ci-C 8 alkynyl, C 3 -C 7 aryl, substituted C 3 -C 7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C 3 - C9 heteroaryl, substituted C3-C9 heteroaryl, Ci-C 8 alkoxy, substituted Ci-C 8 alkoxy, amino, substituted amino, alkylthio, substitute
  • L is selected from the group consisting of: R 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO- polyethylene glycol, substituted sulfonyl, substituted sulfmyl, thioacyl, aminoacyl, phthaiimido, and formyl; and wherein any and all Z groups do not form an (S) ⁇ c ⁇ 2Ci 1 ⁇ 2 c (°) N ⁇ group in the ring starting from the carbon attached to R 2 which is adjacent to the keto-amide functional group; and wherein any two or more Z groups can be bonded together to form a C 3 -C 12 cycloalkyl ring structure, a C3-C 12 fused cycloalkyl ring structure, a C3-C 12 aryl ring structure, a C3-C 12 fused ary
  • the invention is a compound comprising Formula XI:
  • Z l , y. ⁇ / ' ⁇ , Z 5 , ' :, z Z s , and Z 9 are each independently selected from the group consisting of: CH 2 , C(R 2 ) 2 , CHR 2 , O, NH, NR 2 , C( O).
  • each R and R J is independently selected from the group consisting of: hydrogen, Ci-Cg alkyl, substituted Ci-Cg alkyl, Ci-Cg aikenyl, substituted Ci-Cg alkenyl, Ci-Cg alkynyl, substituted Ci-Cg alkynyl, C3-C7 aryl, substituted C3-C7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloal kyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C 3 - C 9 heteroaryl , substituted C3-C9 heteroaryl, Ci-Cg alkoxy, substituted Ci-Cg al koxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR 2 , NH 2 , NHR 2 , SR 2 , substituted sulfonyl, and substituted
  • L 4 is selected from the group consisting of: R ⁇ , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonvloxv, aminosuifonyi, amidino, carboxy ester, -CO-ethylene glycol, ⁇ CO- polyethylene glycol, substituted sulfonyl, substituted sulfmyl, thioacyl, aminoacyl,
  • any and all Z groups do not form an (S) ⁇ CH CH2c (°) NH group in the ring starting from the carbon attached to R 2 which is adjacent to the keto-amide functional group; and wherein any two or more Z groups can be bonded together to form a C 3 -C 12 cycloalkyl ring structure, a C3-C 12 fused cycloalkyl ring structure, a C3-C 12 aryl ring structure, a C3-C12 fused aryl ring structure, a C 3 -C 12 heteroaryl ring structure, a C3-C 12 fused heteroaryl ring structure, a C 3 -C 12 heterocyclic ring structure, and a C 3 -C 12 fused heterocyclic ring structure;
  • the invention is a compound comprising Formula XII:
  • R 3 is independently selected from the group consisting of: hydrogen, Ci-Cg alkyl, substituted Ci-Cg alkyl, Ci-Cg alkenyl, substituted Cj-Cg alkenyl, Ci-Cg alkynyl, substituted C ⁇ -C» alkynyl, C 3 -C 7 aryl, substituted C3-C7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C3-C 10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloaikyl, C3- C 9 heteroaryl, substituted C3-C9 heteroaryl, Cj -Cg alkoxy, substituted Ci-Cg alkoxy, amino, substituted amino, alkyl thio, substituted alkyithio, OH, OR 2 , M f ⁇ .
  • each R 2 is independently selected from the group consisting of: hydrogen, Ci-Cg alkyl, substituted Ci-C 8 alkyl, Cj-Cg alkenyl, substituted Ci-C 8 alkenyl, Ci-Cg alkynyl, substituted Ci-Cg alkynyl, C 3 -C 7 aryl, substituted C 3 -C7 aryl, cyano, OH, Ci-Cg alkoxy, substituted Ci-Cg alkoxy, amino, substituted amino, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycioalkyl, C 3
  • L 4 is selected from the group consisting of: R 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO- polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl; and wherein any and all Z groups do not form an (S) ⁇ C ⁇ ⁇ C 0 ) ⁇ group in the ring starting from the carbon attached to R 2 which is adjacent to the keto-amide functional group, and wherein any two or more Z groups can be bonded together to form a C 3 -C 12 cycloalkyl ring structure, a C 3 -C 12 fused cycioalkyl ring structure, a C 3 -C .
  • aryl ring structure a C 3 -C 12 fused aryl ring staicture, a C 3 -C 12 heteroaryl ring structure, a C 3 -C 12 fused heteroaryl ring structure, a C 3 -C 12 heterocyclic ring structure, and a C 3 -C 12 fused heterocyclic ring structure;
  • the invention is a compound comprising Formula XIII:
  • each R x and R 3 is independently selected from the group consisting of: hydrogen, Ci-Cg alkyl, substituted Cj -Cg alkyl, Ci-Cg alkenyl, substituted Cj-Cg alkenyl, Ci-Cg alkynyl, substituted Ci-C 8 alkynyl, C 3 -C7 aryl, substituted C 3 -C7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, C 3 -C heterocycloalkyl, substituted C 3 -C9 heterocycloaikyl, C 3 - C 9 heteroaryl, substituted C 3 -C9 heteroaryl, Ci-C 8 alkoxy, substituted Ci-C 8 alkoxy, amino, substituted amino
  • L 4 is selected from the group consisting of: R 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO- polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthaiimido, and formyl; and wherein any and all Z groups do not form an (S)
  • any two or more Z groups can be bonded together to form a C 3 -C 12 cycloalkyl ring structure, a C 3 -C 12 fused cycloalkyi ring structure, a C 3 -C 12 aryl ring structure, a C3-C 12 fused aryl ring structure, a C 3 -C 12 heteroaryl ring structure, a C 3 -C 12 fused heteroaryl ring structure, a C 3 -C 12 heterocyclic ring structure, and a C 3 -C 12 fused heterocyclic ring structure;
  • the invention is a compound comprising Formula XIV:
  • R 3 is independently selected from the group consisting of: hydrogen, Ci-C 8 alkyl, substituted Ci ⁇ C 8 alkyl, Ci ⁇ C 8 alkenyl, substituted Ci-Cg alkenyl, Ci-C 8 alkynyl, substituted Ci-C 8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, C3-C 9 heterocycloalkyl, substituted C 3 -C 9 heterocycloalkyl, C 3 - C 9 heteroaryl, substituted C3-C9 heteroaryl, Ci ⁇ C 8 alkoxy, substituted Ci ⁇ C 8 alkoxy, amino, substituted amino, alkylthi
  • L 4 is selected from the group consisting of: R 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, ⁇ CO- polyethylene glycol, substituted sulfonyl, substituted sulfmyl, thioacyl, aminoacyl,
  • any and all Z groups do not form an (S) ⁇ CH ⁇ CH2C (°) NH group in the ring starting from the carbon attached to R 2 which is adjacent to the keto-amide functional group, and wherein any two or more Z groups can be bonded together to form a C 3 -C 12 cycloalkyl ring structure, a C3-C 12 fused cycloalkyl ring structure, a C3-C 12 aryl ring structure, a C3-C 12 fused aryl ring structure, a C 3 -C 12 heteroaryl ring structure, a C3-C 12 fused heteroaryl ring structure, a C 3 -C 12 heterocyclic ring structure, and a C 3 -C 12 fused heterocyclic ring structure;
  • the invention is a compound comprising Formula XV:
  • n is from 1-12; each A is independently selected from the group consisting of: O and S; each R x and R 3 is independently selected from the group consisting of: hydrogen, Ci-Cg alkyl, substituted Cj -Cg alkyl, C ⁇ -C % alkenyl, substituted Cj-C 8 alkenyl, Ci ⁇ C 8 alkynyl, substituted Ci-Cg alkynyl, C3-C7 aryl, substituted C3-C 7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, C3-C 9 heterocycloalkyl, substituted C3-C9 heterocycloalkvl, C 3 - C 9 heteroaryl, substituted C3-C 9 heteroaryl, Ci-Cg alkoxy, substituted Ci-Cg alkoxy, amino, substituted amino, alkyl thio, substituted alkylthio,
  • Z is selected from the group consisting of: C
  • L 4 is selected from the group consisting of: R 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO- polyethylene glycol, substituted sulfonyl, substituted sulfmyl, thioacyl, aminoacyl,
  • any two or more W groups can be bonded together to form a C 3 -C 12 cycloalkyl ring structure, a C3-C 12 fused cycloalkyl ring structure, a C3-C 12 aryl ring structure, a C3-C 12 fused aryl ring structure, a C 3 -C 12 heteroaryl ring structure, a C 3 -Ci 2 fused heteroaryl ring structure, a C 3 -C 12 heterocyclic ring structure, and a C 3 -C 12 fused heterocyclic ring structure; and wherein W n does not form an (S) ⁇ CH2CH2C (°) NH group in the ring starting from the carbon attached to R 2 which is adjacent to the keto-amide or thioketo-amide functional group; or a tautomer and/or a pharmaceutically acceptable salt thereof.
  • the invention is a compound comprising Formula XVI:
  • n is from 1-12; each R x and R 3 is independently selected from the group consisting of: hydrogen, Ci-C 8 alkyl, substituted Ci-C 8 alkyl, Ci-Cs aikenyl, substituted Ci-C 8 alkenyl, Ci-Cg alkynyl, substituted Ci-C 8 alkynyl, C 3 -C 7 aryl, substituted C 3 -C 7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C 3 - C 9 heteroaryl, substituted C3-C9 heteroaryl, Ci-C 8 alkoxy, substituted Ci-C 8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR 2 , NH 2 , NHR 2 , SR 2 ,
  • Z is selected from the group consisting of: Ci-Cg alkyl, substituted Cj-Cg alkyl, Ci-Cg alkenyl, substituted Ci-Cg alkenyl, Ci-Cg alkynyl, substituted Ci-Cg alkynyl, Ci-Cg alkoxy, substituted Ci-Cg alkoxy, substituted amino, alkylthio, substituted alkylthio, sulfonyl, C(R 2 ) 2 , CHR 2 , O, NH, NR. 2 , S, substituted sulfonyl, sulfinyl, substituted sulfinyl ,and a covalent bond;
  • L 4 is selected from the group consisting of: R ⁇ , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyioxy, aminosulfonyl, amidino, carboxy ester, -CO-ethyiene glycol, -CG- polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl,
  • any two or more W groups can be bonded together to form a C 3 -C 12 cycloalkyl ring structure, a C3-C12 fused cycloalkyl ring structure, a C3-C12 aryl ring structure, a C3-C12 fused aryl ring structure, a C3-C12 heteroaryl ring structure, a C3-C12 fused heteroaryl ring structure, a C3-C12 heterocyclic ring structure, and a C 3 -C 12 fused heterocyclic ring structure; and wherein W fin does not form an (S) ⁇ C H _: C H 2 C ( 0 ) N H group in the ring starting from the carbon attached to R ⁇ which is adjacent to the keto-amide functional group; or a tautomer and/or a pharmaceutically acceptable salt thereof
  • the invention is a compound comprising Formula XVII:
  • each A is independently selected from the group consisting of: O and S
  • each R 4 is independently selected from the group consisting of: H and
  • each R ! and R is independently selected from the group consisting of; hydrogen, Ci-C 8 alkyl, substituted Ci-Cg alky], Ci-C 8 alkenyl, substituted C Cg alkenyl, Ci-Cg alkynyl, substituted Cj -Cg alkynyl, C3-C7 aryl, substituted C 3 -C 7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloaikyl, C 3 - C 9 heteroaryl, substituted C3-C9 heteroaryi, Ci-C 8 alkoxy, substituted Ci-C 8 alkoxy, amino, substituted amino, alkylthio, substituted alkyithi
  • each R 2 is independently selected from the group consisting of: hydrogen, Ci-Cg alkyl, substituted Ci-C 8 alkyl, Cj-Cg alkenyl, substituted Ci-C 8 alkenyl, Cj -Cg alkynyl, substituted Ci-Cg alkynyl, C3-C7 aryl, substituted C3-C7 aryl, cyano, OH, Ci-Cg alkoxy, substituted Cj-Cg alkoxy, amino, substituted amino, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl , substituted C
  • L 3 is a group containing 1-8 atoms and is selected from the group consisting of: Ci-Cg alkyl, substituted Ci-C 8 alkyl, Ci-Cg alkenyl, substituted Ci-C 8 alkenyl, Ci-Cg alkynyl, substituted Ci-Cg alkynyl , Ci ⁇ C 8 alkoxy, substituted Ci-C 8 alkoxy, amino, substituted amino, alkylthio, substituted al kylthio, sulfonyl , C(R 2 ) 2 , CHR 2 , O, NFL NR 2 , S, substituted sulfonyl, sulfinyl, and substituted sulfmyi;
  • Z is selected from the group consisting of: C C 8 alkyl, substituted Cj -Cg alkyl, C C 8 alkenyl, substituted Ci-Cg alkenyl, Ci-C 8 alkynyl, substituted Cj-Cg alkynyl, Ci-C 8 alkoxy, substituted Ci-C 8 alkoxy, substituted amino, alkylthio, substituted alkylthio, sulfonyl, C(R 2 ) 2 , CHR 2 , O, NH, NR.
  • L 4 is selected from the group consisting of: R 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO- polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl,
  • each L 3 and Z are capable of being covalently bonded to the same or other R 2 functional groups such that a bicyclic or spirocyclic ring system is formed; and wherein L 3 and Z do not form an (S) ⁇ CH 2 CH 2 C(0)NH g rou p j n ⁇ h e r j n g starting from the carbon atom closest to the keto-amide or thio-keto-amide functional group; or a tautomer and/or a pharmaceutically acceptable salt thereof,
  • the invention is a compound comprising Formula Formula XVf l l:
  • each R 4 is independently selected from the group consisting of: H and ; each R and R J is independently selected from the group consisting of: hydrogen, Ci-Cg alkyl, substituted Ci-C 8 alkyl, Ci-Cg alkenyl, substituted Ci-Cg alkenyl, Cj-Cg alkynyl, substituted Cj-Cg alkynyl, C 3 -C 7 aryl, substituted C3-C7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloaikyl, C 3 - C 9 heteroaryl, substituted C3-C 9 heteroaryl, Ci-C 8 alkoxy, substituted Ci-C 8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR 2 , NH 2 , NHR 2 , SR
  • each R 2 is independently selected from the group consisting of: hydrogen, Ci-C 8 alkyl, substituted d-Cg alkyl, Ci-C 8 alkenyl , substituted d-Cg alkenyl, d-Cg alkyny] , substituted Ci-Cg alkynyl, C3-C7 aryl, substituted C3-C7 aryl, cyano, OH, Ci-Cg al koxy, substituted d-Cg alkoxy, amino, substituted amino, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, C3-C 9 heterocyeloalkyl, substituted C3-C9 heterocycloalkyl, C 3 -C 9 heteroaryl, substituted C 3 -C 9 heteroaryl, and any naturally or non-naturally occurring amino
  • -C-, -CH-, a C3-C spirocyclic group of where m is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl, wherein any two adjacent W atoms may form CR l CR l or C ⁇ C;
  • Z is selected from the group consisting of: d-Cg alkyl, substituted d-Cg al kyl, d-Cg alkenyl, substituted d-Cg alkenyl, d-Cg alkynyl, substituted d-Cg alkynyl, Ci-Cg alkoxy, substituted Ci-C 8 alkoxy, substituted amino, alkylthio, substituted alkylthio, sulfonyl, C(R 2 ) 2 , CHR 2 , O, NH, NR 2 , S, substituted sulfonyl, sulfinyl, substituted sulfinyl ,and a covalent bond;
  • L 4 is selected from the group consisting of: R 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO- polyethyiene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl,
  • any two or more W groups can be bonded together to form a C 3 -C 12 cycloalkyl ring structure, a C 3 -C 12 fused cycloalkyl ring structure, a C3-C 12 aryl ring structure, a C3-C 12 fused aryl ring staicture, a C 3 -C 12 heteroaryl ring structure, a C 3 -C 12 fused heteroatyl ring structure, a C 3 -C 12 heterocyclic ring structure, and a C 3 -C 12 fused heterocyclic ring structure; and wherein W n does not form an (S)
  • the present technology provides two or more compounds of Formula I-XVIII described herein.
  • the compound is of Formula If-XVI!I, wherein all R x and R 3 are I f
  • the compound is of Formula II-XVIII, wherein R 1 is H and all N-R 2 are ⁇ -H.
  • the compound is of Fonnula II, wherein W contains a heteroatom .
  • the compound is of Formula ⁇ , wherein W contains an oxygen heteroatom. In some embodiments, the compound is of Formula II, wherein W contains a sulfur heteroatom. In some embodiments, the compound is of Formula II, wherein W contains a nitrogen heteroatom,
  • the compound is of Formula II, wherein W contains sulfonyl functional group.
  • the compound is of Formula II, wherein one R l is an alkyl functional group.
  • the compound is of Formula ⁇ , wherein one R 1 is an aromatic functional group.
  • the compound is of Formula IE, wherein one R f is an alkyl functional group.
  • the compound is of Formula IH, wherein Z l is nitrogen.
  • the compound is of Formula III, wherein Z ! is CH ? . 77] In some embodiments, the compound is of Formula III, wherein one R on the carbon atom is H and the other is CH(CH 3 ) 2 .
  • the compound is of Formula III, wherein one R 2 on the carbon atom is H and the other is CH 2 -CH(CH 3 ) 2 .
  • the compound is of Formula III, wherein one R 2 on the carbon atom is H and the other is Ar.
  • the compound is of Formula III, wherein one L 4 forms a carbamate functional group.
  • the compound is of Formula III, wherein one L 4 forms a sulfamate functional group.
  • the compound is of Formula III, wherein one L 4 is - C(0)C(CH 3 ) 3 .
  • the compound is of Formula ⁇ , wherein one L 4 is - C(0)C(CH 3 ) 3 .
  • the compound is of Formula IV, wherein Z 1 is CH 2 and R' is H.
  • the compound is of Formula IV, wherein Z 1 is CH 2 , Z is 2, and one R 1 is H.
  • the compound is of Formula IV, wherein Z ' is CH 2 , Z is O, and one R 1 is H.
  • the compound is of Formula V, wherein Z 1 is CH 2 , Z 2 is NH, and both R 1 are H.
  • the compound is of Formula VI, wherein Z 1 is CH 2 , ⁇ ' is
  • the compound is of Formula III-XIV, wherein R 1 is H, both
  • N- are N-H
  • L 4 is [00190]
  • the compound is of Formula III-XIV, wherein both R 1 are
  • the compound is of Formula III-XIV, wherein both R 1 are
  • N-R 2 are N-H
  • L 4 is Ph ⁇ O-3 ⁇ 4
  • the compound is of Formula III-XIV, wherein both IV are,
  • N-R 2 are N-H
  • L 4 is .
  • the compound is of Formula IH-XIV, wherein both R 1 are
  • N-R 2 are N-H
  • one R 2 of R2 is H and the other is H ° CH'
  • L 4 is
  • the compound is of Formula III-XIV, wherein both R x are, both N-R' are N-H, one R 2 of K is H and the other is HsC CHs , and L 4 is
  • the compound is of Formula III-XIV, wherein both R 1 are, both N-R 2 are N-H, one R 2 of R2 r2 is H and the other is H3 ° Ch3 , and L 4 I S
  • the compound is of Formula III, wherein both IV are, both
  • N-R 2 are N-H, one R 2 of R2 ⁇ 2 is H and the other is H 3 C ⁇ C H 3 ; a facilitatord L 4 is Ar- ⁇ O
  • the compound is of Formula IH, wherein both R 1 are, both
  • N-R 2 are N-H, one R 2 of R2 is H and the other is 98]
  • the compound is of Formula III, wherein one R 1 is H, both
  • N-R 2 are N-H, one R 2 of R2 ⁇ 2 is H and the other is H i ° CHa , and L is ⁇ .
  • the compound is of Formula IV, wherein one R 1 is H, both
  • N-R 2 are N-H, one R 2 of R2 ⁇ 2 is H and the other is H3C CH3 , and L 4 is Ar/ O '
  • the compound is of Formula TV, wherein both R ! are H, both N-R 2 are N-H, one R 2 of
  • the compound is of Formula IV, wherein both R 1 are H,
  • N-R 2 are N-H
  • one R 2 of R2 2 is H and the other is H 3 C CH 3
  • L 4 is ⁇ .
  • the compound is of Formula V, wherein both R 1 are H, 1
  • both N-R ⁇ are N-H, one R " of K is H and the other is 3 3 , and L is
  • the compound is of Formula V, wherein one R 1 is H, both
  • the compound is of Formula V, wherein both R 1 are H,
  • both N-R 2 are N-H, one R 2 of
  • the compound is of Formula VI, wherein both R 1 are H, both N-R 2 are N-H, one R 2 of R * 2 is H and the other is H' ° CHa , and L 4 is
  • the compound i s of Formula VI wherein both R 1 are H, both N-R 2 are N-H, one R 2 of
  • the compound is of Formula VI, wherein both R ! are H,
  • both N-R 2 are N-H, one R 2 of .
  • the compound is of Formula VII, wherein both R : are H, both N-R 2 are N-H, one R 2 of R " is H and the other is CHz , and L 4 is
  • the compound is of Formula VII, wherein both R 1 are H, both N-R 2 are N-H, one R 2 of R " r2 is H and the other is CH 3 , and L 4 is
  • the compound is of Formula VII, wherein both R 1 are H,
  • both N-R 2 are N-H, one R 2 of R ⁇ ⁇ 2 is H and the other is H 3 C CH3 , and L 4 is ⁇ .
  • the compound is of Formula ⁇ -XIV, wherein one I 1 is H,
  • both N-R 2 are N-H, one R 2 of .
  • the compound is of Formula ⁇ -XIV, wherein one R f is H,
  • N-R 2 are N-H
  • one R 2 of R “ 2 is H and the other is oh3
  • L 4 is Ph °' f " some embodiments, the compound is of Formula III-XIY, wherein one R 1 is H,
  • the compound is of Formula lil-XIV, wherein one R is H, of is H and the other is selected from the group consisting
  • the compound is of Formula ⁇ - ⁇ , wherein both R ! are
  • the compound is of Formula Ili-XIV, wherein both R 1 are
  • both N-R' r -H n R of K is H and the other is selected from the consisting j o off: [00217]
  • the compound is of Formula V-XIV, wherein both R 1 are
  • the compound is of Formula V-XIV, wherein one iV is H, all N-R 2 are N-H, and L 4 is
  • the compound is of Formula V-XIV, wherein one R 1 is H,
  • the compound is of Formula V-XIV, wherein one R 1 is H,
  • N-R 2 are N-H, and L 4 i s & .
  • the compound is of Formula V-XIV, wherein one R 1 is H,
  • N-R" all N-R" are N-H, two R ' of the two K groups on separate carbon atoms are H and one of the other two R groups is
  • the compound is of Formula V-XIV, wherein one R 1 is H, all N-R 2 are N-H, two R of the two R K ' groups on separate carbon atoms are H and one
  • the compound is of Formula V-XIV, wherein both R ! are
  • th ound is of Formula ⁇ , wherein both R x are H, all N-R" are N-H, two R ' of the two groups on separate carbon atoms are H and one of the other two R groups is
  • the compound is of Formula XIH, wherein both R 1 are H, all N-R 2 are N-H, two R of the two R K ' groups on separate carbon atoms are H and one of the other two R groups is
  • the compound is of Formula XIII, wherein one R ! is H, all
  • N-R are N-H
  • two R of the two K groups on separate carbon atom s are H and one of
  • the compound is of Formula XIV, wherein one R 1 is H, all -R " are N-H, two R of the two groups on separate carbon atoms are H and one of
  • the compound is of Formula XIV, wherein both R 1 are H, both N-R" are N-H, two R" of the two K groups on separate carbon atoms are H and one or the other two R groups i s .
  • the compound is of Formula XIV, wherein both R 1 are H, all N-R 2 are N-H, two R of the two K K ' groups on separate carbon atoms are H and one of
  • the compound is of Formula XV, wherein both R 1 are H, all
  • N-R ⁇ are N-H
  • two R 2 of the two R K' groups on separate carbon atoms are H and one of the other two R groups is
  • the compound is of Formula XV, wherein both R 1 are H, all
  • N-R are N-H, two R " of the two groups on separate carbon atoms are H and one of the other two R groups is
  • the compound is of Formula XV, wherein both R 1 are H, all
  • N-R are N-H
  • two R of the two K groups on separate carbon atom s are H and one of
  • the compound is of Formula XVI, wherein both R 1 are H, all N-R" are N-H, two R z of the two K ' groups on separate carbon atoms are H and one of
  • the compound is of Formula XVI, wherein both R 1 are H, all N-R 2 are N-H, one R 2 of
  • the compound is of Formula XVI, wherein R l is H, all N-R 2 are N-H, two R of the two K ' groups on separate carbon atoms are H and one of the
  • th ound is of Formula XVII, wherein both R 1 are H, all N-R" are N-H, two R ' of the two groups on separate carbon atoms are H and one of the other two R groups is
  • the compound is of Formula XVII, wherein both R 1 are H, all N-R 2 are N-H, two R of the two R K ' groups on separate carbon atoms are H and one of the other two R groups is
  • the compound is of Formula XVII, wherein one R 1 is H, all
  • N-R are N-H
  • two R of the two K groups on separate carbon atom s are H and one of
  • the compound is of Formula V-XIV, wherein one R 1 is H, all N-R " are N-H, two R z of the two K ' groups on separate carbon atoms are H and one of
  • the compound is of Formula V-XIV, wherein both R 1 are
  • one of the other two R 2 groups is Hs
  • L 4 is some embodiments, the compound is of Formula V-XVUI, wherein both R x are all N-R are N-H, two R " of th groups on separate carbon atoms are H and
  • one of the other two R 2 groups is and L 4 is .
  • the compound is of Formula V-XV III, wherein one R 1 is H, all N-R" are N-H, two R" of the two K groups on separate carbon atoms are H and one of
  • the other two R groups is selected from the group consisting of:
  • the compound is of Formula V-XVIII, wherein one R ! is H, all N-R are N-H, two R of the two groups on separate carbon atoms are H and one of
  • the other two R" groups is selected from the group consisting of: ?
  • the compound is of Formula V-XVUI, wherein both R 1 are
  • one of the other two R ? groups is selected from the group consisting of: ⁇ ,
  • the present technology includes a compound which is selected from the compound of the tables below:
  • the present technology is a pharmaceutical composition comprising one or more compounds disclosed herein and a pharmaceutically acceptable excipient.
  • the compounds of the present invention or a pharmaceutically acceptable salt thereof!, or a prodrug or metabolite thereof can be administered in any convenient manner.
  • the compounds represented by Formula I-XVIH or their tautomers and/or pharmaceutically acceptable salts thereof can effectively act as CAPNL CAPN2, and/or CAPN9 inhibitors and treat conditions affected at least in part by CAPNl, CAPN2, and/or CAPN9.
  • the present technology provides pharmaceutical compositions comprising one or more compounds of Formula I-XVIII and a pharmaceutically acceptable excipient.
  • the present technology provides a method for treating a fibrotie disease with an effective amount of one or more compound of Formula I-XVIII as provided herein.
  • the present technology provides a method for inhibiting CAPNl, CAPN2, and/or CAPN9 and/or a method for treating a disease affected at least in part by CAPNl, CAPN2, and/or CAPN9 with an effective amount of one or more compound of Formula I-XVIII as provided herein.
  • the compounds of the present technology are useful in inhibiting CAPN l, CAPN2, and/or CAPN9 enzymes and/or treating disorders relating to fibrosis or
  • the present technology is directed to a method for inhibiting CAPNl, CAPN2, and/or CAPN9 which method comprises contacting cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compound of Formula I-XVIII as described herein,
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds of Formula I-XVDI or a pharmaceutical composition comprising a pharmaceutically acceptable excipient.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNL CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds of Formula I-XVIII or a pharmaceutical composition comprising a pharmaceutically acceptable excipient.
  • a method for inhibiting CAPNl, CAPN2, and/or CAPN9 comprising contacting cells with an effective amount of one or more compounds of Formula I-XVIH.
  • the method for inhibiting CAPNl, CAPN2, and/or CAPN9 is performed in-vitro or in-vivo.
  • Calpains are also expressed in cells other than neurons, microglia and invading macrophages. In particular, they are important in skeletal muscle and herein inhibition of calpains also refers to inhibition in these cells as well.
  • a method for competitive binding with caipastatin comprising contacting a compound of any one of claims 1-56 with CAPNl, CAPN2, and/or CAPN9 enzymes residing inside a subject.
  • the compound specifically inhibits one or more of the enzymes selected from the group consisting of: CAPNl, CAPN2, and CAPN9 by at least 2-fold, by at least 3-fold, by at least 4-fold, by at least 5-fold, by at least 10-fold, by at least 15-fold, by at least 20-fold, by at least 50-fold, by at least 100-fold, by at least 150-fold, by at least 200-fold, by at least 400-fold, or by at least 500-fold.
  • a method is provided for selectively inhibiting CAPN1 in the presence of CAPN2 and CAPN9, which includes contacting cells (including
  • a method for selectively inhibiting CAPN2 in the presence of CAPNl and CAPN9 which includes contacting cells (including
  • a method for selectively inhibiting CAPN9 in the presence of CAPN2 and CAPNl which includes contacting cells (including
  • a method for selectively inhibiting CAPNl and CAPN2 in the presence of CAPN9 which includes contacting cells (including
  • a method for selectively inhibiting CAPN2 and CAPN9 in the presence of CAPNl which includes contacting cells (including
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits CAPNl , CAPN2, and/or CAPN9, said compounds being selected from Formula I-XVIII or a pharmaceutical composition comprising one or more compounds from Formula I-XVIII and a pharmaceutically acceptable excipient.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits CAPN1, CAPN2, and/or CAPN9, said compounds being selected from Formula I- XVIII or a pharmaceutical composition comprising one or more compounds from Formula I- XVIH and a pharmaceutically acceptable excipient.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits CAPN1 , CAPN2, and/or CAPN9, said compounds being selected from Formula I-XVIQ or a pharmaceutical composition comprising one or more compounds from Formula I-XVDI and a pharmaceutically acceptable excipient.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPN1, CAFN2, and/or CAP 9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits CAPN1, CAPN2, and/or CAPN9, said compounds being selected from Formula I- XVIII or a pharmaceutical composition comprising one or more compounds from Formula I- XVIH and a pharmaceutically acceptable excipient.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :5.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1 : 1 : 10.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least : 1 :20.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :50.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least : 1 : 100.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :200.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :250,
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl , CAPN2, and CAPN9 in a ratio of at least 1 : 1 :500.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :5.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 : 10.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of C APNl, C APN2, and CAPN9 in a ratio of at least 1 : 1 :20.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :50.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least : 1 : 100.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :200.
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : :250,
  • the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNl , CAPN2, and CAPN9 in a ratio of at least 1 : 1 :500.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and
  • CAPN9 in a ratio of at least 1 : 1 :5.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 : 10.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl , CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :20.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :50.
  • the present technology is directed to a method for treating a disease affected at least in part by C APNl , CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAP l, CAPN2, and CAPN9 in a ratio of at least 1 : 1 : 100.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :200.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl , CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :250.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least I ; 1 :500.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl , CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :5.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1 : 1 : 10.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl , CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :20.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNl , CAPN2, and CAPN9 in a ratio of at least 1 : 1 :50.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNL CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 : 100.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :200.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 :250.
  • the present technology is directed to a method for treating a disease affected at least in part by CAPNl , CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1 , CAPN2, and CAPN9 in a ratio of at least I : 1 :500.
  • a method for prophylactic therapy or treatment of a subject having a fibrotic disorder comprising administering an effective amount of one or more compounds of Formula I-XVIII to the subject in need thereof.
  • a method for prophylactic therapy or treatment of a subject having a disorder affected by CAPN!, CAPN2, and/or CAPN9 comprising administering an effective amount of one or more compounds of Formula I-XVIII to the subject in need thereof.
  • a method for inhibiting myofibroblast differe tiation e.g., Epithelial/Endothelial-to-Mesenchymal Transition (EpMT/EnMT)
  • the method comprises contacting cells with an effective amount of one or more compounds of Formula I-XVIII disclosed herein.
  • the method for inhibiting myofibroblast differentiation e.g., Epithelial/Endothelial-to-Mesenchymal Transition (EpMT/EnMT)
  • EpMT/EnMT Epithelial/Endothelial-to-Mesenchymal Transition
  • the present technology is a method for treating a disease or condition selected from the group consisting of or that produces a symptom selected from the group consisting of: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vascuiopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases
  • the present technology is a method for treating liver fibrosis.
  • the present technology is a method for treating cardiac fibrosis
  • the present technology is a method for treating fibrosis in rheumatoid arthritis diseases.
  • the present technology is a method for treating a condition affected by CAPNl, CAPN2, and/or CAPN9, which is in both a therapeutic and prophylactic setting for subjects. Both methods comprise administering of one or more compounds of Formula ⁇ - ⁇ to a subject in need thereof.
  • the present technology is a method for treating stiff skin syndrome.
  • the present technology is directed to a method wherein one or more compounds of Formula I-XVIil may be administered with other CAPNl , CAPN2, and/or CAPN9 inhibitor agents, such as anti-CAPNl, CAPN2, AND/OR CAPN9 antibodies or antibody fragments, CAPNl , CAPN2, and/or CAPN9 antisense, iRNA, or other small molecule CAPNl, CAPN2, and/or CAPN9 inhibitors, or in combination with other agents as described in detail herein.
  • CAPNl CAPN2, and/or CAPN9 inhibitor agents
  • CAPN9 inhibitor agents such as anti-CAPNl, CAPN2, AND/OR CAPN9 antibodies or antibody fragments, CAPNl , CAPN2, and/or CAPN9 antisense, iRNA, or other small molecule CAPNl, CAPN2, and/or CAPN9 inhibitors, or in combination with other agents as described in detail herein.
  • CAPNl Diseases and/or disorders or produced symptoms associated or affected at least in part by CAPNl, CAPN2, and/or CAPN9 include those selected from the group consisting of: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis.
  • therapeutically effective amount is a specific amount which causes a specific physiological effect which results in the amelioration of the disorder being treated or protects against a risk associated with the disorder.
  • the compounds of the present technology are useful in the diagnosis and treatment of a variety of human diseases selected from the group consisting of or that produces a symptom selected from the group consisting of: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular
  • pancreatic fibrosis pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft
  • vasculopathy and/or chronic rejection in transplanted organs ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post- vasectomy pain syndrome, and rheumatoid arthriti s.
  • the compounds of the present technology are particularly useful in treating disorders arising from fibrosis and complications thereof.
  • the present technology is directed to a method wherein one or more compounds of Formula I-XVIII which are used as a means to inhibit myofibroblast differentiation (e.g., Epithelial/Endothelial-to-Mesenchymal Transition (EpMT/EnMT)).
  • myofibroblast differentiation e.g., Epithelial/Endothelial-to-Mesenchymal Transition (EpMT/EnMT)
  • one or more of these compounds which are inhibitors of one or more (or all three) CAPNI, CAFN2, and/or CAPN9, alone or in combination with other TGFp signaling inhibitors, could be used to treat or protect againstor reduce a symptom of a fibrotic, sclerotic or post inflammatory disease or condition including: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft
  • vasculopathy and/or chronic rejection in transplanted organs ischemic-reperfusion injur ⁇ ' associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post- vasectomy pain syndrome, and rheumatoid arthritis.
  • micromolar concentratio s and possessing low relative cytotoxicity.
  • compounds of the present technology are shown to have potency, ameliorate, and/or possess efficacy in treating diseases or disorders which include, as a component, some form of fibrosis or inflammation.
  • the amount of active compound administered will vary depending upon the disease treated, the mammalian species, and the particular mode of administration, etc.
  • Suitable doses for the compounds of the present technology can be, for example, between 0.1 mg to about 1000 mg, between 1 mg to about 500 mg, between I mg to about 300 mg, or between 1 mg to about 100 mg per day. Such doses can be administered once a day or more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day.
  • the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration or 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of days, a number of weeks or months, and in some cases, years.
  • the specific dose level for any particular subject will depend on a variety of factors including the activity of the specific compound employed: the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.
  • the compounds of the present technology can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and P. G M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • the compounds of the present technology contain one or more chiral centers, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or dfl ) stereoisomers, or as stereos sorrier-enriched mixtures. All such
  • stereoisomers and enriched mixtures are included within the scope of the present technology, unless otherwise indicated.
  • Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art.
  • racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bach em (Torrance, California , USA), Emka- Chemce or Sigma (St. Louis, Missouri, US A).
  • the method involves starting with an appropriately N- protected amino acid compound with an alkene functionalized side-chain, and coupling it with an appropriately C-protected amino acid compound with an alkene functionalized side- chain as a coupling partner to give the di-functionalized di-amino acid derivative.
  • suitable coupling conditions and reagents such as HOBt and/or DMAP, may be used to form a requisite di-amino acid derivative, di-amino acid derivative is then cyclized upon with a metathesis reaction using, for example, the Grubbs catalyst.
  • the skilled artisan will appreciate that there are many synthetic conditions and catalysts which are capable of metathesizing the olefin groups.
  • the C -protection is removed by reduction with DIBAL to directly give the aldehyde.
  • the C-protection can be reduced with LAH (other reduction conditions such as birch reduction and so forth will work as well) to afford the corresponding alcohol, which is then oxidized with PCC (or DMP conditions or like) to the aldehyde.
  • the aldehyde then undergoes a cyanohydrin reaction upon treatment with KCN, which is then hydrolyzed under acidic conditions in alcohol to the corresponding a-hydroxy ester.
  • any desired groups may be placed onto the nitrogen atom of the keto-amide by a substitution reaction, such as with an aikyl iodide, or perhaps with reductive animation.
  • a substitution reaction such as with an aikyl iodide, or perhaps with reductive animation.
  • the desired compound has functionality on the nitrogen of the amide, the synthesis can use NaNH 2 or a strong base of the like in the step before the cyanohydrin reaction, in order to selectively place a differing group onto those nitrogen atoms as opposed to the nitrogen atom of the keto-amide.
  • the a-hydroxyl group is oxidized under conditions for Dess-Martin Periodinane oxidation (with hvpervaleiit iodine) or by an oxidizing agent such as PCC (pyridinium chlorochromate) or the like.
  • an oxidizing agent such as PCC (pyridinium chlorochromate) or the like.
  • PCC pyridinium chlorochromate
  • the compounds of general Formula I-XXIV can be generally prepared according to representative Scheme I :
  • keto-amide compounds can al so be prepared by converting the amino acid side-chain of the starting material (N-terminus protected) into side-chain with heteroatom functionality.
  • the heteroatom and substituent bond connection on the ring can be affected, optionally stereoseiectively.
  • Such functional group conversions are well known in the art and also allow: for complex substitution at the ring juncture(s) and opens pathways for bi cyclic ring systems.
  • Typical substrates for these kind of intramolecular reactions are usually setup with functional groups, one electrophilic, one nucleophilic in nature and may include, but are not limited to; aldehydes, halides, alkenes, and ketones, and the like.
  • the requisite functional groups may be selected so that heteroatom s and multiple substituents can exist at any position of the ring.
  • the compounds of general Formula I-XXIV can also be generally prepared according to representative Scheme 2: eh erne 2
  • the compounds of general Formula I-XXIV can also be generally prepared according to representative Scheme 3 :
  • the present technology provides novel compounds possessing CAPNl, CAPN2, and/or CAPN9 inhibitory activity and, accordingly, are useful in treating conditions and/or disorders affected by (or at least in part by) CAPNl, CAPN2, and/or CAPN9. Such conditions include fibrosis and/or complications thereof.
  • Methods for treatment of fibrotic diseases are also encompassed by the present invention. Said methods of the invention include administering a therapeutically effective amount of any one of compounds of Formula I-XVIH.
  • the compounds and solvates of the invention can be formulated in pharmaceutical compositions. These compositions can comprise a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. The precise nature of the carrier or other material can depend on the route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes.
  • compositions for oral administration can be in tablet, capsule, powder or liquid form.
  • a tablet can include a solid carrier such as gelatin or an adjuvant.
  • Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included,
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilizers, buffers, antioxidants and/or other additives can be included, as required.
  • a composition can be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
  • the compounds of the present technology will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • the actual amount of the compound of the present technology i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors well known to the skilled artisan.
  • the drug can be administered at least once a day, preferably once or twice a day.
  • a therapeutically effective dose can be estimated initially using a variety of techniques well-known in the art. Initial doses used in animal studies may be based on effective concentrations established in cell culture assays. Dosage ranges appropriate for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays.
  • an effective amount or a therapeutically effective amount or dose of an agent refers to that amount of the agent or compound that results in amelioration of symptoms or a prolongation of survival in a subject.
  • Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD 50 (the dose lethal to 50 % of the population) and the ED 50 (the dose therapeutically effective in 50 % of the population).
  • the dose ratio of toxic to therapeutic effects is therapeutic index, which can be expressed as the ratio LD 50 / ED 50 . Agents that exhibit high therapeutic indices are preferred.
  • the effective amount or therapeutically effective amount is the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinari an, medical doctor or other clinician. Dosages particularly fall within a range of circulating concentrations that includes the ED 50 with little or no toxicity. Dosages may vary within this range depending upon the dosage form employed and/or the route of administration utilized. The exact formulation, route of administration, dosage, and dosage interval should be chosen according to methods known in the art, in view of the specifics of a subject's condition.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety that are suffi cient to achieve the desired effects, i.e., the minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from, for example, in vitro data and animal experiments. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • the amount of agent or composition administered may be dependent on a variety of factors, including the sex, age, and weight of the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.
  • compositions will be administered as pharmaceutical compositions by any one of the foll owing routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • oral systemic
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • the preferred manner of administration is oral using a convenient daily dosage regimen that can be adjusted according to the degree of affliction.
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • Another preferred manner for administering compounds of the present technology is inhalation.
  • the choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance.
  • the compound can be formulated as liquid solution, suspensions, aerosol propeilants or dry powder and loaded into a suitable dispenser for administration.
  • suitable dispenser for administration There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry- powder inhalers (DPI).
  • MDI metered dose inhalers
  • DPI dry- powder inhalers
  • Nebulizer devices produce a stream of high velocity air that causes therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the subject's respirator ⁇ ' tract
  • MDFs typically are formulation packaged with a compressed gas.
  • the device Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent.
  • DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the subject's inspiratory air-stream during breathing by the device.
  • therapeutic agent is formulated with an excipient such as lactose, A measured amount of therapeutic agent is stored in a capsule form and is dispensed with each actuation.
  • compositions of the present technology can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.
  • 107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 rim in which the active material is supported on a crosslinked matrix of
  • U.S. Patent No. 5, 145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions are comprised of in general, a compound of the present technology in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect therapeutic benefit of the claimed compounds.
  • excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of the present technology in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
  • compositions may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient.
  • a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials.
  • the pack or dispenser device may be
  • compositions comprising a compound of the present technology formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the amount of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt %) basis, from about 0.01 99.99 wt % of a compound of the present technology based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1 80 wt %. Representative pharmaceutical formulations are described below.
  • Ingredient Amount compound of this the present technology 1.
  • Veegum K (Vanderbilt Co.) 1.0 g
  • the following ingredients are mixed to form an injectable formulation.
  • Ingredient Amount compound of this the present technology 0.2 mg-20 mg
  • a suppository of total weight 2.5 g is prepared by mixing the compound of the present technology with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid;
  • NaHCOs sodium bicarbonate
  • LAH lithium aluminum hydride
  • TToo aa ssoolluuttiioonn ooff ccoommppoouunndd IIEE ((3344 gg,, 110022..00 mmmmooll)) iinn 11 ⁇ ⁇ ⁇ (( )) ((110066 mmLL)) aanndd MMeeOOHH ((332255 m mLL)) wwaass aaddddeedd LLiiOOHH''HHjjOO ((1111..11 gg,, 226655 mmmmooll)) aatt 77 °°CC..
  • TThhee mmiixxttuurree wwaass eexxttrraacctteedd wwiitthh MMTTBBEE ((22 xx 4400 mmLL)).
  • Step 1 Synthesis of compounds 2A and 2B
  • Step 3 Synthesis of compound 2 To a solution of compound 2D (14 rng, 28.71 umo! in DCM (15 mL) and DMSO (1.5 niL) was added DMP (24.35 mg, 57.42 umol) at 0 °C under N 2 . The mixture was stirred at 5 °C for 16 hrs under N 2 . The reaction mixture was quenched by addition sat. Na 2 S 2 0 3 (10 mL), sat. NaHC0 3 (10 mL) and stirred for 30 min. The mixture was separated.
  • Step 1 Synthesis of compounds SE and 6Z
  • the product 4C was separated by SFC to give two isomers.
  • CCoommppoouunndd 1133 AA ((4400 mmgg,, yyiieelldd 4400..99 %%)) wwaass oobbttaaiinneedd aass aa wwhhiittee ssoolliidd.. 1H x ⁇ ⁇ NNMMRR ((440000MMHHzz,, CCDDCCII33)) ⁇ 88..5500 ((bbrr.. ss..,, IIHH)),, 77..1199 ((bbrr..
  • Step 4 Synthesis of eomponnd 14D

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Abstract

La présente technologie concerne des composés, des kits, des compositions et des méthodes utiles pour le traitement d'une maladie fibreuse. Dans certains aspects, la présente invention concerne le traitement de maladies ou troubles divers associés ou médiés, au moins en partie, par des calpaïnes, telles que CAPN1, CAPN2 et/ou CAPN9. La présente technologie est généralement applicable à des composés qui inhibent la différenciation myofibroblastique.
PCT/US2017/021288 2016-03-09 2017-03-08 Modulateurs de calpaïne et leurs méthodes de production et d'utilisation WO2017156074A1 (fr)

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US10934261B2 (en) 2016-09-28 2021-03-02 Blade Therapeutics, Inc. Calpain modulators and therapeutic uses thereof
CN113773228A (zh) * 2021-10-28 2021-12-10 上海吉奉生物科技有限公司 一种n-苄氧羰基-3-碘-l-丙氨酸甲酯的合成方法
US11292801B2 (en) 2016-07-05 2022-04-05 Blade Therapeutics, Inc. Calpain modulators and therapeutic uses thereof
CN115124448A (zh) * 2022-07-20 2022-09-30 杭州国瑞生物科技有限公司 一种一锅法合成d-焦谷氨酸衍生物的方法
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11292801B2 (en) 2016-07-05 2022-04-05 Blade Therapeutics, Inc. Calpain modulators and therapeutic uses thereof
US10934261B2 (en) 2016-09-28 2021-03-02 Blade Therapeutics, Inc. Calpain modulators and therapeutic uses thereof
US11339130B1 (en) 2016-09-28 2022-05-24 Blade Therapeutics, Inc. Calpain modulators and therapeutic uses thereof
WO2019211434A1 (fr) 2018-05-03 2019-11-07 Landsteiner Genmed, S.L. Dérivés de méta-méthoxyphényle de dipeptidyle-cétoamide et leurs utilisations
US11242312B2 (en) 2018-05-03 2022-02-08 Landsteiner Genmed, S.L. Dipeptidyl ketoamide meta-methoxyphenyl derivatives and uses thereof
CN113773228A (zh) * 2021-10-28 2021-12-10 上海吉奉生物科技有限公司 一种n-苄氧羰基-3-碘-l-丙氨酸甲酯的合成方法
EP4234014A1 (fr) * 2022-02-28 2023-08-30 Insusense ApS Carbamates et/ou urées dérivés d'acides amninés pour le traitement de maladies liées à la sortiline
WO2023161505A1 (fr) * 2022-02-28 2023-08-31 INSUSENSE ApS Carbamates et/ou urées à base d'acides aminés pour le traitement de maladies dépendantes de la sortiline
CN115124448A (zh) * 2022-07-20 2022-09-30 杭州国瑞生物科技有限公司 一种一锅法合成d-焦谷氨酸衍生物的方法

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