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WO2025049640A1 - Conjugués macrolide-nox4 et leurs utilisations - Google Patents

Conjugués macrolide-nox4 et leurs utilisations Download PDF

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Publication number
WO2025049640A1
WO2025049640A1 PCT/US2024/044283 US2024044283W WO2025049640A1 WO 2025049640 A1 WO2025049640 A1 WO 2025049640A1 US 2024044283 W US2024044283 W US 2024044283W WO 2025049640 A1 WO2025049640 A1 WO 2025049640A1
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Prior art keywords
compound
alkyl
cancer
pharmaceutically acceptable
alkenyl
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English (en)
Inventor
Dipak WALUNJ
Louise Hecker
Adegboyega Oyelere
Bocheng WU
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Emory University
Georgia Tech Research Institute
Georgia Tech Research Corp
US Department of Veterans Affairs
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Emory University
Georgia Tech Research Institute
Georgia Tech Research Corp
US Department of Veterans Affairs
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Publication of WO2025049640A1 publication Critical patent/WO2025049640A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases

Definitions

  • Oxidative stress is defined as the imbalance between the production of reactive oxygen species (ROS) and the capability of the cell to elicit an effective antioxidant response.
  • ROS reactive oxygen species
  • Several sources of ROS in cells and tissue have been identified, including mitochondrial electron transfer chain (Liu et al. (2002) J. Neurochem.80(5): 780-787) and NADPH oxidase (NOX) enzymes (Bedhard and Krause (2007) Physiol. Rev.87(1): 245-313).
  • NOX-derived ROS have been identified as the main source of oxidative stress, which promotes key events in the development of fibrotic diseases (such as skin fibrosis (Babalola et al. (2014) Arch. Dermatol.
  • Fibrosis is a complex disease characterized by excessive synthesis and accumulation of extracellular matrices that occur as a result of activation and proliferation of fibroblasts and myofibroblasts. Notably, nearly 45% of all naturally-occurring deaths in the western world are attributed to some form of fibrotic disease (Bitterman and Henke (1991) Chest 99(3 Suppl): 81s- 84s). Briefly, the presence of ROS is believed to activate transforming growth factor beta (TGF- ⁇ ) signaling pathways, then induces elevated production of NOX4-generated ROS (Chen et al. (2013) Biochem. Biophys. Res.
  • TGF- ⁇ transforming growth factor beta
  • NOX4-generated ROS activates various pathways that ultimately lead to fibrosis.
  • NOX4 mRNA expression has been found to be upregulated in both pulmonary fibroblasts isolated from IPF patients (Amara et al. (2010) Thorax 65(8): 733-738) and skin fibroblasts from scleroderma patients (Spadoni et al. (2015) Arthritis Rheumatol.67(6): 1611-1622), as well as in a number of in vivo fibrosis models, including liver fibrosis (Aoyama et al.
  • ARDS is a critical syndrome caused by heterogeneous pathologic factors and characterized by acute development of respiratory failure, bilateral diffuse lung infiltrations, and severe hypoxemia. See, e.g., Kellner et al. (2017) Pulmonary Vasculature Redox Signaling in Health and Disease 967: 105-137. The severity of ARDS is associated with poor prognosis and higher mortality. Id.
  • the invention in one aspect, relates to compounds, compositions, and methods for inhibiting Nox4 signaling.
  • fibrotic disorders e.g., pulmonary fibrosis, heart fibrosis, kidney fibrosis, liver fibrosis, skin fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, scleroderma or systemic sclerosis
  • ARDS acute respiratory distress syndrome
  • cancer e.g., a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell
  • fibrotic disorders e.g., pulmonary fibros
  • n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A 1 is selected from ⁇ O ⁇ and ⁇ CH 2 ⁇ , provided that when A 1 is O, then o is not 0 or 1; wherein L 1 is selected from C2 alkenyl, C2 alkynyl, ⁇ NHSO 2 ⁇ , ⁇ SO 2 NH ⁇ , ⁇ NHC(O) ⁇ , ⁇ C(O)NH ⁇ , and Ar 5 ; wherein Ar 5 , when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C
  • R 3a and R 3b are C1-C4 alkyl and one of R 3a and R 3b is a structure selected from: ; wherein R 13 is selected from hydrogen and ⁇ OH; wherein each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl
  • compositions comprising an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • methods of inhibiting NADPH Oxidase 4 (NOX4) signaling in a cell comprising contacting the cell with an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof.
  • methods of inhibiting NADPH Oxidase 4 (NOX4) signaling in a subject in need thereof comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof.
  • methods of treating acute respiratory distress syndrome (ARDS) in a subject in need thereof the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof.
  • ARDS acute respiratory distress syndrome
  • methods of treating cancer in a subject in need thereof the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof.
  • kits comprising a disclosed compound or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti-fibrotic agent; (b) instructions for treating a fibrotic disorder; (c) an agent known to treat ARDS; (d) instructions for treating ARDS; (e) an agent known to treat cancer; and (f) instructions for treating cancer.
  • FIG.1A and FIG.1B show a representative diagram illustrating a 2-hit preclinical aging muring model of severe ARDS and representative data comparing lung injury scores for young and aged mice, respectively.
  • FIG.2A and FIG.2B show representative data illustrating that senescent ECs exhibit impaired barrier-regulatory responses.
  • FIG.3A and FIG.3B show representative data illustrating that redox imbalance in senescent ECs corresponds with elevated Nox4 levels.
  • FIG.4 shows representative data illustrating that age-dependent severe pre-clinical ARDS is associated with sustained Nox4 levels and excessive ROS production.
  • FIG.5A and FIG.5B show representative data illustrating APX-115, Setanaxib, and GLX failed false-positive screening.
  • FIG.6A-F show representative data illustrating that aged Nox4-eKO mice demonstrate striking protection from ALI.
  • FIG.7A-D show representative data pertaining to the identification of novel Nox4 inhibitors.
  • FIG.8A and FIG.8B show representative data illustrating that Nox4 inhibitors reverse established pro-fibrotic phenotypes in human IPF lung myofibroblasts.
  • FIG.9A-G show representative data illustrating that Nox4 inhibitors protect from pre- clinical ARDS.
  • FIG.10 shows representative structures of Nox4 inhibitors for IV delivery.
  • FIG.11A and FIG.11B show a representative lung-targeted linker attached to a Nox4 inhibitor and predicted docking in Nox4 active site, respectively.
  • FIG.12A and FIG.12B show representative data illustrating IC50 and ROS generation evaluation of compound 13 versus parent Nox4 inhibitors or macrolide alone.
  • FIG.13A-C show representative data demonstrating elevated concentrations of lung targeting Nox4 inhibitor within the lung in vivo versus the parent Nox4 inhibitor.
  • FIG.14A and FIG.14B show representative diagrams of the efficacy testing protocols.
  • FIG.15 shows representative data illustrating BAL cell evaluation of lung targeting Nox4 inhibitor versus parent Nox4 inhibitor.
  • FIG.16A and FIG.16B show representative data demonstrating reduced concentrations of lung targeting Nox4 inhibitor administered by IV versus the parent Nox4 inhibitor in systemic plasma when administered by IV delivery.
  • FIG.17A-D show representative data demonstrating that lung targeting Nox4 inhibitor (LT-Nox4i-1) passed false-positive screening assays..
  • Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention.
  • the term “comprising” can include the aspects “consisting of” and “consisting essentially of.”
  • Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art.
  • an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.
  • references in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent (wt. %) of a component is based on the total weight of the formulation or composition in which the component is included.
  • the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
  • the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non- human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex.
  • therapeutic agent include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action.
  • the term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.
  • the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds.
  • exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.
  • the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption.
  • Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
  • a residue of a chemical species refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species.
  • an ethylene glycol residue in a polyester refers to one or more -OCH 2 CH 2 O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester.
  • a sebacic acid residue in a polyester refers to one or more - CO(CH 2 )8CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.
  • the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described below.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen
  • the heteroatoms can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • substitution or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • a 1 ,” “A 2 ,” “A 3 ,” and “A 4 ” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
  • aliphatic or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1- 20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • alkyl as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t- butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
  • the alkyl group can be cyclic or acyclic.
  • the alkyl group can be branched or unbranched.
  • the alkyl group can also be substituted or unsubstituted.
  • the alkyl group can be substituted with one or more groups including, but not limited to, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo- oxo, or thiol, as described herein.
  • a “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.
  • alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.
  • alkyl is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group.
  • halogenated alkyl or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • halogenated alkyl specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • monohaloalkyl specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine.
  • polyhaloalkyl specifically refers to an alkyl group that is independently substituted with two or more halides, i.e.
  • alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
  • aminoalkyl specifically refers to an alkyl group that is substituted with one or more amino groups.
  • hydroxyalkyl specifically refers to an alkyl group that is substituted with one or more hydroxy groups.
  • alkyl is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like. [0068] This practice is also used for other groups described herein.
  • cycloalkyl refers to both unsubstituted and substituted cycloalkyl moieties
  • the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.”
  • a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy”
  • a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like.
  • cycloalkyl is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.
  • heterocycloalkyl is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
  • the cycloalkyl group and heterocycloalkyl group can be substituted with 0, 1, 2, 3, or 4 groups independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, ⁇ NH 2 , (C1-C4) alkylamino, (C1-C4)(C1-C4) dialkylamino, ether, halogen, ⁇ OH, C1-C4 hydroxyalkyl, ⁇ NO 2 , silyl, sulfo-oxo, ⁇ SH, and C1-C4 thioalkyl, as described herein.
  • polyalkylene group as used herein is a group having two or more CH 2 groups linked to one another.
  • the polyalkylene group can be represented by the formula —(CH 2 ) a —, where “a” is an integer of from 2 to 500.
  • alkoxy and alkoxyl as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA 1 where A 1 is alkyl or cycloalkyl as defined above.
  • Alkoxy also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA 1 —OA 2 or —OA 1 —(OA 2 )a—OA 3 , where “a” is an integer of from 1 to 200 and A 1 , A 2 , and A 3 are alkyl and/or cycloalkyl groups.
  • the alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like.
  • heterocycloalkenyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted with 0, 1, 2, 3, or 4 groups independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C3-C6 cycloalkenyl, C2-C4 alkynyl, aryl, heteroaryl, aldehyde, ⁇ NH 2 , (C1-C4) alkylamino, (C1-C4)(C1-C4) dialkylamino, carboxylic acid, ester, ether, halogen, ⁇ OH, C1-C4 hydroxyalkyl, ketone, azide, ⁇ NO 2 , silyl, sulfo-oxo, ⁇ SH, and C1-C4 thioalkyl, as described herein.
  • alkynyl as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond.
  • the alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • cycloalkynyl as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound.
  • cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like.
  • heterocycloalkynyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted.
  • the cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • aromatic group refers to a ring structure having cyclic clouds of delocalized ⁇ electrons above and below the plane of the molecule, where the ⁇ clouds contain (4n+2) ⁇ electrons.
  • aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference.
  • aromatic group is inclusive of both aryl and heteroaryl groups.
  • aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like.
  • the aryl group can be substituted or unsubstituted.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ⁇ NH 2 , carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • biasryl is a specific type of aryl group and is included in the definition of “aryl.”
  • the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond.
  • biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.
  • aldehyde as used herein is represented by the formula —C(O)H.
  • amine or “amino” as used herein are represented by the formula —NA 1 A 2 , where A 1 and A 2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is ⁇ NH 2 .
  • alkylamino as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein.
  • dialkylamino as used herein is represented by the formula —N(-alkyl)2 where alkyl is a described herein.
  • Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.
  • carboxylic acid as used herein is represented by the formula —C(O)OH.
  • esteer as used herein is represented by the formula —OC(O)A 1 or —C(O)OA 1 , where A 1 can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • polyester as used herein is represented by the formula —(A 1 O(O)C-A 2 -C(O)O) a — or —(A 1 O(O)C-A 2 -OC(O)) a —, where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.
  • polyether as used herein is represented by the formula —(A 1 O-A 2 O) a —, where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500.
  • Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.
  • halo halogen
  • halide as used herein can be used interchangeably and refer to F, Cl, Br, or I.
  • pseudohalide pseudohalogen
  • pseudohalo pseudohalogen
  • pseudohalo can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.
  • heteroalkyl refers to an alkyl group containing at least one heteroatom.
  • heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized.
  • Heteroalkyls can be substituted as defined above for alkyl groups.
  • heteroaryl refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions.
  • the heteroaryl group can be substituted or unsubstituted.
  • heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • Heteroaryl groups can be monocyclic, or alternatively fused ring systems.
  • Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.
  • heterocycle or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon.
  • Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4- thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,
  • heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl.
  • a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like.
  • a C5 heterocyclyl comprises a group, which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like.
  • bicyclic heterocycle or “bicyclic heterocyclyl,” as used herein refers to a ring system in which at least one of the ring members is other than carbon.
  • Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring.
  • Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms.
  • Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H- pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.
  • heterocycloalkyl refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems.
  • the heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • hydroxy or “hydroxyl” as used herein is represented by the formula —OH.
  • ketone as used herein is represented by the formula A 1 C(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • Azide or “azido” as used herein is represented by the formula —N 3 .
  • nitro as used herein is represented by the formula —NO 2 .
  • nitrile or “cyano” as used herein is represented by the formula —CN or — C ⁇ N.
  • sil as used herein is represented by the formula —SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfo-oxo is represented by the formulas —S(O)A 1 , — S(O)2A 1 , —OS(O)2A 1 , or —OS(O)2OA 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula —S(O)2A 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a 1 S(O)2A 2 is represented by the formula A 1 S(O)2A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfoxide as used herein is represented by the formula A 1 S(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • thiol as used herein is represented by the formula —SH.
  • R 1 ,” “R 2 ,” “R 3 ,” “R n ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group.
  • an alkyl group comprising an amino group the amino group can be incorporated within the backbone of the alkyl group.
  • the amino group can be attached to the backbone of the alkyl group.
  • the nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are those that result in the formation of stable or chemically feasible compounds.
  • individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • Suitable monovalent substituents on R ⁇ are independently halogen, —(CH 2 )0–2R ⁇ , –(haloR ⁇ ), –(CH 2 )0–2OH, –(CH 2 )0–2OR ⁇ , –(CH 2 )0– 2 CH(OR ⁇ ) 2 ; -O(haloR ⁇ ), –CN, –N 3 , –(CH 2 ) 0–2 C(O)R ⁇ , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR ⁇ , – (CH 2 )0–2SR ⁇ , –(CH 2 )0–2SH, –(CH 2 )0–2NH 2 , –(CH 2 )0–2NHR ⁇ ,
  • Suitable substituents on the aliphatic group of R * include halogen, – R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).
  • organic residue defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove.
  • Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like.
  • a very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared.
  • a 2,4- thiazolidinedione radical in a particular compound has the structure: , regardless of whether thiazolidinedione is used to prepare the compound.
  • the radical for example an alkyl
  • the number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.
  • an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical.
  • an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.
  • organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein.
  • organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.
  • Inorganic radicals contain no carbon atoms and therefore comprise only atoms other than carbon. Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations.
  • Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together.
  • examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals.
  • the inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical.
  • Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.
  • Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.
  • a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture.
  • Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included.
  • stereoisomers For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non- superimposable mirror images of one another.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*).
  • bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula.
  • bonds to the chiral carbon when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
  • the Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
  • Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance.
  • the disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F and 36 Cl, respectively.
  • Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • the compounds described in the invention can be present as a solvate.
  • the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate.
  • the compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
  • a hydrate which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
  • solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
  • the invention includes all such possible solvates.
  • co-crystal means a physical association of two or more molecules which owe their stability through non-covalent interaction.
  • One or more components of this molecular complex provide a stable framework in the crystalline lattice.
  • the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g.
  • pyrazoles can exist in two tautomeric forms, N 1 -unsubstituted, 3-A 3 and N 1 -unsubstituted, 5-A 3 as shown below.
  • the invention includes all such possible tautomers.
  • chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications.
  • the different modifications of a polymorphic substance can differ greatly in their physical properties.
  • the compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.
  • a structure of a compound can be represented by a formula: , which is understood to be equivalent to a formula: , wherein n is typically an integer. That is, R n is understood to represent five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) , R n(e) .
  • independent substituents it is meant that each R substituent can be independently defined. For example, if in one instance R n(a) is halogen, then R n(b) is not necessarily halogen in that instance.
  • Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art.
  • the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St.
  • A-D a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention.
  • compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.
  • B. COMPOUNDS [00130] In one aspect, the invention relates to compounds that inhibiting Nox4 signaling.
  • the disclosed compounds can be useful in, for example, the treatment of fibrotic disorders (e.g., pulmonary fibrosis, heart fibrosis, kidney fibrosis, liver fibrosis, skin fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, scleroderma or systemic sclerosis), acute respiratory distress syndrome (ARDS) or for treating cancer (e.g., a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell n
  • each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using. 1.
  • STRUCTURE [00132]
  • compounds having a structure represented by a formula: wherein n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A 1 is selected from ⁇ O ⁇ and ⁇ CH 2 ⁇ , provided that when A 1 is O, then o is not 0 or 1; wherein L 1 is selected from C2 alkenyl, C2 alkynyl, ⁇ NHSO 2 ⁇ , ⁇ SO 2 NH ⁇ , ⁇ NHC(O) ⁇ , ⁇ C(O)NH ⁇ , and Ar 5 ; wherein Ar 5 , when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkeny
  • R 13 is selected from hydrogen and ⁇ OH; and wherein Ar 1 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.
  • r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R 3a and R 3b is C1-C4 alkyl and one of R 3a and R 3b is a structure selected from:
  • R 13 is selected from hydrogen and ⁇ OH; wherein each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R 10 is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A 2 is selected from ⁇ C(O) ⁇ and ⁇ SO2 ⁇ ; wherein L 2 is ⁇ (CR 11a R 11b ) 2 ⁇ ; wherein each of R 4a
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula selected from: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula:
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00147] In various aspects, the compound is selected from:
  • the compound a has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound a has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound a has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound a has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound a has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound a has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound is selected from: ,
  • n is selected from 0, 1, 2, 3, 4, and 5. In a further aspect, n is selected from 0, 1, 2, 3, and 4. In a yet further aspect, n is selected from 0, 1, 2, and 3. In a still further aspect, n is selected from 0, 1, and 2. In an even further aspect, n is selected from 0 and In a yet further aspect, n is 0. In a still further aspect, n is 1.
  • o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8. In a further aspect, o is selected from 0, 1, 2, 3, 4, 5, 6, and 7. In a still further aspect, o is selected from 0, 1, 2, 3, 4, 5, and 6. In an even further aspect, o is selected from 0, 1, 2, 3, 4, and 5. In yet a further aspect, o is selected from 0, 1, 2, 3, and 4. In a still further aspect, o is selected from 0, 1, 2, and 3. In a yet further aspect o is selected from 0, 1, and 2. In a still further aspect, o is selected from 0 and 1. In an even further aspect, o is 3. In a yet further aspect, o is 2. In a still further aspect, o is 1.
  • r is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In a further aspect, r is selected from 0, 1, 2, 3, 4, 5, 6, and 7. In a still further aspect, r is selected from 0, 1, 2, 3, 4, 5, and 6. In an even further aspect, r is selected from 0, 1, 2, 3, 4, and 5. In yet a further aspect, r is selected from 0, 1, 2, 3, and 4. In a still further aspect, r is selected from 0, 1, 2, and 3. In a yet further aspect, r is selected from 0, 1, and 2. In a still further aspect, r is selected from 0 and 1. In a yet further aspect, r is selected from 1, 2, and 4. In a further aspect, r is 4. In an even further aspect, r is 3.
  • r is 2. In a still further aspect, r is 1. [00160] In various aspects, s is selected from 0 and 1. In a further aspect, s is 0. In a further aspect, s is 1. [00161] In various aspects, t is selected from 0, 1, and 2. In a further aspect, t is selected from 0 and 1. In a still further aspect, t is selected from 0 and 2. In a yet further aspect, t is selected from 1 and 2. In an even further aspect, t is 2. In a yet further aspect, t is 1. In a yet further aspect, t is 0. a.
  • a 1 GROUP [00162] In one aspect, A 1 is selected from ⁇ O ⁇ and ⁇ CH 2 ⁇ , provided that when A 1 is O, then o is not 0 or 1. In a further aspect, A 1 is –O ⁇ . In a yet further aspect, A 1 is –CH 2 ⁇ . b. A 2 GROUP [00163] In one aspect, A 2 is selected from ⁇ C(O) ⁇ and ⁇ SO 2 ⁇ . In a further aspect, A 2 is ⁇ C(O) ⁇ . In a yet further aspect, A 2 is ⁇ SO 2 ⁇ . c.
  • L 1 GROUP [00164] In one aspect, L 1 is selected from C2 alkenyl, C2 alkynyl, ⁇ NHSO 2 ⁇ , ⁇ SO 2 NH ⁇ , ⁇ NHC(O) ⁇ , ⁇ C(O)NH ⁇ , and Ar 5 . In a further aspect, L 1 is selected from C2 alkenyl, C2 alkynyl, and Ar 5 . In a yet further aspect, L 1 is selected from C2 alkenyl and C2 alkynyl. In a still further aspect, L 1 is C2 alkenyl. In yet a further aspect, L 1 is C2 alkynyl.
  • Ar 5 is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is unsubstituted.
  • Ar 5 is a structure selected from: , wherein * denotes a connection to ⁇ (CH 2 )n ⁇ and ** denotes a connection to Ar 1 . d.
  • L 2 GROUP [00167]
  • L 2 is ⁇ (CR 11a R 11b ) 2 ⁇ .
  • L 2 is ⁇ (CH 2 ) 2 ⁇ . e.
  • each of R 1a , R 1b , R 1c , and R 1d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, and ⁇ NO 2 .
  • each of R 1a , R 1b , R 1c , and R 1d is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, and ⁇ NO 2 .
  • each of R 1a , R 1b , R 1c , and R 1d is independently selected from hydrogen, ⁇ F, and ⁇ OH.
  • each of R 1a , R 1b , R 1c , and R 1d is independently selected from hydrogen and halogen. In a further aspect, each of R 1a , R 1b , R 1c , and R 1d is independently selected from hydrogen, ⁇ F, ⁇ Br, and ⁇ Cl. In a still further aspect, each of R 1a , R 1b , R 1c , and R 1d is independently selected from hydrogen, ⁇ F, and ⁇ Cl. In a still further aspect, each of R 1a , R 1b , R 1c , and R 1d is independently selected from hydrogen and ⁇ Cl.
  • each of R 1a , R 1b , R 1c , and R 1d is independently selected from hydrogen and ⁇ F. [00170] In various aspects, each of R 1a , R 1b , R 1c , and R 1d is hydrogen. f. R 2 GROUPS [00171] In one aspect, R 2 is selected from hydrogen and C1-C4 alkyl. In a further aspect, R 2 is selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a further aspect, R 2 is selected from hydrogen, methyl, and ethyl. In a still further aspect, R 2 is selected from hydrogen and ethyl.
  • R 2 is selected from hydrogen and methyl.
  • R 2 is C1-C4 alkyl.
  • R 2 is selected from methyl, ethyl, propyl, and isopropyl.
  • R 2 is selected from methyl and ethyl.
  • R 2 is ethyl.
  • R 2 is methyl.
  • R 2 is hydrogen. g. R 3A AND R 3B GROUPS In one aspect, one of R 3a and R 3b is C1-C4 alkyl and one of R 3a and R 3b is a structure selected from: .
  • one of R 3a and R 3b is C1-C4 alkyl. In a further aspect, one of R 3a and R 3b is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, one of R 3a and R 3b is selected from methyl and ethyl. In yet a further aspect, one of R 3a and R 3b is methyl. [00175] In various aspects, one of R 3a and R 3b is a structure selected from:
  • one of R 3a and R 3b is a structure: .
  • one of R 3a and R 3b is a structure: .
  • one of R 3a and R 3b is a structure selected from:
  • one of R 3a and R 3b is a structure: .
  • one of R 3a and R 3b is a structure: .
  • one of R 3a and R 3b is a structure selected from:
  • one of R 3a and R 3b is a structure selected from: . [00183] In various aspects, one of R 3a and R 3b is a structure: . [00184] In various aspects, one of R 3a and R 3b is a structure:
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, –NH 2 , –CN, –OH, ⁇ NO 2 , methyl, ethyl, n- propyl, i-propyl, ethenyl, propenyl, isopropenyl, –CH 2 F, –CH 2 Cl, –CH 2 CH 2 F, –CH 2 CH 2 Cl, – CH 2 CH 2 CH 2 F, –CH 2 CH 2 CH 2 Cl, —CH(CH 3 )CH 2 F, –CH(CH 3 )CH 2 Cl, –CH 2 CN, –CH 2 CH 2 CN, – CH 2 CH 2 CH 2 CN, –CH(CH 3 )CH 2 CN, –CH 2 OH, –CH 2 CH 2 OH, –CH 2 CH 2 CH 2 OH, – CH(CH 3 )CH 2 OH
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, –NH 2 , –CN, –OH, ⁇ NO 2 , methyl, ethyl, ethenyl, –CH 2 F, –CH 2 Cl, –CH 2 CH 2 F, –CH 2 CH 2 Cl, –CH 2 CN,–CH 2 CH 2 CN, –CH 2 OH, –CH 2 CH 2 OH, –OCF 3 , –OCH 2 CF 3 , –OCH 3 , –OCH 2 CH 3 , —NHCH 3 , –NHCH 2 CH 3 , – N(CH 3 ) 2 , –N(CH 2 CH 3 ) 2 , –N(CH 3 )(CH 2 CH 3 ), –CH 2 NH 2 , and –CH 2 CH 2 NH 2 .
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, –NH 2 , – CN, –OH, ⁇ NO 2 , methyl, –CH 2 F, –CH 2 Cl, –CH 2 CN, –CH 2 OH, –OCF 3 , –OCH 2 CF 3 , –OCH 3 , – NHCH 3 , –N(CH 3 )2, and –CH 2 NH 2 .
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, and C2-C4 alkenyl.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, –NH 2 , – CN, –OH, ⁇ NO 2 , methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, and isopropenyl.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, – NH 2 , –CN, –OH, ⁇ NO 2 , methyl, ethyl, and ethenyl.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, –NH 2 , –CN, –OH, ⁇ NO 2 , and methyl.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, C1-C4 alkyl, and C1-C4 alkoxy.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, ⁇ CN, methyl, ethyl, n-propyl, i- propyl, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 CH 3 , and –OCH(CH 3 )CH 3 .
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, ⁇ CN, methyl, ethyl, –OCH 3 , and –OCH 2 CH 3 .
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, ⁇ CN, methyl, and –OCH 3 .
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen and C1-C4 alkyl.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a further aspect, each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen and methyl. [00189] In various aspects, each of R 4a , R 4b , R 4c , and R 4d is independently C1-C4 alkyl.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from methyl, ethyl, n- propyl, and i-propyl. In a further aspect, each of R 4a , R 4b , R 4c , and R 4d is independently selected from methyl and ethyl. In a still further aspect, each of R 4a , R 4b , R 4c , and R 4d is methyl.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 haloalkyl, and C1-C4 cyanoalkyl.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, – NH 2 , –CN, –OH, ⁇ NO 2 , –CH 2 F, –CH 2 Cl, –CH 2 CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F, – CH 2 CH 2 Cl, –CH(CH 3 )CH 2 F, –CH(CH 3 )CH 2 Cl, –CH 2 CN, –CH 2 CH 2 CN, –CH 2 CH 2 CH 2 CN, and —CH(CH 3 )CH 2 CN.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, –NH 2 , –CN, –OH, ⁇ NO 2 , –CH 2 F, –CH 2 Cl, –CH 2 CH 2 F, – CH 2 CH 2 Cl, –CH 2 CN, and –CH 2 CH 2 CN.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, –NH 2 , –CN, –OH, ⁇ NO 2 , –CH 2 F, –CH 2 Cl, and – CH 2 CN.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1- C4 alkoxy.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, –NH 2 , –CN, –OH, ⁇ NO 2 , –CH 2 OH, –CH 2 CH 2 OH, –CH 2 CH 2 CH 2 OH, – CH(CH 3 )CH 2 OH, –OCF 3 , –OCH 2 CF 3 , –OCH 2 CH 2 CF 3 , –OCH(CH 3 )CF 3 , –OCH 3 , –OCH 2 CH 3 , – OCH 2 CH 2 CH 3 , and –OCH(CH 3 )CH 3 .
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, –NH 2 , –CN, –OH, ⁇ NO 2 , –CH 2 OH, – CH 2 CH 2 OH, –OCF 3 , –OCH 2 CF 3 , –OCH 3 , and –OCH 2 CH 3 .
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, –NH 2 , –CN, –OH, ⁇ NO 2 , – CH 2 OH, –OCF 3 , –OCH 2 CF 3 , and –OCH 3 .
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, –NH 2 , –CN, –OH, ⁇ NO 2 , –NHCH 3 , –NHCH 2 CH 3 , – NHCH 2 CH 2 CH 3 , –NHCH(CH 3 )CH 3 , –N(CH 3 )2, –N(CH 2 CH 3 )2, –N(CH 2 CH 2 CH 3 )2, – N(CH(CH 3 )CH 3 ) 2 , –N(CH 3 )(CH 2 CH 3 ), —CH 2 NH 2 , –CH 2 CH 2 NH 2 , –CH 2 CH 2 CH 2 NH 2 , and – CH(CH 3 )CH 2 NH 2 .
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, –NH 2 , –CN, –OH, ⁇ NO 2 , –NHCH 3 , –NHCH 2 CH 3 , –N(CH 3 )2, – N(CH 2 CH 3 ) 2 , –N(CH 3 )(CH 2 CH 3 ), –CH 2 NH 2 , and –CH 2 CH 2 NH 2 .
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, –Cl, –NH 2 , –CN, –OH, ⁇ NO 2 , –NHCH 3 , –N(CH 3 )2, and –CH 2 NH 2 .
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen and halogen.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, –F, and –Cl.
  • each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen and –Cl. In a still further aspect, each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen and –F. [00194] In various aspects, each of R 4a , R 4b , R 4c , and R 4d is independently halogen. In a further aspect, each of R 4a , R 4b , R 4c , and R 4d is independently selected from –F and –Cl. In a further aspect, each of R 4a , R 4b , R 4c , and R 4d is –Cl.
  • each of R 4a , R 4b , R 4c , and R 4d is –F.
  • each of R 4a , R 4b , R 4c , and R 4d is hydrogen.
  • R 5 GROUPS [00196]
  • R 5 when present, is selected from hydrogen and C1-C4 alkyl.
  • R 5 when present, is selected from hydrogen, methyl, ethyl, propyl, and isopropyl.
  • R 5 when present, is selected from hydrogen, methyl, and ethyl.
  • R 5 when present, is selected from hydrogen and methyl.
  • R 5 when present, is C1-C4 alkyl. In a further aspect, R 5 , when present, is selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, R 5 , when present, is selected from methyl and ethyl. In a still further aspect, R 5 , when present, is methyl. [00198] In various aspects, R 5 , when present, is hydrogen. j. R 6 GROUPS [00199] In one aspect, R 6 is selected from ⁇ NR 12a R 12b and Ar 2 . In a further aspect, R 6 is from ⁇ NR 12a R 12b . In a yet further aspect, R 6 is Ar 2 .
  • each occurrence of R 11a and R 11b is independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, ⁇ CH 2 F, ⁇ CH 2 CH 2 F, ⁇ CH 2 CH 2 CH 2 F, ⁇ CH(CH 3 )CH 2 F, ⁇ CH 2 Cl, ⁇ CH 2 CH 2 Cl, ⁇ CH 2 CH 2 CH 2 Cl, and ⁇ CH(CH 3 )CH 2 Cl.
  • each occurrence of R 11a and R 11b is independently selected from hydrogen, methyl, ethyl, ⁇ CH 2 F, ⁇ CH 2 CH 2 F, ⁇ CH 2 Cl, and ⁇ CH 2 CH 2 Cl.
  • each occurrence of R 11a and R 11b is independently selected from hydrogen, methyl, ⁇ CH 2 F, and ⁇ CH 2 Cl.
  • each occurrence of R 11a and R 11b is independently selected from hydrogen and C1-C4 alkyl.
  • each occurrence of R 11a and R 11b is independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl.
  • each occurrence of R 11a and R 11b is independently selected from hydrogen, methyl, and ethyl.
  • each occurrence of R 11a and R 11b is independently selected from hydrogen and methyl.
  • each occurrence of R 11a and R 11b is independently C1-C4 alkyl. In a further aspect, each occurrence of R 11a and R 11b is independently selected from methyl, ethyl, n-propyl, and i-propyl. In a yet further aspect, each occurrence of R 11a and R 11b is independently selected from methyl and ethyl. In a still further aspect, each occurrence of R 11a and R 11b is methyl. [00207] In various aspects, each occurrence of R 11a and R 11b is independently selected from hydrogen and C1-C4 haloalkyl.
  • each occurrence of R 11a and R 11b is independently selected from hydrogen, ⁇ CH 2 F, ⁇ CH 2 CH 2 F, ⁇ CH 2 CH 2 CH 2 F, ⁇ CH(CH 3 )CH 2 F, ⁇ CH 2 Cl, ⁇ CH 2 CH 2 Cl, ⁇ CH 2 CH 2 CH 2 Cl, and ⁇ CH(CH 3 )CH 2 Cl.
  • each occurrence of R 11a and R 11b is independently selected from hydrogen, ⁇ CH 2 F, ⁇ CH 2 CH 2 F, ⁇ CH 2 Cl, and ⁇ CH 2 CH 2 Cl.
  • each occurrence of R 11a and R 11b is independently selected from hydrogen, ⁇ CH 2 F, and ⁇ CH 2 Cl.
  • R 12a is selected from hydrogen, C1-C4 alkyl, and Ar 3
  • R 12b is selected from C1-C4 alkyl, ⁇ CH 2 Ar 4 , and Ar 4 .
  • R 12a is selected from hydrogen, C1-C4 alkyl, and Ar 3 .
  • R 12a is selected from hydrogen, methyl, ethyl, propyl, isopropyl, and Ar 3 .
  • R 12a is selected from hydrogen, methyl, ethyl, and Ar 3 .
  • R 12a is selected from hydrogen, methyl, and Ar 3 .
  • R 12a is C1-C4 alkyl. In a further aspect, R 12a is selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, R 12a is selected from methyl and ethyl. In a still further aspect, R 12a is methyl. [00214] In various aspects, R 12a is Ar 3 . [00215] In various aspects, R 12a is hydrogen. [00216] In various aspects, R 12b is selected from C1-C4 alkyl, ⁇ CH 2 Ar 4 , and Ar 4 .
  • R 12b is selected from methyl, ethyl, propyl, isopropyl, ⁇ CH 2 Ar 4 , and Ar 4 . In a further aspect, R 12b is selected from methyl, ethyl, ⁇ CH 2 Ar 4 , and Ar 4 . In a still further aspect, R 12b is selected from methyl, ⁇ CH 2 Ar 4 , and Ar 4 . [00217] In various aspects, R 12b is C1-C4 alkyl. In a further aspect, R 12b is selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, R 12b is selected from methyl and ethyl.
  • R 12b is methyl. [00218] In various aspects, R 12b is selected from ⁇ CH 2 Ar 4 and Ar 4 . In a further aspect, R 12b is Ar 4 . In a still further aspect, R 12b is ⁇ CH 2 Ar 4 .
  • each of R 12a and R 12b together comprise a C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • each of R 12a and R 12b together comprise a C2-C5 heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • each of R 12a and R 12b together comprise a C2-C5 heterocycloalkyl substituted with 0 or 1 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • each of R 12a and R 12b together comprise a C2-C5 heterocycloalkyl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • each of R 12a and R 12b together comprise a C2-C5 heterocycloalkyl and is unsubstituted.
  • Ar 1 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4
  • Ar 1 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1- C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-
  • Ar 1 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0 groups selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • C6-C10 aryls include, but are not limited to, phenyl and naphthyl.
  • Ar 1 is a C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a C6-C10 aryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a C6-C10 aryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is C6-C10 aryl with 0 groups selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is selected from phenyl and naphthyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is selected from phenyl and naphthyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is selected from phenyl and naphthyl, and is substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4 haloalkoxy
  • Ar 1 is selected from phenyl and naphthyl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ⁇ CO 2 H, and ⁇ CO 2 (C1-C4 alkyl).
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalky
  • Ar 1 is selected from phenyl and naphthyl, and is substituted with 0 groups selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • C2-C9 heteroaryls include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, pyrazole, triazole, benzothiazole, benzoxazole, quinolone, isoquinoline, pyridine, pyrimidine, and pyrazine.
  • Ar 1 is a C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a C2-C9 heteroaryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4 haloalkoxy, C1-
  • Ar 1 is a C2-C9 heteroaryl substituted with 0 groups selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a pyridinyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a pyridinyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a pyridinyl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1- C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4 haloalkoxy, C1-C
  • Ar 1 is a pyridinyl substituted with 0 groups selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a quinolinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a quinolinyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a quinolinyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a quinolinyl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4 haloalkoxy, C1-
  • Ar 1 is a quinolinyl substituted with 0 groups selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a isoquinolinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a isoquinolinyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a isoquinolinyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a isoquinolinyl monosubstituted with 0a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 1 is a isoquinolinyl substituted with 0 groups selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. o.
  • Ar 2 is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ⁇ C(O)NH 2 , ⁇ NHC(O)(C1-C4 alkyl), Cy 1 , ⁇ OCy 1 , and ⁇ NH(CH 2 )tCy 1 .
  • Ar 2 is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ⁇ C(O)NH 2 , ⁇ NHC(O)(C1-C4 alkyl), Cy 1 , ⁇ OCy 1 , and ⁇ NH(CH 2 ) t Cy 1 .
  • Ar 2 is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ⁇ C(O)NH 2 , ⁇ NHC(O)(C1-C4 alkyl), Cy 1 , ⁇ OCy 1 , and ⁇ NH(CH 2 )tCy 1 .
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH,
  • Ar 2 is selected from C6-C14 aryl and C2-C10 heteroaryl, and is monosubstitued with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ⁇ C(O)NH 2 , ⁇ NHC(O)(C1-C4 alkyl), Cy 1 , ⁇ OCy 1 , and ⁇ NH(CH 2 ) t Cy 1 .
  • halogen ⁇ CN, ⁇ NH 2 , ⁇
  • Ar 2 is selected from C6-C14 aryl and C2-C10 heteroaryl and is unsubstituted.
  • Ar 2 is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 2 is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and C1-C4 aminoalkyl.
  • Ar 2 is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • Ar 2 is selected from C6-C14 aryl and C2-C10 heteroaryl, and is monosubstitued with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • Ar 2 is selected from C6-C14 aryl and C2-C10 heteroaryl, and is unsubstituted.
  • Ar 2 is C6-C14 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ⁇ C(O)NH 2 , ⁇ NHC(O)(C1-C4 alkyl), Cy 1 , ⁇ OCy 1 , and ⁇ NH(CH 2 ) t
  • Ar 2 is C6-C14 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ⁇ C(O)NH 2 , ⁇ NHC(O)(C1-C4 alkyl), Cy 1 , ⁇ OCy 1 , and ⁇ NH(CH 2 ) t Cy 1 .
  • Ar 2 is C6-C14 aryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ⁇ C(O)NH 2 , ⁇ NHC(O)(C1-C4 alkyl), Cy 1 , ⁇ OCy 1 , and ⁇ NH(CH 2 )tCy 1 .
  • Ar 2 is C6-C14 aryl monosubstitued with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ⁇ C(O)NH 2 , ⁇ NHC(O)(C1-C4 alkyl), Cy 1 , ⁇ OCy 1 , and ⁇ NH(CH 2 ) t Cy 1 .
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • Ar 2 is an unsubstituted C6-C14 aryl.
  • Ar 2 is a C6-C14 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 2 is a C6-C14 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 2 is a C6-C14 aryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 2 is a C6-C14 aryl monosubstitued with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4 haloalkoxy
  • Ar 2 is an unsubstituted C6-C14 aryl.
  • Ar 2 is C2-C10 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ⁇ C(O)NH 2 , ⁇ NHC(O)(C1-C4 alkyl), Cy 1 , ⁇ OCy 1 , and ⁇ NH(CH 2 ) t Cy 1 .
  • Ar 2 is C2-C10 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ⁇ C(O)NH 2 , ⁇ NHC(O)(C1-C4 alkyl), Cy 1 , ⁇ OCy 1 , and ⁇ NH(CH 2 )tCy 1 .
  • Ar 2 is C2-C10 heteroaryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ⁇ C(O)NH 2 , ⁇ NHC(O)(C1-C4 alkyl), Cy 1 , ⁇ OCy 1 , and ⁇ NH(CH 2 ) t Cy 1 .
  • Ar 2 is C2-C10 heteroaryl monosubstitued with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ⁇ C(O)NH 2 , ⁇ NHC(O)(C1-C4 alkyl), Cy 1 , ⁇ OCy 1 , and ⁇ NH(CH 2 )tCy 1 .
  • Ar 2 is an unsubstituted C2-C10 heteroaryl.
  • Ar 2 is a C2-C10 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 2 is a C2-C10 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 2 is a C2-C10 heteroaryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 2 is a C2-C10 heteroaryl monosubstitued with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1- C4 hydroxyalkyl C1-C4 haloalkoxy,
  • Ar 2 is an unsubstituted C2-C10 heteroaryl.
  • Ar 2 is selected from C6-C14 aryl and C2-C10 heteroaryl, and is monosubstitued with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 2 is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 2 is phenyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 2 is phenyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 2 is phenyl monosubstitued with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 2 is unsubstituted phenyl.
  • Ar 2 is phenyl monosubstitued with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4 haloalkoxy
  • Ar 2 is phenyl monosubstituted with a C1-C4 haloalkyl group.
  • Ar 2 is phenyl monosubstituted with a group selected from ⁇ CH 2 F, ⁇ CH 2 CH 2 F, ⁇ CH 2 CH 2 CH 2 F, ⁇ CH(CH 3 )CH 2 F, ⁇ CH 2 Cl, ⁇ CH 2 CH 2 Cl, ⁇ CH 2 CH 2 CH 2 Cl, and ⁇ CH(CH 3 )CH 2 Cl.
  • Ar 2 is phenyl monosubstituted with a group selected from ⁇ CH 2 F, ⁇ CH 2 CH 2 F, ⁇ CH 2 Cl, and ⁇ CH 2 CH 2 Cl.
  • Ar 2 is phenyl monosubstitued with a group selected from ⁇ CH 2 F and ⁇ CH 2 Cl.
  • Ar 3 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4
  • Ar 3 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1- C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-
  • Ar 3 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is unsubstituted.
  • Ar 3 is C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • C6-C10 aryls include, but are not limited to, phenyl and naphthyl.
  • Ar 3 is a C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is a C6-C10 aryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is a C6-C10 aryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is an unsubstituted C6-C10 aryl.
  • Ar 3 is selected from phenyl and naphthyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is selected from phenyl and naphthyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is selected from phenyl and naphthyl, and is substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4 haloalkoxy
  • Ar 3 is selected from phenyl and naphthyl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ⁇ CO 2 H, and ⁇ CO 2 (C1-C4 alkyl).
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalky
  • Ar 3 is selected from unsubstituted phenyl and unsubstituted naphthyl.
  • Ar 3 is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • C2-C9 heteroaryls include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, pyrazole, triazole, benzothiazole, benzoxazole, quinolone, isoquinoline, pyridine, pyrimidine, and pyrazine.
  • Ar 3 is a C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is a C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is a C2-C9 heteroaryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4 haloalkoxy, C1-
  • Ar 3 is an unsubstituted C2-C9 heteroaryl.
  • Ar 3 is a pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is a pyridinyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is a pyridinyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is a pyridinyl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is an unsubstituted pyridinyl.
  • Ar 3 is a quinolinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is a quinolinyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is a quinolinyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is a quinolinyl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is an unsubstituted quinolinyl.
  • Ar 3 is a isoquinolinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is a isoquinolinyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is a isoquinolinyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is a isoquinolinyl monosubstituted with 0a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 3 is an unsubstituted isoquinolinyl.
  • Ar 4 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1- C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-
  • Ar 4 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is unsubstituted.
  • Ar 4 is C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • C6-C10 aryls include, but are not limited to, phenyl and naphthyl.
  • Ar 4 is a C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is a C6-C10 aryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is a C6-C10 aryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is an unsubstituted C6-C10 aryl.
  • Ar 4 is selected from phenyl and naphthyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is selected from phenyl and naphthyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is selected from phenyl and naphthyl, and is substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4 haloalkoxy
  • Ar 4 is selected from phenyl and naphthyl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ⁇ CO 2 H, and ⁇ CO 2 (C1-C4 alkyl).
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalky
  • Ar 4 is selected from unsubstituted phenyl and unsubstituted naphthyl.
  • Ar 4 is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • 5- to 10- membered heteroaryls include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, pyrazole, triazole, benzothiazole, benzoxazole, quinolone, isoquinoline, pyridine, pyrimidine, and pyrazine.
  • Ar 4 is a C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is a C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is a C2-C9 heteroaryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is an unsubstituted C2-C9 heteroaryl.
  • Ar 4 is a pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is a pyridinyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is a pyridinyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is a pyridinyl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is an unsubstituted pyridinyl.
  • Ar 4 is a quinolinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is a quinolinyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is a quinolinyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is a quinolinyl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is an unsubstituted quinolinyl.
  • Ar 4 is a isoquinolinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is a isoquinolinyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is a isoquinolinyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is a isoquinolinyl monosubstituted with 0a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 4 is an unsubstituted isoquinolinyl. r. AR 5 GROUPS [00251]
  • Ar 5 is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • C2-C9 heteroaryls include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, pyrazole, triazole, benzothiazole, benzoxazole, quinolone, isoquinoline, pyridine, pyrimidine, and pyrazine.
  • Ar 5 is a C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 5 is a C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 5 is a C2-C9 heteroaryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4 haloalkoxy, C1-
  • Ar 5 is an unsubstituted C2-C9 heteroaryl.
  • Ar 5 is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 5 is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 5 is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is substituted with 0 or 1 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 5 is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Ar 5 is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is unsubstituted.
  • Ar 5 is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is unsubstituted.
  • Ar 5 is selected from triazolyl, oxadiazolyl, tetrazolyl, and oxazolyl, and is unsubstituted.
  • Ar 5 is selected from triazolyl and tetrazolyl, and is unsubstituted. In an even further aspect, Ar 5 is an unsubstituted triazole. [00254] In various aspects, Ar 5 is a structure selected from: , wherein * denotes a connection to ⁇ (CH 2 )n ⁇ and ** denotes a connection to Ar 1 . s.
  • Cy 1 is selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is selected from C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0 or 1 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is monosubstituted with a groups selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is unsubstituted.
  • Cy 1 is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is selected from C3- C6 cycloalkyl and C3-C6 heterocycloalkyl, and is substituted with 0 or 1 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, and is monosubstituted with a groups selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, and is unsubstituted.
  • Cy 1 is selected from C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is selected from C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is selected from C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0 or 1 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is selected from C6-C14 aryl, and C2-C10 heteroaryl, and is monosubstituted with a groups selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is selected from C6-C14 aryl, and C2-C10 heteroaryl, and is unsubstituted.
  • Cy 1 is a C3-C6 cycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is a C3-C6 cycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is a C3-C6 cycloalkyl, and is substituted with 0 or 1 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is a C3-C6 cycloalkyl, and is monosubstituted with a groups selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4 haloal
  • Cy 1 is a C3-C6 cycloalkyl, and is unsubstituted.
  • Cy 1 is a C3-C6 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is a C3-C6 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is a C3-C6 heterocycloalkyl, and is monosubstituted with a groups selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4 haloal
  • Cy 1 is a C3-C6 heterocycloalkyl, and is unsubstituted.
  • Cy 1 is a C6-C14 aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is a C6- C14 aryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is selected a C6-C14 aryl, and is substituted with 0 or 1 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is a C6-C14 aryl, and is monosubstituted with a groups selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C1-C4 haloalkoxy,
  • Cy 1 is a C6-C14 aryl, and is unsubstituted.
  • Cy 1 is a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is a C2-C10 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is a C2-C10 heteroaryl, and is monosubstituted with a groups selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl.
  • Cy 1 is a C2-C10 heteroaryl, and is unsubstituted.
  • EXEMPLARY COMPOUNDS [00262]
  • a compound can be present as one or more of the following structures: ,
  • a compound can be present as the following structure:
  • a compound is: ,
  • a compound is: ,
  • a compound is: ,
  • a compound can be present as the following structure: , or a pharmaceutically acceptable salt thereof.
  • one or more compounds can optionally be omitted from the disclosed invention.
  • the disclosed compounds can be used in connection with the disclosed methods, compositions, kits, and uses.
  • pharmaceutical acceptable derivatives of the disclosed compounds can be used also in connection with the disclosed methods, compositions, kits, and uses.
  • the pharmaceutical acceptable derivatives of the compounds can include any suitable derivative, such as pharmaceutically acceptable salts as discussed below, isomers, radiolabeled analogs, tautomers, and the like.
  • compositions comprising an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula: , wherein n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A 1 is selected from ⁇ O ⁇ and ⁇ CH 2 ⁇ , provided that when A 1 is O, then o is not 0 or 1; wherein L 1 is selected from C2 alkenyl, C2 alkynyl, ⁇ NHSO 2 ⁇ , ⁇ SO 2 NH ⁇ , ⁇ NHC(O) ⁇ , ⁇ C(O)NH ⁇ , and Ar 5 ; wherein Ar 5 , when present,
  • R 13 is selected from hydrogen and ⁇ OH; and wherein Ar 1 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Ar 1 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH
  • compositions comprising an effective amount of a compound having a structure represented by a formula: , wherein r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R 3a and R 3b is C1-C4 alkyl and one of R 3a and R 3b is a structure selected from:
  • R 13 is selected from hydrogen and ⁇ OH; wherein each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R 10 is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A 2 is selected from ⁇ C(O) ⁇ and ⁇ SO2 ⁇ ; wherein L 2 is ⁇ (CR 11a R 11b ) 2 ⁇ ; wherein each of R 4a
  • the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration.
  • the compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients.
  • a pharmaceutical composition can be formulated for local or systemic administration, e.g., administration by drops or injection into the ear, insufflation (such as into the ear), intravenous, topical, or oral administration.
  • the nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art.
  • the pharmaceutical composition is sterile or sterilizable.
  • the therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans.
  • Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol.
  • the nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral.
  • a modulatory compound can be formulated in various ways, according to the corresponding route of administration.
  • liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application.
  • Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.
  • the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants.
  • compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. [00278]
  • the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets can be coated by standard aqueous or nonaqueous techniques
  • a tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants.
  • the instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices.
  • compositions can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods.
  • a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
  • the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • compositions containing a compound of the invention, and/or pharmaceutically acceptable salts thereof can also be prepared in powder or liquid concentrate form.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactically effective amount.
  • the pharmaceutical composition is administered to a mammal.
  • the mammal is a human.
  • the human is a patient.
  • the pharmaceutical composition is used to treat a disorder associated with over-activation of NOX4 signaling.
  • the pharmaceutical composition is used to treat a disorder that is a fibrotic disorder or acute respiratory distress syndrome (ARDS).
  • ARDS acute respiratory distress syndrome
  • the fibrotic disorder is pulmonary fibrosis, heart fibrosis, kidney fibrosis, liver fibrosis, skin fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, or scleroderma or systemic sclerosis.
  • the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using. D.
  • RESULTS OF INHIBITING NADPH OXIDASE 4 (NOX4) SIGNALING IN A CELL METHODS OF INHIBITING NADPH OXIDASE 4 (NOX4) SIGNALING IN A CELL [00291]
  • the compounds and compositions disclosed herein are useful for inhibiting NADPH Oxidase 4 (NOX4) signaling in a cell.
  • n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A 1 is selected from ⁇ O ⁇ and ⁇ CH 2 ⁇ , provided that when A 1 is O, then o is not 0 or 1; wherein L 1 is selected from C2 alkenyl, C2 alkynyl, ⁇ NHSO 2 ⁇ , ⁇ SO 2 NH ⁇ , ⁇ NHC(O) ⁇ , ⁇ C(O)NH ⁇ , and Ar 5 ; wherein Ar 5 , when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN,
  • R 13 is selected from hydrogen and ⁇ OH; and wherein Ar 1 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.
  • R 13 is selected from hydrogen and ⁇ OH; wherein each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R 10 is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A 2 is selected from ⁇ C(O) ⁇ and ⁇ SO2 ⁇ ; wherein L 2 is ⁇ (CR 11a R 11b ) 2 ⁇ ; wherein each of R 4a
  • the cell is mammalian.
  • the cell is a human.
  • the cell has been isolated from a mammal prior to the contacting step.
  • the contacting is ex vivo.
  • the contacting is in vitro.
  • contacting is via administration to a mammal.
  • the mammal has been diagnosed with a need for inhibiting NOX4 signaling prior to the administering step.
  • the mammal has been diagnosed with a need for treatment of a disorder associated with over-activation of NOX4 signaling prior to the administering step.
  • the disorder is a fibrotic disorder or acute respiratory distress syndrome (ARDS).
  • ARDS acute respiratory distress syndrome
  • the mammal has been diagnosed with a need for inhibition of NOX4 signaling prior to the administering step.
  • NOX4 NADPH Oxidase 4
  • disclosed are methods of inhibiting NADPH Oxidase 4 (NOX4) signaling in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.
  • n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A 1 is selected from ⁇ O ⁇ and ⁇ CH 2 ⁇ , provided that when A 1 is O, then o is not 0 or 1; wherein L 1 is selected from C2 alkenyl, C2 alkynyl, ⁇ NHSO 2 ⁇ , ⁇ SO 2 NH ⁇ , ⁇ NHC(O) ⁇ , ⁇ C(O)NH ⁇ , and Ar 5 ; wherein Ar 5 , when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN,
  • R 13 is selected from hydrogen and ⁇ OH; and wherein Ar 1 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.
  • R 13 is selected from hydrogen and ⁇ OH; wherein each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R 10 is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A 2 is selected from ⁇ C(O) ⁇ and ⁇ SO2 ⁇ ; wherein L 2 is ⁇ (CR 11a R 11b ) 2 ⁇ ; wherein each of R 4a
  • the subject is a mammal. [00302] In various aspects, the subject is a human. [00303] In various aspects, the subject has been diagnosed with a need for inhibiting NOX4 signaling to the administering step. [00304] In various aspects, the method further comprising identifying a subject in need of inhibition of NOX4 signaling as further described herein. F. METHODS OF TREATING A FIBROTIC DISORDER IN A SUBJECT [00305] In one aspect, disclosed are methods of treating a fibrotic disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof.
  • ROS reactive oxygen species
  • Nox4 NADPH oxidase
  • a 1 is selected from ⁇ O ⁇ and ⁇ CH 2 ⁇ , provided that when A 1 is O, then o is not 0 or 1;
  • L 1 is selected from C2 alkenyl, C2 alkynyl, ⁇ NHSO 2 ⁇ , ⁇ SO 2 NH ⁇ , ⁇ NHC
  • a fibrotic disorder in a subject comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R 3a and R 3b is C1-C4 alkyl and one of R 3a and R 3b is a structure selected from: ; wherein R 13 is selected from hydrogen and ⁇ OH; wherein each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkoxy, C1-C4 alkoxy, C1-C
  • fibrotic disorders include, but are not limited to, pulmonary fibrosis, heart fibrosis, kidney fibrosis, liver fibrosis, skin fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, or scleroderma or systemic sclerosis.
  • the fibrotic disorder is pulmonary fibrosis.
  • the pulmonary fibrosis is idiopathic pulmonary fibrosis.
  • the subject is a mammal.
  • the subject is a human.
  • the subject has been diagnosed with the fibrotic disorder prior to the administering step.
  • the method further comprises the step of identifying a subject in need of treatment of the fibrotic disorder.
  • the method further comprises administering to the subject an anti-fibrotic agent.
  • anti-fibrotic agents include, but are not limited to, nintedanib and pirfenidone. G.
  • ARDS acute respiratory distress syndrome
  • methods comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof.
  • Oxidative stress has been implicated as a major contributor to the pathogenesis of ARDS.
  • aged mice with severe ARDS exhibited sustained upregulation of Nox4 and elevated ROS levels.
  • strategies that block the source of ROS production are more specific and effective in comparison to antioxidant strategies because the damage from highly reactive ROS molecules occur rapidly.
  • Pulmonary endothelial cells line the surface of the lung vasculature and are a critical regulator of vascular homeostasis. Located at the interface between the bloodstream and lung tissue, the endothelium serves as a barrier that regulates the influx of inflammatory cells and fluid into the interstitial space.
  • a key pathological feature of ARDS is EC barrier disruption, which results in increased vascular permeability and inflammatory influx. The accumulation of inflammatory cells and protein-rich fluid into the alveolar space can result in alveolar filling, hypoxemia, and ultimately respiratory failure.
  • Autopsy reports from COVID-19 patients revealed severe injury to lung ECs accompanied by significant inflammatory cell influx, and transcriptomics are consistent with EC dysregulation.
  • ARDS and COVID-19-associated ARDS would combat EC barrier dysfunction and inflammatory injury to circumvent pulmonary edema and reduce the risk of respiratory failure and death.
  • oxidative stress as a major contributor to the pathogenesis of ARDS.
  • Numerous studies have demonstrated high levels of ROS in the lungs following acute lung injury (ALI) in animal models and in ARDS patients. Excessive ROS production has been shown to promote EC barrier dysfunction and increased vascular permeability, which amplifies tissue damage, capillary leak, and pulmonary edema.
  • antioxidants function to scavenge existing ROS (that has already been produced), they do not block the source of ROS production. Oxidants are highly reactive molecules, and once generated, can rapidly induce damage to cells and surrounding tissues and induce inflammatory responses. Thus, strategies that directly block the source of ROS production are likely to be more specific and effective in comparison to antioxidant strategies because the damage from highly reactive ROS molecules may occur rapidly.
  • the proposed treatment method seeks to develop a novel therapeutic, which targets the critical pathological features of ARDS: excessive ROS production, barrier dysfunction, and inflammatory injury. [00317] As life expectancy continues to increase, there is a demographic shift toward a growing elderly population, including the U.S. elderly veteran population.
  • ARDS disproportionately affects the elderly population; higher incidence and mortality are associated with advancing age. ARDS incidence is 16/100,000 persons for adolescents (15-19 years) vs. 306/100,000 among the elderly (75-84 years). ARDS mortality increases with age; 24% in adolescents vs.60% in elderly. ARDS mortality is 2-fold higher in patients >70 years vs. under 70, and elderly survivors have more difficulties recovering. Older age is also a significant risk factor for COVID-19-associated hospitalization, including the development of ARDS and progression from ARDS to death; 75% of hospitalized COVID-19 patients were ⁇ 50 years. Of those who required intensive care, mechanical ventilation, or died, the median age was 63.
  • COVID-19 mortality rate is also highly correlated to older age: 42% (80-89 years), 32% (70-79), 8% (60-69), and 2% (50-59).
  • ARDS oxidative stress, barrier dysfunction, and inflammation – discussed above
  • therapeutic targeting of age-dependent pathological mechanisms has yet to be explored in the development of ARDS treatments. This may explain the lack of successful treatment options for ARDS, which primarily afflicts the elderly.
  • Data herein suggests that targeting age-dependent pathological mechanisms may be the key to improving survival outcomes for elderly ARDS patients.
  • ARDS acute respiratory distress syndrome
  • the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A 1 is selected from ⁇ O ⁇ and ⁇ CH 2 ⁇ , provided that when A 1 is O, then o is not 0 or 1; wherein L 1 is selected from C2 alkenyl, C2 alkynyl, ⁇ NHSO2 ⁇ , ⁇ SO2NH ⁇ , ⁇ NHC(O) ⁇ , ⁇ C(O)NH ⁇ , and Ar 5 ; wherein Ar 5 , when present, is a C2-
  • ARDS acute respiratory distress syndrome
  • a compound having a structure represented by a formula: wherein r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R 3a and R 3b is C1-C4 alkyl and one of R 3a and R 3b is a structure selected from:
  • R 13 is selected from hydrogen and ⁇ OH; wherein each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R 10 is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A 2 is selected from ⁇ C(O) ⁇ and ⁇ SO2 ⁇ ; wherein L 2 is ⁇ (CR 11a R 11b ) 2 ⁇ ; wherein each of R 4a
  • administering is via oral administration, intraperitoneal administration, or intravenous (IV) administration. In a further aspect, administering is via oral administration. In a still further aspect, administering is via intraperitoneal administration. In a yet further aspect, administering is via intravenous (IV) administration.
  • the subject is a mammal. [00322] In various aspects, the subject is a human. [00323] In various aspects, the subject has been diagnosed with ARDS prior to the administering step. [00324] In various aspects, the subject has been diagnosed with coronavirus disease (COVID) prior to the administering step. In a further aspect, COVID is coronavirus disease 2019 (COVID-19).
  • COVID coronavirus disease 2019 (COVID-19).
  • the method further comprising the step of identifying a subject in need of treatment of ARDS.
  • the method further comprising administering to the subject an agent known to treat ARDS.
  • agents known to treat ARDS include, but are not limited to, nitric oxide and corticosteroids (e.g., cortisone, hydrocortisone, and prednisone).
  • H. METHODS OF TREATING CANCER IN A SUBJECT [00327]
  • disclosed are methods treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof.
  • Nox4 is the most frequently expressed member of the Nox members reported to be dysregulated in a wide variety of tumors (Gong et. al., (2022) Frontier in Cell and Developmental Biology 10: 1-7). As such, strategies that modulate Nox4 can be useful in the treatment of cancer.
  • n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A 1 is selected from ⁇ O ⁇ and ⁇ CH 2 ⁇ , provided that when A 1 is O, then o is not 0 or 1; wherein L 1 is selected from C2 alkenyl, C2 alkynyl, ⁇ NHSO2 ⁇ , ⁇ SO2NH ⁇ , ⁇ NHC(O) ⁇ , ⁇ C(O)NH ⁇ , and Ar 5 ; wherein Ar 5 , when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • R 13 is selected from hydrogen and ⁇ OH; and wherein Ar 1 is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.
  • R 13 is selected from hydrogen and ⁇ OH; wherein each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R 10 is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A 2 is selected from ⁇ C(O) ⁇ and ⁇ SO2 ⁇ ; wherein L 2 is ⁇ (CR 11a R 11b ) 2 ⁇ ; wherein each of R 4a
  • treating disrupts tumor-promoting desmoplasia.
  • treating inhibits desmoplastic tumor growth.
  • administering is via oral administration, intraperitoneal administration, or intravenous (IV) administration.
  • administering is via oral administration.
  • administering is via intraperitoneal administration.
  • administering is via intravenous (IV) administration.
  • the subject is a mammal.
  • the subject is a human.
  • the subject has been diagnosed with cancer prior to the administering step.
  • the subject has been diagnosed with desmoplasia prior to the administering step.
  • the method further comprising the step of identifying a subject in need of treatment of cancer.
  • the method further comprising the step of identifying a subject in need of treatment of desmoplasia.
  • the method further comprising administering to the subject an agent known to treat cancer.
  • the agent known to treat cancer is a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to alkylating agents, antimetabolite agents, antineoplastic antibiotic agents, mitotic inhibitor agents, and mTor inhibitor agents.
  • the chemotherapeutic agent is an antineoplastic antibiotic agent.
  • antineoplastic antibiotic agents include, but are not limited to, doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.
  • the chemotherapeutic agent is an antimetabolite agent.
  • antimetabolite agents include, but are not limited to, gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.
  • the chemotherapeutic agent is an alkylating agent.
  • alkylating agents include, but are not limited to, carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.
  • the chemotherapeutic agent is a mitotic inhibitor agent.
  • mitotic inhibitor agents include, but are not limited to, irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.
  • the chemotherapeutic agent is a mTOR inhibitor agent.
  • mTOR inhibitor agents include, but are not limited to, everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  • the compound and the agent are administered sequentially.
  • the compound and the agent are administered simultaneously.
  • the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).
  • the cancer is breast cancer or pancreatic cancer.
  • I. ADDITIONAL METHODS OF USING THE COMPOUNDS [00348]
  • the compounds and pharmaceutical compositions of the invention are useful in treating or controlling disorders associated with over-activation of NOX4.
  • fibrotic disorders e.g., pulmonary fibrosis, heart fibrosis, kidney fibrosis, liver fibrosis, skin fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, scleroderma or systemic sclerosis
  • ARDS acute respiratory distress syndrome
  • cancer e.g., a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell neoplasm (my), pulmonary fibrosis, heart
  • the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian.
  • a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is preferably a mammal, such as a human.
  • the subject Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of a disorder associated with associated with over-activation of NOX4.
  • the compounds or compositions can be administered to the subject according to any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent.
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
  • a preparation can also be administered prophylactically; that is, administered for prevention of a disorder associated with over-activation of NOX4.
  • the therapeutically effective amount or dosage of the compound can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded.
  • the daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion.
  • Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. 1.
  • the invention relates to a method for the manufacture of a medicament for the treatment associated with over-activation of NOX4 in a subject in need thereof, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically acceptable carrier or diluent Also disclosed herein is the use of the disclosed compounds or a pharmaceutically acceptable salt thereof, together with a compound or agent known for treating or controlling disorders associated with over-activation of NOX4, in the manufacture of a medicament.
  • the manufacture of the medicament can comprise co-formulating or co-packaging the disclosed compounds, or a pharmaceutically acceptable salt thereof, together with a therapy targeting a fibrotic disorder, ARDS, or cancer.
  • Non-limiting examples include anti-fibrotic agents (e.g., nintedanib, pirfenidone), agents known to treat ARDS (e.g., nitric oxide, corticosteroids), and chemotherapeutic agents.
  • the method for the manufacture of a medicament comprises combining a therapeutically effective amount of the disclosed compounds, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier or diluent and/or with a compound known for treating the fibrotic disorder, ARDS, or cancer.
  • a method for the manufacture of a medicament for treating syndrome fibrotic disorder, ARDS, or cancer the method comprising combining a therapeutically effective amount of a disclosed compounds or a pharmaceutically acceptable salt thereof with a therapeutically effective amount of a compound known for treating the fibrotic disorder, ARDS, or cancer, together with a pharmaceutically acceptable carrier or diluent.
  • the invention relates to the use of a disclosed compound, a disclosed composition, or a product of a disclosed method.
  • a use relates to the manufacture of a medicament for treating or controlling disorders associated with over- activation of NOX4.
  • a use relates to the manufacture of a medicament for treating a disorder that is a fibrotic disorder or acute respiratory distress syndrome (ARDS).
  • ARDS acute respiratory distress syndrome
  • the compounds and pharmaceutical compositions of the invention are useful in treating or controlling disorders associated with over-activation of NOX4.
  • the invention relates to use of at least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  • the compound used is a product of a disclosed method of making.
  • the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament.
  • the use relates to a process for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.
  • the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits.
  • the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a disorder associated with over- activation of NOX4. 3.
  • kits comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti-fibrotic agent; (b) instructions for treating a fibrotic disorder; (c) an agent known to treat ARDS; (d) instructions for treating ARDS; (e) an agent known to treat cancer; and (f) instructions for treating cancer.
  • kits comprising a compound having a structure represented by a formula: , wherein n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A 1 is selected from ⁇ O ⁇ and ⁇ CH 2 ⁇ , provided that when A 1 is O, then o is not 0 or 1; wherein L 1 is selected from C2 alkenyl, C2 alkynyl, ⁇ NHSO 2 ⁇ , ⁇ SO 2 NH ⁇ , ⁇ NHC(O) ⁇ , ⁇ C(O)NH ⁇ , and Ar 5 ; wherein Ar 5 , when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C
  • kits comprising a compound having a structure represented by a formula: , wherein r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R 3a and R 3b is C1-C4 alkyl and one of R 3a and R 3b is a structure selected from: ; wherein R 13 is selected from hydrogen and ⁇ OH; wherein each of R 4a , R 4b , R 4c , and R 4d is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and
  • kit includes the anti-fibrotic agent.
  • anti-fibrotic agents include, but are not limited to, nintedanib and pirfenidone.
  • the kit includes the agent known to treat ARDS.
  • agents known to treat ARDS include, but are not limited to, nitric oxide and corticosteroid.
  • the kit includes the agent known to treat cancer such as, for example, a chemotherapeutic agent as further described herein.
  • the compound and the anti-fibrotic agent are co-formulated.
  • the compound and the anti-fibrotic agent are co-packaged.
  • the compound and the agent known to treat ARDS are co- formulated. In various further aspects, the compound and the agent known to treat cancer are co- packaged. [00370] In various aspects, the compound and the agent known to treat cancer are co- formulated. In various further aspects, the compound and the agent known to treat cancer are co- packaged. [00371] In various further aspects, a disclosed compound or a pharmaceutically-acceptable salt thereof, the instructions for the use thereof (when present) and/or a combination therapy including a compound known for treating the target condition can be co-packaged and/or co- formulated.
  • kits can also comprise compounds and/or products co-packaged, co- formulated, and/or co-delivered with other components.
  • a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and/or product and another component for delivery to a patient.
  • the disclosed kits can be prepared from the disclosed compounds and pharmaceutical formulations. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using the compounds and pharmaceutical formulations.
  • the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises an effective amount of the compound and the agent.
  • each dose of the compound and the agent are co-packaged.
  • each dose of the compound and the agent are co- formulated. 4.
  • the subject of the herein disclosed methods is a vertebrate, e.g., a mammal.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • a patient refers to a subject afflicted with a disease or disorder.
  • the term “patient” includes human and veterinary subjects.
  • the subject has been diagnosed with a need for treatment prior to the administering step.
  • the subject has been diagnosed with a disorder of uncontrolled cellular proliferation prior to the administering step.
  • the subject has been identified with a need for treatment prior to the administering step.
  • a subject can be treated prophylactically with a compound or composition disclosed herein, as discussed herein elsewhere.
  • Toxicity and therapeutic efficacy of the agents and pharmaceutical compositions described herein can be determined by standard pharmaceutical procedures, using either cells in culture or experimental animals to determine the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD 50 /ED 50 .
  • Data obtained from cell culture assays and further animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity, and with little or no adverse effect on a human's ability to hear.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (that is, the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
  • Exemplary dosage amounts of a differentiation agent are at least from about 0.01 to 3000 mg per day, e.g., at least about 0.00001, 0.0001, 0.001, 0.01, 0.1, 1, 2, 5, 10, 25, 50, 100, 200, 500, 1000, 2000, or 3000 mg per kg per day, or more.
  • the formulations and routes of administration can be tailored to the disease or disorder being treated, and for the specific human being treated. For example, a subject can receive a dose of the agent once or twice or more daily for one week, one month, six months, one year, or more. The treatment can continue indefinitely, such as throughout the lifetime of the human.
  • Treatment can be administered at regular or irregular intervals (once every other day or twice per week), and the dosage and timing of the administration can be adjusted throughout the course of the treatment.
  • the dosage can remain constant over the course of the treatment regimen, or it can be decreased or increased over the course of the treatment.
  • the dosage facilitates an intended purpose for both prophylaxis and treatment without undesirable side effects, such as toxicity, irritation or allergic response.
  • individual needs may vary, the determination of optimal ranges for effective amounts of formulations is within the skill of the art. Human doses can readily be extrapolated from animal studies (Katocs et al., (1990) Chapter 27 in Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA).
  • the dosage required to provide an effective amount of a formulation will vary depending on several factors, including the age, health, physical condition, weight, type and extent of the disease or disorder of the recipient, frequency of treatment, the nature of concurrent therapy, if required, and the nature and scope of the desired effect(s) (Nies et al., (1996) Chapter 3, In: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al., eds., McGraw-Hill, New York, NY).
  • b. ROUTES OF ADMINISTRATION Also provided are routes of administering the disclosed compounds and compositions.
  • the compounds and compositions of the present invention can be administered by direct therapy using systemic administration and/or local administration.
  • the route of administration can be determined by a patient's health care provider or clinician, for example following an evaluation of the patient.
  • an individual patient's therapy may be customized, e.g., the type of agent used, the routes of administration, and the frequency of administration can be personalized.
  • therapy may be performed using a standard course of treatment, e.g., using pre-selected agents and pre-selected routes of administration and frequency of administration.
  • Systemic routes of administration can include, but are not limited to, parenteral routes of administration, e.g., intravenous injection, intramuscular injection, and intraperitoneal injection; enteral routes of administration e.g., administration by the oral route, lozenges, compressed tablets, pills, tablets, capsules, drops (e.g., ear drops), syrups, suspensions and emulsions; rectal administration, e.g., a rectal suppository or enema; a vaginal suppository; a urethral suppository; transdermal routes of administration; and inhalation (e.g., nasal sprays).
  • parenteral routes of administration e.g., intravenous injection, intramuscular injection, and intraperitoneal injection
  • enteral routes of administration e.g., administration by the oral route, lozenges, compressed tablets, pills, tablets, capsules, drops (e.g., ear drops), syrups, suspensions and emulsions
  • rectal administration
  • reaction mixture was quenched with water (50 mL), extracted with CH 2 Cl 2 (2 ⁇ 20 mL), and the combined organic layer was sequentially washed with a saturated solution of NaHCO 3 and brine (30 mL). The organic layer was dried over Na 2 SO 4, and then filtered. The solvent was removed using a rotary evaporator and the crude material was purified on silica gel column chromatography, eluting with Hexane: ethyl acetate (7:3), v/v, to afford the desired product (4-(chloromethyl)-N-(2-(indolin-1-yl) ethyl)benzamide) as a light brown solid; yield: 254 mg (86 %).
  • reaction was quenched with water (50 mL), extracted with CH 2 Cl 2 (3 ⁇ 20 mL), and sequentially washed with a saturated solution of NaHCO 3 and brine (30 mL). The organic layers were combined, dried over Na 2 SO 4 , and then filtered. The solvent was removed using a rotary evaporator, and the crude product was used for the next reaction without further purification.
  • Senescent ECs Exhibit Defective Barrier-Regulatory Responses.
  • the increased presence of senescent cells at sites of age-associated pathologies supports a role for senescence in the pathogenesis (Vasile E, et al. (2001) FASEB 15(2):458-66).
  • the impact of senescence in EC barrier-regulatory responses was evaluated using an in vitro cellular model of replicative senescence using characterized human ECs characterized.
  • FIG.2B In response to insult, senescent cells exhibit significantly increased permeability (FIG.2B), as compared to control “young” ECs (FIG.2A). Without wishing to be bound by theory, these studies indicate that EC senescence leads to impaired barrier function.
  • Nox4 An ROS-Generating Enzyme that Mediates EC Permeability. Numerous studies have demonstrated that excessive ROS production plays a major role in EC barrier dysfunction resulting in pulmonary edema. It has been demonstrated that although both young and senescent ECs generate ROS in response to insult, senescent ECs with defective barrier- regulatory responses generated significantly greater ROS levels compared to young ECs (FIG. 3A) (Palumbo et al.
  • NADPH oxidase (Nox) enzymes are an evolutionarily conserved gene family linked to host defense mechanisms. The only known role of Nox enzymes is the production of ROS, which is important for cellular homeostasis and stress-induced repair-responses.
  • NADPH oxidase-4 (Nox4) is a constitutively active enzyme, which specifically generates H 2 O 2 , a relatively stable oxidant compared to other ROS types. Nox4 is the most abundantly expressed Nox isoform in ECs, and Nox4 is the primary enzymatic source of ROS in ECs.
  • Nox4-dependent ROS mediates EC permeability.
  • expression levels of other Nox isoforms remained unchanged (only Nox4 was increased).
  • Nox4-dependent ROS plays a critical in mediating EC barrier regulatory responses, and aberrant/sustained upregulation of Nox4 in senescent ECs promotes persistently elevated ROS levels resulting in exacerbated permeability and inflammatory responses.
  • Aged Mice with Severe ARDS Exhibit Sustained Upregulation of Nox4 and Elevated ROS. It was previously demonstrated that aged mice with severe ARDS (FIG.1B) exhibited significantly elevated Nox4 protein levels in the lungs, which corresponded with increased ROS levels in lung BAL (FIG.4) (Palumbo et al. (2017) American Journal of Physiology-Lung Cellular and Molecular Physiology 312.3: L297-L308).
  • Nox4 The crystal structure of Nox4 is unknown, which precludes traditional rational drug design approaches. Screening methods for Nox inhibitors typically utilize ROS detection- based screening assays that have limited specificity. Thus, it may be difficult to discern whether a putative inhibitor is acting directly on Nox versus regulation of upstream signaling pathway(s). Accordingly, one study reported that of >350 “Nox inhibitors” described, a majority of these did not directly block Nox enzymatic activity, but rather showed interference with upstream signaling pathways or demonstrated antioxidant activity. An additional challenge to the field is reports of putative “Nox inhibitors,” which have been subsequently challenged and disproven.
  • APX-115 is a “putative Nox1,2,4 inhibitor” (Aptabio Therapeutics Inc) that is currently in a clinical trial for Type 2 diabetic nephropathy.
  • APX-115 and Setanaxib might be interesting non-toxic pharmacological agents, their Nox inhibitory activity has either been disproven (Setanaxib) or is not convincing (APX-115).
  • Current data demonstrate that APX-115 is an antioxidant: in a cell-free assay with exogenous H 2 O 2 , APX- 115 showed 56% inhibition at 10 ⁇ M, and 100% inhibition at higher concentrations >30 ⁇ M (FIG.5A).
  • GLX351322 is a putative Nox inhibitor developed by Glucox Biotech, which was initially identified via a high-throughput approach using a Nox4 overexpressing cell line and an Amplex Red assay (similar to our primary screening assay).
  • DPI Diphenylene iodonium
  • Nox inhibitory activity has either been disproven or is not convincing.
  • limited antioxidant activity lack of effect on other sources of ROS upstream of Nox4 signaling
  • demonstrated direct inhibition of Nox4 activity and high selectivity for Nox4.
  • FIG.5A shows compounds at (10mM), Vehicle (DMSO), or Catalase (750U/mL; positive control for antioxidant activity) were incubated with H 2 O 2 (5 ⁇ M) for 1h. H 2 O 2 was assessed by ROS-Glo Amplex Red (HRP-dependent assay); these data demonstrate that other putative Nox inhibitors act as antioxidants.
  • FIG.5B shows data of HEK cells stably transfected to overexpress Nox4 (HEK-Nox4 cells) were treated with compounds (10 ⁇ M), vehicle control (DMSO), or digitonin (positive control cell death) and incubated for 1h. Cellular viability was evaluated by CellTiter-Glo® Assay. These data demonstrate that GLX treatment leads to significant cell death. 4. PRELIMINARY STUDIES a. NOX4 TARGET VALIDATION [00435] Previous studies have demonstrated that Nox4 mediates EC barrier responses, and that Nox4 is upregulated in senescent ECs. Microarray data further corroborated these findings at the transcriptional level (Table 2). Importantly, no other Nox isoforms are upregulated.
  • ECs were isolated from wild-type (WT) and Nox4-eKO mice via FACS. Indeed, ECs isolated from Nox4-eKO mice demonstrated significant knockdown of Nox4, as compared to WT isolated ECs (FIG.6B). Young (2m) and aged (18m) WT and Nox4-eKO mice were then subjected to ALI (LPS via IT delivery).
  • FIG.6A shows Nox4-eKO mice were generated by crossing Nox4 floxed mouse (gift from Dr. Sadoshima, Rutgers University) with EC specific promoter-driven Cre (EC- targeted Cre) mouse (Jackson Laboratory); confirmed by genotyping.
  • FIG.6B shows data of lung ECs from WT and Nox4-eKO mice were isolated via FACS and evaluated for Nox4 expression via WB.
  • FIG.6C-F show young and aged mice were subjected to intratracheal instillation of LPS (0.2mg/kg) via IT delivery for 24h.
  • HTS high-throughput screening
  • UANOX48 has a low molecular weight (384.4 g/mole) and a relatively high solid-to-liquid melting phase transition (Tonset 89.72 ⁇ C, Tpeak 92.3°C), indicating high stability at both room and body temperatures (32-37°C); this is important from a pharmaceutical standpoint, as these data indicate high stability at drug manufacturing/processing and delivery temperatures.
  • UANOX48 passed false-positive screening: demonstrated no scavenger activity (does not act as an antioxidant) (FIG.7A and FIG.7B), does not interfere with assay reagents (FIG.7A), and has no effect on cellular viability (FIG.7C).
  • UANOX48 demonstrated high selectivity for Nox4 over Nox2 or xanthine oxidase (Nox-independent ROS generation) (FIG.7D).
  • the inducibility of Nox4-dependent H 2 O 2 by TGF- ⁇ 1 is a highly specific and unique function of Nox4. This unique feature of Nox4 was exploited in the screening cascade.
  • FIG.7A-D shows assays associated with identification of a novel Nox4 inhibitor.
  • FIG.7A-C show results for false-positive screening: UANOX48 (10 ⁇ M), Vehicle (DMSO), or Catalase (750U/mL; positive control for scavenger activity) were incubated with H 2 O 2 (5 ⁇ M) for 1h.
  • FIG.7A shows HEK cells stably transfected to overexpress Nox4 (HEK-Nox4 cells) were treated with UANOX48 (10 ⁇ M), vehicle control (DMSO), or digitonin (positive control cell death) and incubated for 1h. Cellular viability was evaluated by CellTiter-Glo® Assay.
  • FIG.7D shows selectivity assay data: IC 50 evaluation was performed in cell-based assays.
  • FIG.8A shows myofibroblasts isolated from the lungs of IPF patients treated with UANOX48 (10 ⁇ M or as indicated) or vehicle (DMSO). H 2 O 2 levels were evaluated at 24h by Amplex Red assay.
  • UANOX48 was utilized to demonstrate proof-of-concept for targeting Nox4 in an animal model of ARDS. Treatment with UANOX48 led to reduced ROS levels in senescent ECs (FIG.9A) and increased proliferation of non-senescent ECs (FIG.9B). [00445] The PK profile and lung distribution of UANOX048 via IV delivery was evaluated in mice; half-life (t 1/2 ) 3h (plasma), and 2.9h (lung). The efficacy of UANOX048 was evaluated in a murine model of ALI.
  • mice were pre-treated with inhibitor or vehicle via IV administration and subjected to ALI.
  • Mice treated with UANOX48 demonstrated reduced blood ROS levels (FIG.9C) and significant protection from ALI including significantly reduced lung albumin (FIG.9D) and inflammation inflammatory (specifically decreased neutrophil influx) (FIG.9E-G)).
  • FIG.9A-G Nox4 inhibitors protect from pre-clinical ARDS.
  • FIG.9C blood ROS levels
  • FIG.9D lung albumin
  • inflammation inflammatory specifically decreased neutrophil influx
  • FIG.9A shows senescent ECs were treated with Nox4 inhibitor (20 ⁇ M), vehicle (DMSO), or DPI (10 ⁇ M) for 2h; H 2 O 2 was assesed by Amplex Red.
  • FIG.9C-G show young (2m) C57BL/6 mice were treated with UANOX48 (50 mg/kg) or vehicle via IV followed by IT instillation of LPS (0.2 mg/kg).
  • Macrolides are a class of antibiotics, which commonly used to treat various respiratory conditions. Their use in respiratory indications is advantageous due to a unique property of macrolide-based compounds: they have a high affinity for the lung and are able to effectively penetrate lung tissue. Significant distribution of macrolides in the lung occurs within 2h of IV delivery, and sustained lung levels are detectable for up to 8.5 days.
  • a macrocycle is a molecule that contains a cyclic framework of >12 atoms that can encapsulate drugs, thereby being used as a drug delivery vehicle, particularly to exploit a key property of macrolides: lung-targeting. It has been shown that the tissue accumulation property of macrocycle is tolerant of changes to their key moieties, resulting in compounds and nano- conjugates, which accumulate in the lung. This class of bioconjugate serves as an effective platform for intracellular drug delivery in the context of pulmonary disease and is highly amenable to IV delivery (vs. other delivery routes). A significant number of macrocycle-based IV drugs are currently on the market, as they are well-tolerated, with no serious adverse events reported in clinical trials.
  • Treprostinil and Macitentan are two examples of FDA-approved macrocycle drugs specifically utilized for pulmonary indications (pulmonary hypertension).
  • a Lung-Targeting Nox4 inhibitor (LT-Nox4i) series was developed in an effort to improve distribution and concentration of candidate inhibitors within the lung.
  • LT-Nox4 i designed demonstrated either similar binding affinity to Nox4 (-8.6--9 kcal/mol) and some LT-Nox4 i ’s demonstrated significantly increased binding affinity for Nox4 (up to -9.7--10.4 kcal/mol) vs parent inhibitor alone; these data suggest that the medicinal chemistry features of LT-Nox4i’s may exhibit improved binding to Nox4.
  • LT-Nox4i Artificial intelligence (AI) platform was utilized to perform blinded screening of two LT-Nox4 i structures; as compared to 50 of our top parent Nox4 inhibitors, LT-Nox4i’s were predicted to have up to ⁇ 30-fold increased distribution within the lungs, as compared to parent Nox4 inhibitors alone (Table 3). TABLE 3. [00452] Further, docking simulations predicted significantly increased binding affinity for Nox4 for macrocycle-Nox4 inhibitors (up to -10.4 kcal/mol) vs parent inhibitor alone (-8.6 kcal/mol) (Table 4). Macrocycles are an ideal vehicle to develop lung-targeted Nox4 inhibitors intended for IV delivery.
  • LT-Nox4 i -1 Nox4 inhibitor attached to azithromycin
  • LT-Nox4 i -1 Nox4 inhibitor attached to azithromycin
  • the efficacy of LT-Nox4i analogs were also evaluated for inhibiting Nox4-dependent ROS in senescent ECs; LT-Nox4 i ’s also showed similar potency to parent Nox4 i ’s for inhibiting ROS in senescent ECs (FIG.12B).
  • FIG.12A and FIG.12B comparisons of IC50 evaluation of LT- Nox4i vs parent Nox4 inhibitors or macrolide (azithromycin) alone are shown.
  • Lung-Targeting-Nox4 inhibitors (LT-Nox4 i -1; shown as compound 7 or LT- Nox4i-7; shown as compound 13 in graph) vs parent Nox inhibitors (compounds 3 and 6). These data demonstrate that adding the linker does not interfere with Nox4 inhibitory activity. [00455] Lung-targeting approach in vivo, was to be evaluated by performing PK studies with parent Nox4 inhibitor versus LT-Nox4i. The LT-Nox4i demonstrated significantly increased maximal concentrations (Cmax) within the lung (up to ⁇ 65-fold higher than parent) which remain elevated in the lungs even at 24h post-administration (vs.
  • Cmax maximal concentrations
  • Lung-targeting Nox4 inhibitor demonstrated significantly elevated concentrations within the lung in vivo vs. parent Nox4 inhibitor.
  • C57/Bl6 male mice (2m) were administered Lung-targeting Nox4 inhibitor (LT-Nox4i-1) or parent Nox4 inhibitors via IV delivery (1mg/kg).
  • Plasma and lung tissues were harvested at various time points following administration and assessed by LC-MS/MS. Analysis was performed using Pksolver 2.0 and one-compartment model. Blood plasma PK (FIG.13A) and lung PK (FIG.13B and FIG.13C) parameters are shown.
  • LPS (1mg/kg) was administered to mice followed by treatment vehicle, parent Nox4i, or LT-Nox4i-1 (5.7mg/kg;days 0-3) and endpoints were assessed 4 days post-injury.
  • Treatment with LT-Nox4i-1 significantly reduced lung BAL cells (FIG.15).
  • parent Nox4i showed no efficacy.
  • AUC area under the curve
  • AUC is used to assess the extent of drug exposure (AUC accounts for C max , t 1/2 , and clearance rate).
  • LT-Nox4 i -1 drug concentration remained elevated in the lungs 24 hours post administration, whereas concentrations of parent Nox4i (via both IV and inhaled delivery) were negligible within 1h post administration (FIG.16A and Table 5).
  • LT-Nox4 i -1 resulted in a 50% decrease in plasma AUC levels (FIG.16A and Table 5), indicating significantly reduced systemic exposure and decreased toxicity risk.
  • this directed approach dramatically improves drug exposure within the lungs and simultaneously decrease systemic exposure, which reduce the potential for off-target effects and/or toxicity. TABLE 5.
  • FIG.17A demonstrates that LT-Nox4i-1 inhibits ROS production in a stable cell line overexpressing Nox4.
  • FIG.17B demonstrates that LT-Nox4i-1 does not induce cell death in a viability assay (Digitonin is a positive control for cell death).
  • FIG.17C demonstrates that LT-Nox4i-1 does not inhibit Nox-independent ROS production (via xanthine oxidase).
  • FIG.17D demonstrates that LT-Nox4i-1 shows no antioxidant activity in a cell-free assay with exogenous ROS (catalase is a positive control for antioxidant activity).
  • Nox4 represents an “antagonistically pleiotropic” enzyme – it confers a reproductive advantage early in life but can have detrimental effects in late life (during post-reproductive age).
  • Nox4 an attractive target from a drug targeting perspective. Further, it is important to note that Nox4 knockout mice are viable with no appreciable phenotype in the unstressed (uninjured) state; suggesting lower risk for toxicity or off-target effects from Nox4 inhibition in unaffected tissues. [00461] Extensive epidemiological data demonstrates that susceptibility, severity, hospitalization, and mortality from ARDS is significantly higher in the elderly population. It is therefore hypothesized that therapeutic strategies targeting age-associated pathologic mechanisms offer the greatest potential for developing successful ARDS treatments; targeting the persistent upregulation of Nox4 (a major source of excessive oxidant generation) represents one plausible strategy.
  • UANOX48 was used to demonstrate proof-of-concept for targeting Nox4 in an animal model of ARDS. However, UANOX48 is not ideally suited for subsequent clinical development for ARDS primarily due to poor bioavailability within the lung; this is largely attributed to poor metabolic stability (high liver microsomal clearance, 349 ⁇ L/min/mg) and relatively high logD (4.05).
  • LT-Nox4 i s lung-targeting Nox4-inhibitors
  • FIG.13A-C proof-of-concept that for the development of LT-Nox4is using a macrocycle-based approach was demonstrated.
  • the initial data demonstrate that compared to parent Nox4 inhibitor alone, this approach results in significantly increased drug exposure (>1,000-fold) within the lung, with significantly reduced systemic exposure.
  • This directed approach dramatically boosts bioavailability of Nox4 inhibitor within the lung while reducing the risk of systemic toxicity.
  • LT-Nox4 i candidates were prepared.
  • LT-Nox4i candidates will be designed by integrating novel macrocycle lung- targeted linkers into the molecular architecture of previously identified top Nox4 inhibitor candidates. Candidates will be evaluated via in silico docking/binding simulations. ii. DEVELOP A LUNG-TARGETING NOX4 INHIBITOR SERIES AIMED TO ENHANCE DISTRIBUTION AND CONCENTRATION IN THE LUNG. [00465] Preliminary data suggests that macrocycle-based Nox4 inhibitors could significantly improve binding to Nox4 and selective distribution to the lung. If successfully validated, this will significantly advance the goal of improved Nox4 inhibitor distribution and bioavailability within the lung, which could potentially reduce toxicity risk.
  • Efficacy for inhibition of H 2 O 2 will be measured by Amplex red fluorescence assay.
  • Cytotoxicity Assay Ensuring that Nox4 inhibitors are not cytotoxic is a key parameter that requires assessment.
  • Cell Titer Glo assay is an industry-standard that measures cellular ATP levels. Analogs will be evaluated in this assay relative to vehicle control. Digitonin (200 ⁇ g/ml) will be used as a positive control for cell death.
  • Antioxidant Activity Analogs will be incubated in 96-well-plates containing exogenous H 2 O 2 (5 ⁇ M) and Amplex Red (a HRP-dependent assay mechanism to detect H 2 O 2 ).
  • XO generates superoxide and H 2 O 2 independent of Nox activity. This assay will be used to eliminate non-specific ROS scavengers.
  • v. FUNCTIONAL SCREENING FOR IN VITRO EFFICACY [00474] Proliferation. ECs will be evaluated for BrdU incorporation (by ELISA). [00475] Inflammatory Responses.
  • Senescent EC supernatant will be evaluated to assess changes in inflammatory cytokines using a Multiplex kit (Human Magnetic 65-Plex, ThermoFisher).
  • a Multiplex kit Human Magnetic 65-Plex, ThermoFisher.
  • Senescent ECs will be plated in a confluent monolayer in electric cell-substrate impedance sensing (ECIS) array plates coated with 0.1% gelatin. Cells will be treated with Nox4 inhibitor and stimulated with LPS. Trans-endothelial electrical resistance (TEER) will be evaluated using an electrical cell substrate impedance sensing system (Applied Biophysics): b.
  • ECIS electric cell-substrate impedance sensing
  • aqueous solubility is a pre- requisite for a drug designed for IV route of administration, to this end, it is important to track and optimize solubility, in order to develop a successful candidate. Goals will be to achieve thermodynamic solubility >200 ⁇ M at physiological pH in 0.5% aqueous DMSO, and aqueous solubility >10 ⁇ M at physiological pH.
  • LogD is a measure of compound lipophilicity. The distribution coefficient is determined between octanol and an aqueous phase buffered to physiological pH. The value is an important metric and most typically marketed small molecule drug molecules have a LogD between 1-3.
  • PPB Plasma Protein Binding
  • Binding of compounds to human serum albumin will be measured. This assay will provide the information required to determine that bioavailability of free compound for interaction with Nox4 to elicit inhibitory effect. Compounds that are highly protein bound, have little or no free fraction to elicit a response and this often requires optimization.
  • Polar Surface Area Polar surface area will be calculated.
  • Cytochrome P450 (CYP) Inhibition The potential for a compound to inhibit CYP oxidative enzymes is indicative of the potential for undesirable drug-drug interactions. Compounds will be tested against selected CYP isoforms. These studies will also identify metabolism products, including reactive metabolites. ii.
  • Scale-up Scale-up of selected lead analogs to gram quantities will be required for in vivo studies. Successful and reproducible scale-up of analogs from 200 mg to 8 g quantities has been previously demonstrated. Analogs will be tailored to 3-4 step synthesis protocols using commercially available materials. This approach will allow synthesis of molecules at grams quantities with minimal or no batch-to-batch variations. [00485] C57BL/6 male mice will be administered candidates in a single dose (1 mg/kg) via IV administration. Mice will be sacrificed by CO 2 inhalation at various time points (0, 30m, 1, 2, 4, 6, 8, 24h) following drug administration.
  • Plasma plasma will be isolated, and tissues (lung, heart, liver, kidney, and spleen) will be harvested and snap frozen in liquid nitrogen. Tissues will be then homogenized in 300 ul of acetonitrile with a mechanical homogenizer, centrifuged, and supernatant will be used for analyses. Plasma and tissue concentration over time will be determined by liquid chromatography/mass spectroscopy (LC/MS).
  • LC/MS liquid chromatography/mass spectroscopy
  • ARDS is more prevalent in males (>60% of ARDS patients are male), and COVID-19-ARDS mortality is 2.4 times greater in males compared to females. Thus, initial efforts will utilize male mice only. However, the top 2 candidates will also be evaluated for their PK profile in female mice. [00487] Specific Measured Endpoints. Standard PK parameters of clearance, drug half- life (T 1/2 ), T max , C max , C min , drug elimination constant (k e ), drug absorption constant (k a ), and area under the curve (AUC), bioavailability, and lung/plasma ratio will be calculated. c.
  • TI Therapeutic Index
  • CLP Cecal Ligation Puncture
  • mice At 20h post-LPS, anesthetized mice will be subjected to VILI by high tidal volume ventilation for 4h (room air, 20 ml/kg tidal volume, 85 breaths/min; Inspira rodent ventilator, Harvard Apparatus).
  • Lung injury barrier dysfunction and inflammatory responses: i) Total BAL cells: evaluated by Coulter counter, ii) Total BAL protein: evaluated by BCA assay. iii) Neutrophil influx: cytospin preparations of cellular BAL fraction will be stained with Hema 3 solution, and % neutrophils will be quantified.
  • Gross pathology will consist of a complete external and internal examination including body orifices (ears, nostrils, mouth, anus, etc.) and cranial, thoracic, and abdominal organs and tissues. All gross findings will be recorded, including size, shape, color, and consistency. Organs with lesions will be fixed for histopathologic evaluation. Blood will be collected at regular intervals during treatment to correlate drug levels with toxicity results. Hematology will be conducted by an Advia 120 Series Hematology System. Clinical chemistry will be performed to quantify endpoints (e.g. albumin, calcium, chloride, creatinine, glucose, potassium, protein, triglycerides). Blood and lung tissue will be collected at terminal necropsy for quantification of drug and correlation to biological finding of tolerance.
  • endpoints e.g. albumin, calcium, chloride, creatinine, glucose, potassium, protein, triglycerides.
  • TD will be determined by clinical observations, chiefly the side effects can range from mild effects such as reduced weight gain, moderate effects such as weight loss up to 20% or substantial effects such as unresponsiveness.
  • SCIENTIFIC RIGOR AND STATISTICAL ANALYSES [00500] Statistical significance will be analyzed using Prism 7 (GraphPad Software) and p ⁇ 0.05 will be considered significant. Student’s t-tests will be used when comparing two groups. When comparing 3 or more groups, 2-way analysis of variance (ANOVA) with Bonferroni post- test will be performed. p ⁇ 0.05 will be considered significant. A power analysis was performed to calculate the number of mice needed per experimental arm.
  • Cell Titer Glo assay is an industry-standard that measures cellular ATP levels. Analogs were evaluated in this assay relative to vehicle control. Digitonin (200 ⁇ g/ml) was used as a positive control for cell death. [00503] Antioxidant Activity. Analogs were incubated in 96-well-plates containing exogenous H 2 O 2 (5 ⁇ M) and Amplex Red (a HRP-dependent assay mechanism to detect H 2 O 2 ). Compounds that inhibit H 2 O 2 in the absence of cells were considered scavengers and eliminated. Catalase (750 U/ml) was also be used as a positive control for scavenger activity.
  • Reddy SP Hassoun PM, Brower R. Redox imbalance and ventilator-induced lung injury. Antioxidants & redox signaling.2007;9(11):2003-12. doi: 10.1089/ars.2007.1770. PubMed PMID: 17822361.
  • Pendyala S Gorshkova IA, Usatyuk PV, He D, Pennathur A, Lambeth JD, Thannickal VJ, Natarajan V. Role of Nox4 and Nox2 in hyperoxia-induced reactive oxygen species generation and migration of human lung endothelial cells. Antioxid Redox Signal. 2009;11(4):747-64. Epub 2008/1512.
  • Quinlan GJ Lamb NJ, Tilley R, Evans TW, Gutteridge JM. Plasma hypoxanthine levels in ARDS: implications for oxidative stress, morbidity, and mortality. Am J Respir Crit Care Med.1997;155(2):479-84. Epub 1997/02/01. doi: 10.1164/ajrccm.155.2.9032182. PubMed PMID: 9032182.
  • Li TB Zhang JJ, Liu B, Liu WQ, Wu Y, Xiong XM, Luo XJ, Ma QL, Peng J. Involvement of NADPH oxidases and non-muscle myosin light chain in senescence of endothelial progenitor cells in hyperlipidemia. Naunyn Schmiedebergs Arch Pharmacol. 2016;389(3):289-302. Epub 2015/12/22. doi: 10.1007/s00210-015-1198-y. PubMed PMID: 26685858.
  • APX-115 a first-in- class pan-NADPH oxidase (Nox) inhibitor, protects db/db mice from renal injury. Lab Invest. 2017;97(4):419-31. Epub 2017/02/07. doi: 10.1038/labinvest.2017.2. PubMed PMID: 28165467. [00578] Kwon G, Uddin MJ, Lee G, Jiang S, Cho A, Lee JH, Lee SR, Bae YS, Moon SH, Lee SJ, Cha DR, Ha H. A novel pan-Nox inhibitor, APX-115, protects kidney injury in streptozotocin-induced diabetic mice: possible role of peroxisomal and mitochondrial biogenesis.
  • Cytochrome P450 enzymes but not NADPH oxidases are the source of the NADPH-dependent lucigenin chemiluminescence in membrane assays.
  • Belenkiy SM Buel AR, Cannon JW, Sine CR, Aden JK, Henderson JL, Liu NT, Lundy JB, Renz EM, Batchinsky AI, Cancio LC, Chung KK.
  • Calfee CS Matthay MA, Kangelaris KN, Siew ED, Janz DR, Bernard GR, May AK, Jacob P, Havel C, Benowitz NL, Ware LB. Cigarette Smoke Exposure and the Acute Respiratory Distress Syndrome. Crit Care Med.2015;43(9):1790-7. Epub 2015/201727. doi: 10.1097/CCM.0000000000001089.
  • Aboumrad M Shiner B, Riblet N, Huizenga H, Neupane N, Young-Xu Y.

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Abstract

La présente divulgation concerne des composés, des compositions et des procédés d'inhibition de la signalisation de Nox4. L'invention concerne également des méthodes de traitement de troubles fibrotiques (par exemple, la fibrose pulmonaire, la fibrose cardiaque, la fibrose rénale, la fibrose hépatique, la fibrose cutanée, la fibrose médiastinale, la fibrose de la cavité rétropéritonéale, la fibrose de la moelle osseuse, la sclérodermie ou la sclérose systémique), le syndrome de détresse respiratoire aiguë (SDRA) ou pour le traitement du cancer (par exemple, un sarcome, un carcinome, un cancer hématologique, une tumeur solide, le cancer du sein, le cancer du col de l'utérus, le cancer gastro-intestinal, le cancer colorectal, le cancer du cerveau, le cancer de la peau, le cancer de la prostate, le cancer de l'ovaire, le carcinome pulmonaire non à petites cellules, le cancer de la thyroïde, le cancer des testicules, le cancer du pancréas, le cancer du foie, le cancer de l'endomètre, le mélanome, le gliome, la leucémie, le lymphome, le trouble myéloprolifératif chronique, le syndrome myélodysplasique, le néoplasme myéloprolifératif, le néoplasme des cellules plasmatiques (myélome)) à l'aide des composés et des compositions selon l'invention. Le présent abrégé est destiné à être utilisé comme outil d'exploration à des fins de recherche dans ce domaine technique particulier, et ne se limite pas à la présente divulgation.
PCT/US2024/044283 2023-08-29 2024-08-28 Conjugués macrolide-nox4 et leurs utilisations Pending WO2025049640A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190135746A1 (en) * 2016-07-08 2019-05-09 Arizona Board Of Regents On Behalf Of The University Of Arizona Indoline derivatives and method for using and producing the same
US20200138799A1 (en) * 2017-04-14 2020-05-07 Arizona Board Of Regents On Behalf Of The University Of Arizona Compositions and methods for treating pulmonary fibrosis
US20220033379A1 (en) * 2018-09-28 2022-02-03 Genkyotex Suisse Sa Novel compounds as nadph oxidase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190135746A1 (en) * 2016-07-08 2019-05-09 Arizona Board Of Regents On Behalf Of The University Of Arizona Indoline derivatives and method for using and producing the same
US20200138799A1 (en) * 2017-04-14 2020-05-07 Arizona Board Of Regents On Behalf Of The University Of Arizona Compositions and methods for treating pulmonary fibrosis
US20220033379A1 (en) * 2018-09-28 2022-02-03 Genkyotex Suisse Sa Novel compounds as nadph oxidase inhibitors

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