Substituted 1,2-diamine compounds as inhibitors for ferroptosis and use thereof

Abstract

The present disclosure is directed in one aspect to substituted 1,2-diamine compound inhibitors for ferroptosis, as well as pharmaceutical compositions comprising one or more of these compounds and one or more pharmaceutically acceptable excipients. The disclosure is also directed in one aspect to a method for treating, ameliorating, and / or preventing a disease or disorder comprising administering an effective amount of the pharmaceutical composition to the subject.

Description

[0001] Attorney Docket No. 047162-7600W01(02785)

[0002] TITLE

[0003] Substituted 1,2-Diamine Compounds as Inhibitors for Ferroptosis and Use thereof

[0004] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U. S. C. § 119(e) to U. S. Provisional Patent Application No. 63 / 724,770. filed November 25, 2024, which is incorporated herein by reference in its entirety.

[0005] BACKGROUND OF DISCLOSURE

[0006] Ferroptosis, first defined in 2012, is a mechanism of regulated necrotic cell death characterized by iron-dependent accumulation of reactive lipid peroxides. Morphologically, it is characterized by cellular, organelle and cytoplasmic swelling and the loss of plasma membrane integrity, with the release of intracellular components. Ferroptosis is initiated in cells with dysregulated iron and thiol redox metabolism, resulting in the robust but selective accumulation of hydroperoxyl polyunsaturated fatty acid-containing phospholipids. This accumulation is further propagated through subsequent enzymatic and non-enzymatic processes, leading to the generation of oxidatively truncated electrophilic species and their adducts with proteins. Thus, ferroptosis is dependent on the interplay between iron, thiol, and lipid metabolic pathways. Many studies have reported that ferroptosis may act as a trigger of different pathological and physiological processes, such as neurodegenerative diseases, tumor suppression, and ischemia / reperfusion.

[0007] Bacterial and viral infection of lungs cause acute pulmonary inflammation, which can lead to acute lung injury (ALI) and may even progress to the more severe acute respiratory distress syndrome (ARDS). ALI and ARDS are characterized by diffuse alveolar damage, neutrophilic inflammation, and increased permeability of the alveolar-capillary barrier, leading to protein-rich edema and subsequent impairment of arterial oxygenation. ALI / ARDS represents a serious health problem with a high mortality7rate. The incidence of ALI / ARDS is reported to be around 200,000 per year in the US with a high mortality rate before the current COVID-19 pandemic. The recent COVID-19 as well as previous SARS-CoV and Middle Eastern respiratory syndrome (MERS) are all associated with respiratory illness due to alveolar damage, which can lead to severe ALI / ARDS and progressive respiratory failure and contribute to high mortality7rates of these diseases. Currently there are no pharmacological interventions for ALI / ARDS. The incomplete understanding of ALI / ARDS pathogenesis and pulmonary cell responses to inflammation hampers the progress in ALI / ARDS therapeutic -1- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0008] development. Ferroptosis in ALI / ARDS and lungs infected with coronavirus including COVID- 19 was detected, and effects of ferroptotic inhibitors on lung injury’ in animal models were observed.

[0009] Acute kidney injury (AKI) is a life-threatening condition with substantial morbidity and mortality rates. It manifests in roughly 10-15% of hospitalized individuals and affects over 50% of patients in intensive care units. AKI is characterized by a rapid deterioration of renal function and further triggers the accumulation of metabolic waste and toxins, leading to complications and dysfunction of other organs. Multiple pathogenic factors, such as rhabdomyolysis, infection, nephrotoxic medications, and ischemia-reperfusion injury, contribute to the onset and progression of AKI. Epidemiological investigations suggest that 13.3 million people worldwide are affected by AKI annually and up to 1.7 million deaths occur each year from AKI. The current therapeutic methods for AKI mainly include correcting acid-base balance and electrolyte disorder, correcting volume load, avoiding nephrotoxic drugs, and renal replacement therapy. Nonetheless, the precise mechanism responsible for the onset and progression of AKI remains incompletely understood. At present, there are no effective treatments to proactively prevent AKI, slow down its advancement, or facilitate its recovery’.

[0010] The main pathological manifestations of AKI are cell injury', cell death, and renal tubular epithelial cell abscission. Recent studies have shown that iron-overload induced ferroptosis of renal tubular epithelial cells is positively correlated with the incidence rate and mortality of clinical AKI. In addition, genetic ablation of glutathione peroxidase 4 (Gpx4), a key regulator of ferroptosis process, causes cell death in a pathologically relevant form of ferroptosis, ultimately leading to the onset of acute renal failure in mice. Moreover, genetic knockout of Tripartite motif containing 21 (TRIM21), acting as an E3 ubiquitin ligase, resulted in the upregulation of Gpx4. This, in turn, alleviated ischemia / reperfusion induced AKI by inhibiting ferroptosis. There is direct evidence that iron chelating agents and small molecular ferroptosis inhibitors possess renal protective effects among various animal models of AKI, suggesting that ferroptosis plays an important role in the initiation and progression of AKI.

[0011] In addition to acute lung injury / ARDS, ferroptosis is also involved in many’ other lung diseases including obstructive lung diseases (chronic obstructive pulmonary’ disease, asthma, and cystic fibrosis), interstitial lung diseases (pulmonary' fibrosis of different causes), pulmonary diseases of vascular origin (ischemia-reperfusion injury and pulmonary hypertension), pulmonary infections (bacteria, viruses, and fungi), and pulmonary alveolar -2- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0012] proteinosis. Moreover, ferroptosis is involved in a broad range of ischemic tissue damage including ischemic heart diseases, brain stroke, trauma and surgery-related ischemic tissue damage. Furthermore, ferroptosis is involved in fibrotic diseases (including kidney fibrosis and liver fibrosis), immune suppression during tumor formation, systemic autoimmunity, iron-overloading diseases due to either genetic mutations in iron regulatory genes or dietary7overload. Sedaghatian-type spondylometaphyseal dysplasia (SSMD). organ injury including microparticle-induced liver injury, kidney injury due to defective kidney repair and the formation of inflammatory proximal tubular cells, multi organ injury due to vascular leakage during sepsis or heme release from ferroptotic ery throcytes in Sickle cell disease and other diseases involving leakage of heme, multi organ dysfunction syndrome (MODS) common in critically ill patients in intensive care units (ICUs), retinal degeneration, and neurodegenerative diseases, including Huntington’s disease (HD), Alzheimer’s disease (AD), PD, and amyotrophic lateral sclerosis (ALS).

[0013] Ferrostatin-1 (Feri), an arylalkylamine with antioxidative properties, was identified as one of the first inhibitors of ferroptosis for its ability to reduce oxidative, iron-dependent cell death in cancer cells induced by ferroptosis inducers such as erastin. Liproxstatin-1 (Lipl) is another archetypal ferroptosis inhibitor identified for its ability to attenuate lipid peroxidation and ferroptotic cell death. Both inhibitors prevent ferroptosis at its core mechanism by acting as radical-trapping antioxidants (RTAs) to reduce lipid peroxides and prevent oxidative damage to membrane lipids. However, these inhibitors do not even have the ADME (Absorption, Distribution, Metabolism, and Excretion) properties suitable for preclinical development largely due to poor metabolic stability.

[0014] There are continued needs for new compounds and pharmaceutical compositions that can be used to treat, ameliorate, and / or prevent ferroptosis and related diseases.

[0015] BRIEF SUMMARY OF DISCLOSURE

[0016] The present disclosure is directed in one aspect to substituted 1,2-diamine compound inhibitors for ferroptosis and pharmaceutical compositions for treatment of diseases.

[0017] This disclosure is directed to a compound having formula (1), wherein the variables X, Y, Rl, R2, and R3 are defined elsewhere herein:

[0018] -3- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0019] R I 1

[0020]

[0021] This disclosure is also directed to certain compounds disclosed herein (for example Compounds 3 — 71) and pharmaceutical compositions comprising at least one of these compounds and one or more pharmaceutically acceptable excipients.

[0022] The present disclosure is further directed to a method for treating, ameliorating, and / or preventing a disease or disorder in a subject in need thereof. In certain embodiments, the method comprises administering an effective amount of a pharmaceutical composition disclosed herein to the subj ect. In certain embodiments, the disease or disorder comprises post-stroke brain ischemia-reperfusion injury (IRI), ischemia-reperfusion injury (IRI) not caused by post-stroke brain ischemia, ischemic heart diseases, lung injury related to a coronavirus infection, SARS-CoV infection, SARS-CoV-2 infection (COVID-19), Middle Eastern respiratory syndrome (MERS), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), kidney injury, respiratory illness due to alveolar damage, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, inflammatory bowel disease (IBS), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), Sedaghatian-type spondylometaphyseal dysplasia (SSMD), organ injury due to vascular leakage during sepsis or heme release, iron-overloading diseases, neurodegenerative diseases, Huntington’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), chronic kidney disease (CKD), kidney fibrosis, traumatic brain injury, tumor, or combinations thereof.

[0023] BRIEF DESCRIPTION OF DRAWING FIG. 1A - FIG. IB. Representative examples of the compounds. (FIG. 1 A) An example of a compound of formula (1). (FIG. IB) An example of a compound of formula (2).

[0024] FIG. 2A - FIG. 2B. Representative examples of the compounds. (A) Examples of Compounds 3 -14. (B) Examples of Compounds 15 -22.

[0025] FIG. 3. A representative example of ferroptosis inhibition activity assay. The assay was conducted with Compound 3,

[0026] FIG. 4. A representative example of ferroptosis inhibition activity assay. The assay

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[0028] was conducted with Compound 17.

[0029] FIG. 5. A representative example of ferroptosis inhibition activity’ assay. The assay was conducted with Compound 5.

[0030] FIG. 6. A representative example of ferroptosis inhibition activity assay. The assay was conducted with Compound 20.

[0031] FIG. 7. Oral administration of Compound 6 reduces lung permeability. Mice were induced ALI by intratracheal instillation of LPS and given by oral gavage of Compound 309 (10 mg / kg). FITC-albumin was then given via IV 20 hours after ALI induction. BALs of the mice were collected 2 hour later. BAL FITC albumin was measured, and the average reading of LPS+vehicle is taken as 100%. **, P<0.01 (Student’s t-test, n>5).

[0032] FIG. 8A - FIG. 8C. Compound 6 alleviated kidney IRI. Male mice aged 8-9 weeks were administered with either vehicle or Compound 6 via gavage before surgery. AKI was induced by bilateral pedicle clamping for 30 minutes. Mice were sacrificed 24hr after surgery to collect plasma and kidneys. FIG. 8 A: Plasma creatinine level (black bar: sham; red bars: surgery). FIG. 8B: PAS staining of kidney sections. FIG. 8C: Quantification of injured renal tubule. Data are presented as means±SEM (One Anova for A, tow-tailed student t-test for C).

[0033] FIG. 9. PK graph for Compound 6.

[0034] DETAILED DESCRIPTION

[0035] The features and advantages of the present invention will be more readily understood, by those of ordinary skill in the art, from reading the following detailed description. It is to be appreciated that certain features of the invention, which are, for clarity, described above and below in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. In addition, references in the singular may also include the plural (for example, “a’' and “an” may refer to one, or one or more) unless the context specifically states otherwise.

[0036] The use of numerical values in the various ranges specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both proceeded by the word "about." In this manner, slight variations above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. Also, the disclosure of these ranges is intended as a continuous range including every value between the minimum and -5- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0037] maximum values.

[0038] In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0039] As used herein, each of the following terms has the meaning associated with it in this section. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary' skill in the art to which this disclosure belongs. Generally, the nomenclature used herein and the laboratory’ procedures in animal pharmacology, pharmaceutical science, separation science and organic chemistry are those well-known and commonly employed in the art. It should be understood that the order of steps or order for performing certain actions is immaterial, so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously or not.

[0040] Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of ‘'about 0.1 % to about 5%” or '‘about 0.1 % to 5%” should be interpreted to include notjust about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0041] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as '‘A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting: information that is relevant to a section heading may occur within or outside of that particular section. All -6- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0042] publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference.

[0043] The term '‘about’’ as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range.

[0044] As used herein, the term “alkenyl,” employed alone or in combination with other terms, means, unless otherwise stated, a stable monounsaturated or diunsaturated straight chain or branched chain hydrocarbon group having the stated number of carbon atoms.

[0045] Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and the higher homologs and isomers. A functional group representing an alkene is exemplified by -CH2-CH=CH2.

[0046] As used herein, the term '‘alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined elsewhere herein, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1 -propoxy, 2-propoxy (or isopropoxy) and the higher homologs and isomers. A specific example is (Ci-C3)alkoxy, such as, but not limited to, ethoxy and methoxy.

[0047] As used herein, the term “alkyl” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbon atoms) and includes straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. A specific embodiment is (Ci-Ce) alkyl, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, / r-pentyl, / 7-hexyl and cyclopropylmethyl.

[0048] The term '‘alkylene” or “alkylenyl” as used herein refers to a bivalent saturated aliphatic radical (e.g., -CH2-, -CH2CH2-, and -CH2CH2CH2-, inter alia). In certain embodiments, the term may be regarded as a moiety' derived from an alkene by opening of the double bond or from an alkane by removal of two hydrogen atoms from the same (e.g.. -CH2-) different (e.g, -CH2CH2-) carbon atoms.

[0049] As used herein, the term “alkynyl” employed alone or in combination with other terms means, unless otherwise stated, a stable straight chain or branched chain hydrocarbon group with a triple carbon-carbon bond, having the stated number of carbon atoms. Nonlimiting examples include ethynyl and propynyl, and the higher homologs and isomers. The term “propargylic” refers to a group exemplified by -CH2-C=CH. The term

[0050] -7- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0051] "homopropargy lie" refers to a group exemplified by -CH2CH2-C=CH.

[0052] As used herein, the term “aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized n (pi) electrons, where ‘n’ is an integer.

[0053] As used herein, the term “aryl” employed alone or in combination with other terms means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl and naphthyl. Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g, bicyclo[4.2.0]octa-l, 3,5-trienyl. or indanyl), which can be substituted at one or more carbon atoms of the aromatic and / or saturated or partially saturated rings.

[0054] As used herein, the term “aryl-(C i-C6)alkyl” refers to a functional group wherein a one to six carbon alkylene chain is attached to an ary l group, e.g., -CEECEE-phenyl or -CH2-phenyl (or benzyl). Specific examples are aryl-CEb- and aryl-CH(CH3)-. The term “substituted aryl-(Ci-C6)alky ’ refers to an aryl-(Ci-C6)alkyl functional group in which the aryl group is substituted. A specific example is substituted aryl(CH2)-. Similarly, the term “heteroaryl-(Ci-C6)alkyl” refers to afunctional group wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g, -CFbCFh-pyridyl. A specific example is heteroaryl-(CH2)-. The term “substituted heteroaryl-(Ci-C6)alkyl” refers to aheteroaryl-(Ci-Ce)alkyl functional group in which the heteroaryl group is substituted. A specific example is substituted heteroaryl-(CH2)-.

[0055] As used herein, the term “cycloalky l” by itself or as part of another substituent refers to, unless otherwise stated, a cyclic chain hydrocarbon having the number of carbon atoms designated (i.e., C3-C6 refers to a cyclic group comprising a ring group consisting of three to six carbon atoms) and includes straight, branched chain or cyclic substituent groups.

[0056] Examples of (C3-C6)cycloalky 1 groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl rings can be optionally substituted. Non-limiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxy cyclohexyl, 3,3,5-trimethylcyclohex-l-yl, octahydropental enyl. octahydro- l / Z-indenyl, 3a.4.5.6.7.7a-hexahydro-3f / -inden-4-yl. decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro- \H- -8- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0057] fluorenyl. The term “cycloalky 1” also includes bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyL l,3-dimethyl[2.2.1] heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

[0058] As used herein, the term “halide"’ refers to a halogen atom bearing a negative charge. The halide anions are fluoride (F"), chloride (CE), bromide (Br ). and iodide (I").

[0059] As used herein, the term “halo” or “halogen” alone or as part of another substituent refers to, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0060] The term “haloalky 1” group, as used herein, includes mono-halo alkyl groups, polyhalo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1 -di chloroethyl, 1,2-dichloroethyL l,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

[0061] As used herein, the term “heteroalkenyl” by itself or in combination with another term refers to, unless otherwise stated, a stable straight or branched chain monounsaturated or diunsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized. Up to two heteroatoms may be placed consecutively. Examples include -CH=CH-O-CH3. -CH=CH-CH2-OH, -CH2-CH=N-OCH3. -CH=CH-N(CH3)-CH3, and -CH2-CH=CH-CH2-SH.

[0062] As used herein, the term “heteroalkyl” by itself or in combination with another term refers to, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quatemized. The heteroatom(s) may¬ be placed at any position of the heteroalkyl group, including betw een the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -OCEECEUCEh, -CH2CH2CH2OH, -CH2CH2NHCH3, -CH2SCH2CH3, and -CH2CH2S(=O)CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2NH-OCH3. or -CEI2CH2SSCH3.

[0063] As used herein, the term “heteroary 1” or “heteroaromatic” refers to a heterocycle having aromatic character. A polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuryl.

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[0065] As used herein, the term “heterocycle” or “heterocyclyl” or “heterocyclic” by itself or as part of another substituent refers to. unless otherwise stated, an unsubstituted or substituted, stable, mono- or multi-cyclic heterocyclic ring system that comprises carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quatemized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure. A heterocycle may be aromatic or non-aromatic in nature. In certain embodiments, the heterocycle is a heteroar l.

[0066] Examples of non-aromatic heterocycles include monocy clic groups such as aziridine, oxirane, thiirane. azetidine, oxetane. thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-l,3-dioxepin and hexamethyleneoxide.

[0067] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl. 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

[0068] Examples of polycyclic heterocycles include indolyl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and 5 -quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, but not limited to, 2-benzothiazolyl and 5 -benzothiazolyl), purinyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.

[0069] The present listing of heterocyclyl and heteroaryl moieties is intended to be representative and not limiting.

[0070] The term “independently selected from” as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise.

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[0072] Thus, under this definition, the phrase “X1, X2, and X3are independently selected from noble gases” would include the scenario where, for example, X1, X2, and X3are all the same, where X1, X2, and X3are all different, where X1and X2are the same but X3is different, and other analogous permutations.

[0073] As used herein, the term “substituted” refers to that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.

[0074] In certain embodiments, the term “substituted alkyd,” “substituted cycloalkyl,” “substituted alkenyl,” or “substituted alkynyl” refers to alkyl, cycloalkyl, alkenyl or alkynyl, as defined elsewhere herein, substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, l-methyl-imidazol-2-yl, pyridin-2-yl. pyridin-3-yl. pyridin-4-yl, -C(=O)OH, -C(=O)O(Ci-C6)alkyl, trifluoromethyl, -C=N, -C(=O)NH2, -C(=O)NH(Ci-C6)alkyl, -C(=O)N((Ci-C6)alkyl)2, -SO2NH2, -SO2NH(CI-C6alkyl), -SO2N(CI-Ce alkyl)2, -C(=NH)NH2, and -NO2, in certain embodiments containing one or two substituents independently selected from halogen. -OH, alkoxy. -NH2, trifluoromethyl. -N(CH3)2. and -C(=O)OH, in certain embodiments independently selected from halogen, alkoxy and -OH. Examples of substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2-carboxy cyclopentyl and 3-chloropropyl.

[0075] In certain embodiments, For aryl, ary I -(C 1 -C3 )alky I and heterocyclyl groups, the term “substituted” as applied to the rings of these groups refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In certain embodiments, the substituents vary in number between one and four. In other embodiments, the substituents vary in number between one and three. In yet another embodiments, the substituents vary in number between one and two. In yet other embodiments, the substituents are independently selected from the group consisting of Ci-Ce alky l, -OH, Ci-Ce alkoxy, halo, amino, acetamido and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic.

[0076] In certain embodiments, each occurrence of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyd, optionally substituted heterocycloalkyleny l, optionally substituted C1-C3 alkylenyl, optionally substituted C3-C8 cycloalkylenyl, optionally substituted benzyl. optionally substituted aralkyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted -11- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0077] heteroaryl, is independently optionally substituted with at least one substituent selected from the group consisting of Ci-Ce alkyl, Cs-Cs cycloalkyl. C2-C12 heterocycloalkyl. Ci-Cs hydroxyalkyl, halogen, CN, NO2 ORa, N(Ra)(Rb), Ci-Cs haloalkoxy, C3-Cs halocycloalkoxy, aryl, heteroaryl, (Ci-Ce alkylenyl)C(=O)N(Ra)(Rb), (Ci-Ce alkylenyl)C(=O)ORa, O(Ci-C3alkylenyl)C(=O)ORa, O(Ci-C3alkylenyl)C(=O)N(Ra)(Rb), C(=O)Ra, C(=O)ORa, OC(=O)Ra, OC(=O)ORa. SRa, S(=O)Ra, S(=O)2Ra, S(=O)2N(Ra)(Rb), S(=O)2NRaC(=O)NHRb, N(Ra)S(=O)2Rb, N(Ra)C(=O)Rb, and C(=O)NRaRb, wherein Raand Rbare each independently selected from the group consisting of H, -C(=O)(Ci-C6 alkyl), Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, C3-Cs cycloalkyl, C2-C12 heterocycloalkyl, C7-C12 aralkyl, ary l, and heteroaryl.

[0078] In certain embodiments, each occurrence of alkyl or cycloalkyl is independently optionally substituted with at least one substituent selected from the group consisting of Ci-Ce alkyl, halo, -OR, phenyl (thus yielding, in non-limiting examples, optionally substituted phenyl-(Ci-C3alkyl), such as, but not limited to, benzyl or substituted benzyl) and -N(R)(R), wherein each occurrence of R is independently H. Ci-Cs alkyl or C3-Cs cycloalkyl. In other embodiments, each occurrence of aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of Ci-Cs alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, halo, -CN, -OR, -N(R)(R), -NO2, -S(=O)2N(R)(R), acyl, and Ci-Ce alkoxycarbonyl, wherein each occurrence of R is independently H, Ci-Ce alkyl or C3-Cs cycloalkyl. In yet other embodiments, each occurrence of aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, halo, -CN, -OR, -N(R)(R), and Ci-Ce alkoxy carbonyl, wherein each occurrence of R is independently H, Ci-Ce alkyl or C3-Cs cycloal kyl.

[0079] Unless otherwise noted, when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R2and R3taken together with the nitrogen to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen, oxygen, or sulfur. The ring can be saturated or partially saturated, and can be optionally substituted with one or more substituents, non-limiting examples including a carbonyl (C=O).

[0080] Whenever a term or either of their prefix roots appear in a name of a substituent the name is to be interpreted as including those limitations provided herein. For example, whenever the term '‘alkyl” or “aryl” or either of their prefix roots appear in a name of a -12- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0081] substituent (e.g., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given elsewhere herein for “alkyl” and “aryl” respectively.

[0082] In certain embodiments, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term “Ci-6 alkyl” is specifically intended to individually disclose Ci, C2, C3, C4, C5, Ce, Ci-Ce, C1-C5, C1-C4, C1-C3, C1-C2. C2-C6, C2-C5, C2-C4. C2-C3, C3-C6, C3-C5. C3-C4, C4-C6, C4-C5. and C5-C6 alkyl.

[0083] The term “isotope” or “isotopes” refers to different forms of a chemical element which have the same number of protons but a different number of neutrons in their atoms. An isotope can have different physical properties but the same chemical ones. The term also includes radioactive or non-radioactive isotopes. All compounds disclosed herein can comprise one or more isotopes. Some non-limiting examples of isotopes can include deuterium (2H), tritium (3H), isotoiodine-125 (125I), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C),14N,15N,160.17O,180,31P.32P,32S,33S,34S.36S,35S and others, and a combination thereof. Throughout this disclosure, all isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0084] As used herein, the term “disease” as used herein refers to a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.

[0085] As used herein, the term “disorder” refers to, in an animal or a human patient (herein referred to as “a subject”), a state of health in which the subject is able to maintain homeostasis, but in which the subject's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the subject's state of health.

[0086] The term “COPD” refers to chronic obstructive pulmonary disease that can typically be treated with Albuterol, Levalbuterol, Glycopyrronium, Ipratropium, Tiotropium, Indacaterol, Vilanterol, Aclidinium, Umeclidinium, Beclomethasone, Betamethasone, Budesonide, Cortisone, Dexamethasone, Azithromycin, Amoxicillin / Clavulanate, orN-acetylcysteine.

[0087] Some examples of medicines for treating Asthma can include Albuterol, Terbutaline. Fluticasone, Budesonide, Formoterol, Salmeterol, Zafirlukast, Zileuton, Theophylline,

[0088] -13- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0089] Levalbuterol, Metaproterenol, Reslizumab, Prednisone, Beclomethasone dipropionate, Mepolizumab, and Benralizumab.

[0090] Some examples of medicines for treating cystic fibrosis can include Tobramycin, Colistin, Aztreonam, Ibuprofen, Acetylcysteine. Albuterol, and Salmeterol.

[0091] The term “IPF” refers to idiopathic pulmonary fibrosis that can ty pically be treated with Nintedanib and Pirfenidone.

[0092] The term “PAH” refers to pulmonary arterial hypertension that can typically be treated with Epoprostenol, Bosentan, Macitentan, Ambrisentan, Amlodipine, Diltiazem, Nifedipine, Tadalafil, Sildenafil, Riociguat, Digoxin, Furosemide, and Warfarin.

[0093] Some examples of medicines for treating ischemic heart diseases can include Acebutolol, Betaxolol. Isradipine, Felodipine. Spironolactone, Eplerenone. Triamterene, and Hydrochlorothiazide.

[0094] The term “SSMD” refers to Sedaghatian-type spondylometaphyseal dysplasia.

[0095] Currently no specific medicines for its treatment.

[0096] Some examples of medicines for treating kidney injury can include Chlorothiazide. Bumetanide, and Polystyrene sulfonate.

[0097] Some examples of medicines for treating Huntington’s disease can include Tetrabenazine, Amantadine, Fluoxetine, Sertraline, Quetiapine, Risperidone, Olanzapine, Valproate, and Carbamazepine.

[0098] Some examples of medicines for treating Alzheimer’s disease (AD) can include Donepezil, Galantamine, and Rivastigmine.

[0099] The term “ALS” refers to amyotrophic lateral sclerosis: Currently no specific medicines for its treatment.

[0100] The terms “effective amount,” “pharmaceutically effective amount” or “therapeutically effective amount” refers to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and / or alleviation of one or more signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0101] The term “patient” or “patients” refers to, in non-limiting embodiments, a human subject(s).

[0102] The term “pharmaceutically acceptable excipients”, “pharmaceutically acceptable excipient”, or “pharmaceutical excipients” refers to a pharmaceutical surfactant, emulsifier, filler, carrier, isotonicifier, dispersing agent, viscosity modifier, resuspending agent, buffer or -14- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0103] a combination thereof. Pharmaceutically acceptable excipients typically do not have properties of a medicinal or drug active ingredient, also known as active pharmaceutical ingredient (API) and are typically used to streamline the manufacture process or packaging of the active ingredients, or to deliver an API to a patient or other subject. Pharmaceutically acceptable carriers, excipients, or inactive ingredients from the Inactive Ingredients Database available from US FDA (www dot fda dot gov / drugs / drug-approvals-and-databases / inactive-ingredients-database-download) can be suitable and is incorporated by reference. Some of Generally Recognized As Safe (GRAS) food substances available form US FDA’s GRAS Substances (SCOGS) Database (www dot fda dot gov / food / generally-recognized-safe-gras / gras-substances-scogs-database) can also be suitable.

[0104] Further, the term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition or earner, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carry ing or transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound(s) described herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil. safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a

[0105] -15- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0106] pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0107] The term “prevent,” “preventing,” or “prevention” as used herein means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such symptoms at the time the administering of an agent or compound commences. Disease, condition and disorder are used interchangeably herein.

[0108] The terms “subject”, “subjects”, or “individual” can be used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein.

[0109] The terms “treat,” “treating,” and “treatment,” as used herein, means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject.

[0110] The present disclosure is directed in one aspect to a compound having formula (1):

[0111] R1

[0112] HNx

[0113] HN X^X 1^RS

[0114] R

[0115]

[0116] 2>

[0117] (1),

[0118] wherein:

[0119] each occurrence of X is independently N or CH;

[0120] Y is a bond, -CH2-. -C(=O), -CH(R4)-, -C(R4)2-, or a combination thereof;

[0121] R1 is C1-C12 alkyl, C3-C12 cycloalkyl, benzyl, Cs-Cio aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl, or a combination thereof;

[0122] R2 is C1-C12 alky l, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, Ce-Cio ary l, 5-or 6-membered heteroaryl, 5- or 6-membered heterocyclyl, or a combination thereof;

[0123] R3 is C1-C12 alkyl, C2-C12 alkenyl. C2-C12 alkynyl, Ce-Cio aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroaryl heterocyclyl, -CH=CHR6, or a combination thereof;

[0124] each occurrence of R4 is independently C1-C12 alkyl, halogen, CN, or a combination thereof;

[0125] each occurrence of R5 is independently C1-C12 alkyl, C3-C12 cycloalkyl, C1-C12 -16- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0126] alkoxy, or a combination thereof; and

[0127] R6 is aryl, 5- or 6-membered heteroaryl heteroaryl, 5- or 6-membered heteroaryl. 5-or 6-membered heteroaryl heterocyclyl, carbocyclic, -C(=O)NR5R5, -C(=O)(N-linked heterocyclyl), or a combination thereof;

[0128] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, benzy l, aryl, heteroaryl, and heterocyclyl is independently optionally substituted;

[0129] a salt thereof, an isomer thereof, or an isotope containing derivative thereof.

[0130] FIG. 1A shows a representative example of formula 1. FIG. 1C shows a representative example of the group R6 (formula la).

[0131] In certain embodiments, R3 can be -CH=CHR6 and the compound can be a compound of formula (2):

[0132] R1

[0133] HN X

[0134] HN X X' I R6

[0135]

[0136] (2).

[0137] In certain embodiments, the compound of formula 2 can comprise an isomer thereof, an isotope containing derivative thereof, or a combination thereof. FIG. IB shows a representative example of a compound of formula 2.

[0138] In certain embodiments, R1 is selected from the group consisting of optionally substituted phenyl, optionally substituted benzyl, optionally substituted cyclohexyl, and optionally substituted heterocyclyl.

[0139] In certain embodiments, R1 is selected from the group consisting of:

[0140]

[0141] -17- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0142]

[0143] In certain embodiments, R1 is Q. In certain embodiments, R1 is 0. In certain

[0144] embodiments, R

[0145]

[0146] 1 is

[0147] embodiments, R

[0148]

[0149] 1 is. In certain

[0150] embodiments,

[0151]

[0152] R1 is. In certain embodiments,

[0153]

[0154] R1 is. In certain embodiments, R1

[0155]

[0156] In certain embodiments, R2 is selected from the group consisting of optionally substituted phenyl, optionally substituted benzyl, optionally substituted cyclohexyl, optionally substituted pyridinyl, optionally substituted -CFb-pyridinyl, optionally substituted 1,4-benzodioxinyl, optionally substituted 2,3-dihydrobenzofuranyl, optionally substituted -(CH2)I-2C(=O)N(CI-C6 alkyl)(Ci-Ce alkyl), optionally substituted -(CH2)i-2C(=O)(N-linked heterocyclyl), optionally substituted -(CH2)i-2C(=O)O(Ci-Ce alkyl), optionally substituted -(CH2)I-2S(=O)2(CI-C6 alkyl), optionally substituted -(CH2)i-2NHC(=O)O(Ci-Ce alkyl), optionally substituted -(CH2)i-2C(=O)NH(heterocyclyl), optionally substituted -(CH2)I-2CN, optionally substituted -(CH2)i-2isoindolinyl-l, 3-dione, and optionally substituted C2-C6 alkynyl.

[0157] In certain embodiments, R2 is selected from the group consisting of:

[0158] -18- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0159]

[0160] o

[0161] embodiments,

[0162]

[0163] R2 is OH. In certain embodiments,

[0164]

[0165] R2 is \. In certain embodiments,

[0166]

[0167] In certain embodiments, R2

[0168] -19- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0169]

[0170] certain embodiments, R

[0171]

[0172] 2 is. In certain embodiments.

[0173]

[0174] R2 is. In certain

[0175] embodiments, R2 is

[0176]

[0177] . In certain embodiments,

[0178]

[0179] R2 is0\. In certain embodiments, R2

[0180] i

[0181]

[0182] s F in certain embodiments, R2 is In certain embodiments, R

[0183]

[0184] 2 is F?in

[0185] certain embodiments,

[0186]

[0187] R2 is. In certain embodiments,

[0188]

[0189] R2 is. In certain

[0190] embodiments,

[0191]

[0192] R2 is. In certain embodiments, R

[0193]

[0194] 2 is F. In certain

[0195] embodiments,

[0196]

[0197] R2 is. In certain embodiments,

[0198]

[0199] R2 is. In certain

[0200] O.

[0201] embodiments, R2 is

[0202]

[0203] . In certain embodiments, R2 is

[0204]

[0205] '. In certain

[0206] -20- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0207] embodiments, R2 is

[0208]

[0209] NO In certain embodiments,

[0210]

[0211] R2 is

[0212]

[0213] In certain embodiments, R2 is

[0214] certain embodiments, R

[0215]

[0216] 2 is

[0217] certain embodiments,

[0218]

[0219] R2 is

[0220] In certain embodiments, R3 is selected from the group consisting of optionally substituted oxazolyl, optionally substituted triazolyl, and optionally substituted oxadiazolyL In certain embodiments, R3 is -CH=CHR6, whereon R6 is selected from the group consisting of -C(=O)NH2, -C(=O)NH(CI-C6alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -C(=O)(N-heterocyclyl), and optionally substituted phenyl.

[0221] In certain embodiments, R3 is selected from the group consisting of:

[0222]

[0223] -21- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0224]

[0225] y-0 Q N~- Cl”

[0226]

[0227] 3certain embodiments, R3 is 'N. In certain embodiments, R3 is

[0228]

[0229] N" N In

[0230] N'N" N

[0231] N

[0232]

[0233] certain embodiments,

[0234]

[0235] R3 is. In certain embodiments, R3 is o. In H

[0236] N

[0237] certain embodiments, R3 is

[0238]

[0239] O. In certain embodiments, R3 is

[0240]

[0241] . In certain embodiments, R3 is

[0242]

[0243] F. In certain embodiments,

[0244]

[0245] R3 is. In certain embodiments, R3 is. In certain

[0246] Cl embodiments, R3 is

[0247]

[0248] . In certain embodiments, R3

[0249]

[0250] is. In CF3certain embodiments, R3 is. In certain embodiments, R3 is

[0251]

[0252] In certain embodiments, Y comprises a chemical bond. In certain embodiments, Y comprises a one-atom linker, such as -CH2-. -C(=0), -CH(R4)-, and -C(R4)2-. In certain -22- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0253] embodiments, Y comprises a two-atom linker, comprising two divalent groups independently selected from the group consisting of -CH2-, -C(=O), -CH(R4)-, and -C(R4)2-. In certain embodiments, Y comprises a three-atom linker, comprising three divalent groups independently selected from the group consisting of -CH2-, -C(=O), -CH(R4)-, and -C(R4)2-In certain embodiments, Y comprises a four-atom linker, comprising four divalent groups independently selected from the group consisting of -CH2-, -C(=O), -CH(R4)-, and -C(R4)2-In certain embodiments, Y comprises a five or more-atom linker, comprising five or more divalent groups independently selected from the group consisting of -CH2-, -C(=O), -CH(R4)-, and -C(R4)2-.

[0254] In certain embodiments, the compound is selected from the group consisting of: N2-benzyl-Nl-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;

[0255] Nl-benzyl-N2-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;

[0256] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N, N-dimethyl-prop-2-enamide;

[0257] N2-benzyl-Nl -cy cl ohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-di amine;

[0258] N2-benzyl-Nl-cyclohexyl-4-[(E)-2-(4-methoxyphenyl)vinyl]benzene-l,2-diamine:

[0259] N1 -benzyl-N2-(4-methoxycyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[0260] N1 -benzyl-N2-(4,4-difluorocy cl ohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[0261] Nl-benzyl-N2-(4-methylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[0262] Nl-[(4-chlorophenyl)methyl]-N2-cyclohexyl-4-oxazol-5-yl-benzene-1.2-diamine;

[0263] Nl-benzyl-N2-(4,4-dimethylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[0264] N2-benzyl-N I -cyclohexyl-4-(l,3, 4-oxadiazol-2-yl)benzene-l,2-di amine;

[0265] N2-cyclohexyl-4-oxazol-5-yl-Nl-(l-phenylethyl)benzene-l,2-di amine;

[0266] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N-isopropyl-prop-2-enamide;

[0267] Nl-benzyl-N2-cyclohexyl-4-[4-(p-tolyl)triazol-l-yl]benzene-1.2-diamine;

[0268] Nl-cy cl ohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)benzene-l,2-di amine; N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]benzamide;

[0269] Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(2-methoxyphenyl)vinyl]benzene-l,2-diamine;

[0270] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-l-morpholino-prop-2-en-l-one;

[0271] N2-benzyl-4-[(E)-2-(2-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-l,2-diamine;

[0272] Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(4-pyridyl)vinyl]benzene-l,2-diamine;

[0273] Nl-cy clohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-methyl-2-pyridyl)methyl]benzene- 1,2-diamine;

[0274] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-fluoro-2-pyridyl)methyl]benzene-l,2- di amine;

[0275] -23- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0276] N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]-2,3-dihydro-l,4- benzodioxine-6-carboxamide;

[0277] N2-benzyl-N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;

[0278] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]benzene-l,2- di amine;

[0279] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-(2-pyridylmethyl)benzene-l,2-diamine;

[0280] N1 -cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[[4-(4-methylpiperazin-l - yl)phenyl]methyl]benzene-l,2-diamine;

[0281] Nl-cyclohexyl-N2-(2,3-dihydrobenzofuran-5-ylmethyl)-4-[(E)-2-(4- fluorophenyl) vinyl] benzene- 1,2-di amine;

[0282] Nl-cyclohexyl-N2-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-4-[(E)-2-(4- fluorophenyl)vinyl]benzene-l,2-di amine;

[0283] Nl-cyclohexyl-N2-[(4-morpholinophenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2- diamine;

[0284] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[[4-(trifluoromethoxy)phenyl]methyl]benzene- 1.2-di amine;

[0285] Nl-cyclohexyl-N2-[(4-methoxyphenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2- di amine;

[0286] N1 -cy clohexyl-N2- [ [4-(4-methy Ipiperazin- 1 -yl)phenyl]methy l]-4-( 1,3,4-oxadiazol-2- yl)benzene- 1,2-diamine;

[0287] Nl-cyclohexyl-N2-[(3,5-dimethoxyphenyl)methyl]-4-[(E)-2-(4-fluorophenyl)vinyl]benzene- 1.2-diamine;

[0288] 4-[[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]methyl]phenol;

[0289] N1 -cy cl ohexyl-N2-(2,3-dihydrobenzofuran-6-ylmethyl)-4-(1.3.4-oxadiazol-2-yl)benzene- 1,2- di amine;

[0290] N2-benzyl-4-[(E)-2-(3-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-l,2-di amine;

[0291] N2-benzyl-Nl-cyclohexyl-4-[(E)-2-[3-(trifluoromethyl)phenyl]vinyl]benzene-l,2-di amine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]pyridine-2,3- di amine;

[0292] N2-benzyl-4-[(E)-2-(4-fluorophenyl)vinyl]-Nl-tetrahydropyran-4-yl-benzene-l,2-diamine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)pyridine-2,3-diamine; Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-phenyl-benzene-l,2-diamine;

[0293] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[2-(2-pyridyl)ethyl]benzene-1.2-di amine; Nl-benzyl-N2-cy cl ohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene- 1,2-di amine;

[0294] -24- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0295] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-tetrahydropyran-4-yl-pyridine-2,3-di amine; N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;

[0296] 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-N, N-dimethyl-propanamide: N2-benzyl-Nl-cyclohexyl-4-[5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl]benzene-l,2-diamine; N2-benzyl-N3-cyclohexyl-6-[5-(tri fluoromethyl)-!, 3, 4-oxadiazol-2-yl]pyridine-2,3-di amine; tert-butyl 4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]piperidine-l- carboxylate;

[0297] N2-benzyl-N3-cyclohexyl-6-(l,3,4-oxadiazol-2-yl)pyridine-2,3-diamine;

[0298] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(4-piperidyl)pyridine-2,3- diamine;hydrochloride;

[0299] 1-[4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-l- piperidyl]ethenone;

[0300] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(l-methyl-4-piperidyl)pyridine-2,3-diamine; N2-benzyl-Nl-cyclohexyl-4-(5-methyl-l,3,4-oxadiazol-2-yl)benzene-l,2-diamine; methyl 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoate;

[0301] Nl-cyclohexyl-4-t(E)-2-(4-fluorophenyl)vinyl]-N2-prop-2-ynyl-benzene-l,2-diamine;

[0302] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-methylsulfonylethyl)benzene-l,2- diamine;

[0303] N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-!luorophenyl)vinyl]pyridine-2,3-diamine;

[0304] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-1.2-diamine;

[0305] N1 -cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-l,2- diamine;hydrochloride;

[0306] 3-[2-(cyclohexylamino)-5-(l,3,4-oxadiazol-2-yl)anilino]propanenitrile;

[0307] 3- [2-(cy clohexylamino)-5 - [(E)-2-(4-fluorophenyl) vinyl] anilino] - 1 -pyrrolidin- 1 -y 1-propan- 1 - one;

[0308] 2-[2-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]ethyl]isoindoline-l,3- dione;

[0309] tert-butyl N-[2-[2-(cyclohexylamino)-5-[(E)-2-(4- fluorophenyl)vinyl]anilino]ethyl]carbamate;

[0310] 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-l-morpholino-propan-l-one; tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4- fluorophenyl)vinyl]anilino]propanoylamino]piperidine-l -carboxylate;

[0311] tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4- fluorophenyl)vinyl]anilino]propanoyl]piperazine-l -carboxylate;

[0312] -25- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0313] [4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-l -piperidyl] -phenylmethanone:

[0314] a salt thereof, an isomer thereof, and / or an isotope containing derivative thereof. Compounds of the disclosure are also shown in FIG. 2A - FIG. 2B. Chemical structures and standard nomenclature of the compounds disclosed herein are listed in Table 1 below.

[0315] f

[0316] Z —

[0317] Table 1. Chemical Structure of c / ompounds and standard nomenclature.

[0318] Compoun

[0319] Structure Chemical Name

[0320] ds

[0321] N2-benzyl-N 1 -cy clohexyl-4-oxazol-5-yl- 3

[0322] benzene- 1,2-diamine

[0323] \

[0324] 0

[0325] yj*

[0326] 0^ y}

[0327] 4 > ( Z, Z— — Nl-benzyl-N2-cyclohexyl-4-oxazol-5-yl- / _ \ _ x x \ benzene- 1,2-diamine

[0328] dN

[0329] (E)-3-[3-(benzylamino)-4- 5 (cyclohexylamino)phenyl]-N, N-dimethyl-prop- 2-enamide

[0330] N2-benzyl-N 1 -cyclohexy l-4-[(E)-2-(4- 6 L l fl uorophenyl)vinyl] benzene- 1,2-di amine

[0331] N2-benzyl-N 1 -cy clohexyl-4-[(E)-2-(4- 7

[0332] methoxyphenyl)vinyl] benzene- 1,2-di amine

[0333]

[0334] -26- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0335] 0.

[0336] N 1 -benzyl-N2-(4-methoxycyclohexyl)-4- 8

[0337] A l? oxazol-5-yl-benzene-l,2-di amine

[0338] (J "

[0339] A O CPx

[0340] Ok]

[0341] HN. ^ O Z^ Nl-benzyl-N2-(4,4-difluorocyclohexyl)-4- 9

[0342] oxazol-5-yl-benzene-l,2-diamine

[0343] (J A

[0344] FXF

[0345] Ck,

[0346] N 1 -benzy l-N2-(4-methylcy clohexyl)-4-oxazol- 10

[0347] 5-yl-benzene- 1.2-di amine

[0348] Nl-[(4-chlorophenyl)methyl]-N2-cyclohexyl-4- 11

[0349] _ \ _ / X X \ oxazol-5-yl-benzene-l,2-diamine

[0350] vJ

[0351] 0,

[0352] HN^M

[0353] Nl-benzyl-N2-(4,4-dimethylcyclohexyl)-4- 12

[0354] oxazol-5-yl-benzene-l,2-diamine

[0355] N2-benzyl-Nl-cyclohexyl-4-(l,3,4-oxadiazol-2- 13

[0356] yl)benzene-l, 2-di amine

[0357] Ok^

[0358] HNx^\ N2-cy clohexyl-4-oxazol-5-yl-N 1 -( 1 - 14

[0359] phenylethy l)benzene- 1.2-di amine

[0360]

[0361] dN

[0362] -27- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0363] (E)-3-[3-(benzylamino)-4- 15 (cyclohexylamino)phenyl]-N-isopropyl-prop-2- enamide

[0364] 0

[0365] Nl-benzyl-N2-cyclohexyl-4-[4-(p-tolyl)triazol- 16 XT'21 -y l]benzene- 1,2-di amine

[0366] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]- 17

[0367] N2-(2-pyridy lmethyl)benzene- 1,2-diamine

[0368] 4 N-[2-(cyclohexylamino)-5-[(E)-2-(4- 18 Y 1 fluorophenyl)vinyl]phenyl]benzamide QX ( ) Z—°

[0369] Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(2- 19HN" A methoxy pheny l)vinyl] benzene- 1,2-diamine 60

[0370] (E)-3-[3-(benzylamino)-4- 20 Y0l (cyclohexylamino)phenyl]-l-morpholino-prop- 2-en-l-one

[0371] c / °

[0372] N2-benzyl-4-[(E)-2-(2-chlorophenyl)vinyl]-Nl- 21HNyx[clcyclohexyl-benzene- 1,2-diamine

[0373] 0

[0374]

[0375] -28- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0376] a,

[0377] Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(4- 22 L 1 / py ridy l)vinyl] benzene- 1,2-diamine

[0378] o —

[0379] ^3 °

[0380] Q

[0381] 7 \ Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]- 23 11 4, N2-[(6-methyl-2-pyridyl)methyl]benzene-l,2- diamine

[0382] Cl

[0383] Ur

[0384] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]- 24 N2-[(6-fluoro-2-pyridyl)methyl]benzene-l,2- diamine

[0385] yy

[0386] Q 4

[0387] HNYAx / \ N-[2-(cyclohexylamino)-5-[(E)-2-(4- 25 _

[0388] \ X ) y \ z _ /

[0389] _ _ < Z T I \ ( / KZ Z—— T I fluorophenyl)vinyl]phenyl]-2,3-dihydro-l,4- / X \ —— O

[0390] o \ _ _ / i i \ < ) \z z——

[0391] OOz zX L JL benzodioxine-6-carboxamide c \j:u0

[0392] N2-benzyl-N3-cyclohexyl-6-[(E)-2-(4- 26

[0393] fluorophenyl)vinyl]pyridine-2,3-diamine

[0394] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]- 27 N2-[(4-methoxyphenyl)methyl]benzene- 1,2- diamine

[0395] N 1 -cy clohexy l-4-( l,3,4-oxadiazol-2-yl)-N2-(2- 28

[0396] pyridylmethyl)benzene- 1,2-diamine

[0397]

[0398] -29- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0399] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]- 29 N2- [[4-(4-methy Ipiperazin- 1 - y l)phenyl] methyl] benzene- 1,2-diamine b

[0400] Q N 1 -cyclohexyl-N2-(2,3-dihydrobenzofuran-5- 30 Ll ylmethyl)-4-[(E)-2-(4- fl uorophenyl)vinyl] benzene- 1,2-di amine 7 \

[0401] Nl-cyclohexyl-N2-(2,3-dihydro-l,4- 31 L l / benzodioxin-6-ylmethyl)-4-[(E)-2-(4- o _ J L 1 fluorophenyl)vinyl] benzene- 1,2-di amine bXOZjNZ

[0402] & <■

[0403] Q

[0404] Nl-cyclohexyl-N2-[(4- 32 morpholinophenyl)methyl]-4-(l,3,4-oxadiazol- N-N2-yl)benzene-l,2-diamine o A

[0405] o JL y

[0406] \ /

[0407] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[[4- 33 (trifluoromethoxy )phenyl]methy 1] benzene- 1,2- diamine

[0408] FN-N

[0409] F'^ PO'L^^Y

[0410] Nl-cyclohexyl-N2-[(4-methoxyphenyl)methyl]- 34

[0411] 4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine

[0412] Nl-cyclohexyl-N2-[[4-(4-methylpiperazin-l- 35 yl)phenyl]methyl]-4-(l,3,4-oxadiazol-2- yl)benzene-l,2-diamine

[0413]

[0414] -30- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0415] Nl-cyclohexyl-N2-[(3.5- 36 dimethoxyphenyl)methyl]-4-[(E)-2-(4- / \ o o fluoropheny l)vinyl] benzene- 1,2-di amine ' / \ \ i i

[0416] < ^y \ oz z '= z

[0417] 6 \ z Z—

[0418] \7

[0419] 4

[0420] 4-[[2-(cyclohexylamino)-5-[(E)-2-(4- 37

[0421] CX F? fluorophenyl)vinyl]anilino]methyl]phenol S c

[0422] Q N 1 -cy clohexyl-N2-(2.3-dihy drobenzofuran-6- 38 _J X o ylmethyl)-4-(l,3,4-oxadiazol-2-yl)benzene-l,2- y Xj* N-N diamine

[0423] CCJ 4

[0424] yj*

[0425] y)

[0426] _ \ _ / z z \ \ r \z-z- —~ ~ ~

[0427] N2-benzyl-4-[(E)-2-(3-chlorophenyl)vinyl]-Nl- 39

[0428] T vJ o* cy clohexyl-benzene- 1,2-di amine

[0429] QHN'^X N2-benzyl-Nl-cyclohexyl-4-[(E)-2-[3- 40 „NT^ 1^yy I+.F(tri fl uoromethyl)phenyl] vinyl] benzene- 1,2- O> U diamine

[0430] N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]- 41 N2-[(4-methoxyphenyl)methyl]pyridine-2,3- diamine

[0431] N2-benzyl-4-[(E)-2-(4-fluorophenyl)vinyl]-Nl- 42

[0432] tetrahy dropyran-4-yl-benzene- 1,2-diamine

[0433]

[0434] -31- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0435] N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]- 43

[0436] N2-(2-pyridylmethyl)pyridine-2,3-diamine

[0437] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]- 44

[0438] N2-phenyl-benzene-l,2-diamine Q

[0439] Y 1 Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]- 45

[0440] N2-[2-(2-pyridyl)ethyl]benzene-l,2-di amine y yy

[0441] yy

[0442] 0 _ \ _ / T T / . / ( >^— M o

[0443] — Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(4- 46

[0444] o \ _ / \ / X I — T ji

[0445] y^a. fluorophenyl)vinyl] benzene- 1,2-di amine

[0446] y N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3- 47 X tetrahydropyran-4-yl-pyndine-2,3-diamine

[0447] N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4- 48

[0448] fluorophenyl)vinyl]pyridine-2,3-diamine

[0449]

[0450] -32- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0451] 3-f2-(cyclohexylamino)-5-f(E)-2-(4- 49 o fluorophenyl)vinyl] anilino] -N, N-dimethyl- propanamide

[0452] o <

[0453] ' \ / \ I T

[0454] < ' Z Z ——

[0455] H> z

[0456] z\=

[0457] N2-benzyl-Nl-cyclohexyl-4-[5- 50 T

[0458] JL X O F F (tri fluoromethyl)-!, 3,4-oxadiazol-2-yl]benzene- 1 " / / — \ 1,2-di amine

[0459] N~N F

[0460] M

[0461] Q HN^-, N2-benzyl-N3-cyclohexyl-6-[5- 51 JL JL 0 F F (trifluoromethyl)-l,3,4-oxadiazol-2-yl]pyridine-N2,3-diamine

[0462] 'N F

[0463] kJ

[0464] V. vV / \ X Xxz z z—

[0465] VA v^z tert-butyl 4-[ [2-(benzylamino)-6- [(E)-2-(4- 52 fluorophenyl)vinyl]-3-pyridyl]amino]piperidine- 1 -carboxylate

[0466] N2-benzyl-N3-cyclohexyl-6-(l,3,4-oxadiazol-2- 53

[0467] yl)pyridine-2,3-diamine

[0468] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3- 54

[0469] (4-piperidyl)pyridine-2,3-diamine

[0470]

[0471] -33- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0472] 0 1 - [4- [ [2-(benzy lamino)-6- [(E)-2-(4- 55 HN. / x fluorophenyl)vinyl] -3-pyridy l]amino] - 1 - piperidyl]ethanone

[0473] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3- 56

[0474] (l-methyl-4-piperidyl)pyridine-2,3-diamine

[0475] N2-benzyl-Nl-cyclohexyl-4-(5-methyl-l,3,4- 57

[0476] y yyy oxadiazol-2-yl)benzene- 1,2-diamine C / vz' °

[0477] C

[0478] y}

[0479] yX o

[0480] ( 2 \ O

[0481] A^ Q W V> I Iz z

[0482] o °5■!

[0483] methyl 3-[2-(cyclohexylamino)-5-[(E)-2-(4- 58 L 1 /

[0484] fluorophenyl)vinyl]anilino]propanoate y OF

[0485] 0^0

[0486] 1

[0487] Q

[0488] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]- 59 Y N2-prop-2-ynyl-benzene- 1.2-diamine

[0489] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]- 60

[0490] N2-(2-methylsulfonylethyl)benzene-l, 2-diamine

[0491]

[0492] -34- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0493] (X

[0494] HN

[0495] N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4- 61 X fluorophenyl)vinyl]pyridine-2,3-diamine 6 ^

[0496] Q

[0497] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2- 62

[0498] (2-pyridyl)ethy 1] benzene- 1,2-diamine o

[0499] Q HN. / V

[0500] y yyy Nl-cyclohexyl-4-(1.3.4-oxadiazol-2-yl)-N2-[2- 63

[0501] JNX\ ( > (2-pyridyl)ethy 1] benzene- 1,2-diamine y XX_ MZ M °

[0502] _ \ _ \ / 6 r r / \ / \ z z z vv ——— T '

[0503] o o

[0504] Q

[0505] 3-[2-(cyclohexylamino)-5-(l,3,4-oxadiazol-2- 64 HNXJLO yl)anilino] propanenitrile

[0506] J N-N^

[0507] / ) /

[0508] N

[0509] 3-[2-(cyclohexylamino)-5-[(E)-2-(4- 65 fluoropheny l)viny 1] anilino] - 1 -py rrolidin- 1 -yl- propan-l-one

[0510] 2-[2-[2-(cyclohexylamino)-5-[(E)-2-(4- 66 fluorophenyl)vinyl]anilino]ethyl]isoindoline- 1.3 -di one

[0511]

[0512] -35- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0513] QHN'^X

[0514] tert-butyl N-[2-[2-(cyclohexylamino)-5-[(E)-2- 67

[0515] o 0 (4-fluoropheny l)vinyl] anilino] ethyl] carbamateHN\< ° O= 7 - \ / - - k / - \ k

[0516] ^^^A^ \ / \ T T T T / I ZE Vzzz 'z z z- — — / o \ /

[0517] 0 o

[0518] 4

[0519] k r~

[0520] 3-[2-(cyclohexylamino)-5-[(E)-2-(4- 68 fluoropheny l)vinyl] anilino] - 1 -morpholino- propan- 1 -one

[0521] tert-butyl 4-[3-[2-(cvclohexylamino)-5-[(E)-2- ' (4- 69

[0522] fluorophenyl) vinyl] anilino] propanoylamino] pip eridine- 1 -carboxylate

[0523] Q

[0524] Y ) tert-butyl 4-[3-[2-(cvclohexylamino)-5-[(E)-2- 70 2 OF' (4- fluorophenyl)vinyl]anilino]propanoyl]piperazine -1 -carboxylate

[0525] 'ArV

[0526] O 1

[0527] [4-[[2-(benzylamino)-6-[(E)-2-(4- 71 fluorophenyl)vinyl] -3-pyridy l]amino] - 1 - piperidyl]-phenyl-methanone

[0528]

[0529] Synthesis and chemical properties of the compounds disclosed herein is described in details elsewhere herein.

[0530] -36- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0531] In certain embodiments, this disclosure is directed to a pharmaceutical composition comprising at least one compound having formula (1), or a salt thereof, an isomer thereof, an isotope containing derivative thereof, or combinations thereof, and at least one pharmaceutically acceptable excipient.

[0532] In certain embodiments, R3 can be -CH=CHR6 and the compound can have formula (2):

[0533] R1

[0534] HN X

[0535] T il

[0536] HN""'X R6

[0537]

[0538] In certain embodiments, the compound of formula (2) can comprise an isomer thereof, an isotope containing derivative thereof, or a combination thereof.

[0539] In certain embodiments, the compound is selected from the group consisting of:

[0540] N2-benzyl-Nl-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;

[0541] Nl-benzyl-N2-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;

[0542] (E)-3-t3-(benzylamino)-4-(cyclohexylamino)phenyl]-N, N-dimethyl-prop-2-enamide;

[0543] N2-benzyl-Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-I,2-diamine;

[0544] N2-benzyl-Nl-cyclohexyl-4-[(E)-2-(4-methoxyphenyl)vinyl]benzene-l,2-diamine;

[0545] N1 -benzyl-N2-(4-methoxycy cl ohexy l)-4-oxazol-5-yl-benzene- 1,2-di amine;

[0546] N 1 -benzyl-N2-(4,4-difluorocyclohexyl)-4-oxazol-5-yl-benzene- 1,2-di amine;

[0547] Nl-benzyl-N2-(4-methylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[0548] N 1 - [(4-chloropheny l)methyl] -N2-cy clohexyl-4-oxazol-5-yl-benzene- 1,2-diamine;

[0549] Nl-benzyl-N2-(4,4-dimethylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[0550] N2-benzyl-Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-di amine;

[0551] N2-cyclohexyl-4-oxazol-5-yl-Nl-(l-phenylethyl)benzene-I,2-di amine;

[0552] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N-isopropyl-prop-2-enamide;

[0553] N 1 -benzyl-N2-cy clohexyl-4-[4-(p-tolyl)triazol- 1 -yl]benzene-l,2-diamine;

[0554] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)benzene-I,2-diamine; N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]benzamide;

[0555] Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(2-methoxyphenyl)vinyl]benzene-l,2-diamine;

[0556] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-l-morpholino-prop-2-en-l-one;

[0557] N2-benzyl-4-[(E)-2-(2-chlorophenyl)vinyl]-NI-cyclohexyl-benzene-l,2-diamine;

[0558] -37- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0559] Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(4-pyridyl)vinyl]benzene-l,2-diamine;

[0560] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-methyl-2-pyridyl)methyl]benzene- 1,2-diamine;

[0561] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-fluoro-2-pyridyl)methyl]benzene-l,2- diamine;

[0562] N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]-2,3-dihydro-l,4- benzodioxine-6-carboxamide;

[0563] N2-benzyl-N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;

[0564] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]benzene-l,2- diamine;

[0565] N1 -cy cl ohexyl-4-(l, 3, 4-oxadiazol-2-yl)-N2-(2-pyridylmethyl)benzene- 1,2-diamine;

[0566] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[[4-(4-methylpiperazin-l- yl)phenyl]methyl]benzene-l,2-diamine;

[0567] Nl-cyclohexyl-N2-(2,3-dihydrobenzofuran-5-ylmethyl)-4-[(E)-2-(4- fluoro phenyl) vinyl] benzene- 1,2-di amine;

[0568] Nl-cyclohexyl-N2-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-4-t(E)-2-(4- fluorophenyl)vinyl]benzene-l,2-di amine;

[0569] Nl-cyclohexyl-N2-[(4-morpholinophenyl)methyl]-4-(l, 3, 4-oxadiazol-2-yl)benzene- 1,2- di amine;

[0570] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[[4-(trifluoromethoxy)phenyl]methyl]benzene- 1,2-diamine;

[0571] Nl-cyclohexyl-N2-[(4-methoxyphenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2- diamine;

[0572] Nl-cyclohexyl-N2-[[4-(4-methylpiperazin-l-yl)phenyl]methyl]-4-(1.3.4-oxadiazol-2- yl)benzene- 1,2-diamine;

[0573] Nl-cyclohexyl-N2-[(3,5-dimethoxyphenyl)methyl]-4-[(E)-2-(4-fluorophenyl)vinyl]benzene- 1,2-diamine;

[0574] 4-[[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]methyl]phenol;

[0575] N1 -cy cl ohexyl-N2-(2,3-dihydrobenzofuran-6-ylmethyl)-4-(l,3,4-oxadiazol-2-yl)benzene- 1,2- diamine;

[0576] N2-benzyl-4-[(E)-2-(3-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-l,2-diamine;

[0577] N2-benzyl-Nl-cyclohexyl-4-[(E)-2-[3-(trifluoromethyl)phenyl]vinyl]benzene-l,2-di amine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]pyridine-2,3- diamine;

[0578] -38- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0579] N2-benzyl-4- [(E)-2-(4-fluorophenyl)viny 1] -N 1 -tetrahy dropy ran-4-yl-benzene- 1,2-diamine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)pyridine-2.3-diamine; Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-phenyl-benzene-l,2-di amine;

[0580] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[2-(2-pyridyl)ethyl]benzene-l,2-di amine; Nl-benzyl-N2-cy cl ohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-di amine;

[0581] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-tetrahydropyran-4-yl-pyridine-2,3-di amine; N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;

[0582] 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-N, N-dimethyl-propanamide; N2-benzyl-Nl-cyclohexyl-4-[5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl]benzene-l,2-diamine; N2-benzyl-N3-cyclohexyl-6-[5-(tri fluoromethyl)-!, 3, 4-oxadiazol-2-yl]pyridine-2,3-di amine; tert-butyl 4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]piperidine-l- carboxylate;

[0583] N2-benzyl-N3-cyclohexyl-6-(l,3,4-oxadiazol-2-yl)pyridine-2,3-diamine;

[0584] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(4-piperidyl)pyridine-2,3- diamine;hydrochloride;

[0585] 1-t4-[[2-(benzylamino)-6-t(E)-2-(4-fluorophenyl)vinylJ-3-pyridyl]ammo]-l- piperidyl]ethenone;

[0586] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(l-methyl-4-piperidyl)pyridine-2,3-diamine; N2-benzyl-Nl-cyclohexyl-4-(5-methyl-l,3,4-oxadiazol-2-yl)benzene-l,2-di amine; methyl 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoate;

[0587] N1 -cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-prop-2-ynyl-benzene-l,2-diamine;

[0588] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-methylsulfonylethyl)benzene-l,2- di amine;

[0589] N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;

[0590] N 1 -cyclohexyl-4-( 1,3,4-oxadiazol-2-y l)-N2-[2-(2-pyridyl)ethyl]benzene- 1,2-diamine;

[0591] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-l,2- diamine;hydrochloride;

[0592] 3-[2-(cyclohexylamino)-5-(l,3,4-oxadiazol-2-yl)anilino]propanenitrile;

[0593] 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-l-pyrrolidin-l-yl-propan-l- one;

[0594] 2-[2-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]ethyl]isoindoline-l,3- dione;

[0595] tert-butyl N-[2-[2-(cyclohexylamino)-5-[(E)-2-(4- fluorophenyl)vinyl]anilino]ethyl]carbamate;

[0596] -39- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0597] 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]- 1 -morpholino-propan- 1-one; tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4- fluorophenyl)vinyl]anilino]propanoylamino]piperidine-l -carboxylate;

[0598] tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4- fluorophenyl)vinyl]anilino]propanoyl]piperazine-l -carboxylate;

[0599] [4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-l-piperidyl]-phenyl- methanone;

[0600] a salt thereof, an isomer thereof, an isotope containing derivative thereof, or combinations thereof.

[0601] In certain embodiments, the pharmaceutical composition can be formulated for injection administration, oral administration, inhale administration, topical administration, or combinations thereof.

[0602] In certain embodiments, the pharmaceutical composition can be formulated for an administration route comprising oral, intracranial, nasal, intranasal, rectal, transrectal, parenteral, sublingual, transdermal, transmucosal (i.e., systemic delivery of drug through the mucous membrane of the oral cavity, e.g., sublingual or lingual, buccal or transbuccal administration), urethral, transurethral, vaginal (including trans- and perivaginal), intravesical, intravesical, intrapulmonary. intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous (IV), intrabronchial, inhalation, and / or topical route(s).

[0603] In certain embodiments, the pharmaceutical composition can be formulated for intravenous (IV) injection, subcutaneous (SC) injection, intramuscular (IM) injection, intradermal (ID) injection, oral administration, and / or aerosol administration.

[0604] In certain embodiments, the pharmaceutical composition can be formulated for treatment of post-stroke brain ischemia-reperfusion injury (IRI), ischemia-reperfusion injury (IRI) not caused by post-stroke brain ischemia, ischemic heart diseases, lung injury related to a coronavirus infection, SARS-CoV infection, SARS-CoV-2 infection (COVID-19), Middle Eastern respiratory syndrome (MERS), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), kidney injury, respiratory illness due to alveolar damage, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, inflammatory bowel disease (IBD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), Sedaghatian-type spondylometaphyseal dysplasia (SSMD), organ injury- due to vascular leakage during sepsis or heme release, iron-overloading diseases, neurodegenerative diseases, Huntington’s disease, Alzheimer’s disease (AD), amyotrophic -40- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0605] lateral sclerosis (ALS), chronic kidney disease (CKD), kidney fibrosis, traumatic brain injury, tumor, or combinations thereof.

[0606] Non-limiting examples of a pharmaceutically acceptable excipients can include a pharmaceutical surfactant, emulsifier, filler, carrier, isotonicifier, dispersing agent, viscosity modifier, resuspending agent, buffer, or combinations thereof.

[0607] In certain embodiments, the at least one pharmaceutically acceptable excipient can comprise acacia, animal oils, benzyl alcohol, benzyl benzoate, calcium stearate, carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol, cyclodextrins, dextrose, diethanolamine, emulsifying wax, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glycerol stearate,, glyceryl monooleate, glyceryl monostearate, hydrous, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-P-cyclodextrin (HPBCD). hypromellose (hydroxypropyl methylcellulose (HPMC)), lanolin, lanolin alcohols, lecithin, medium-chain triglycerides, metallic soaps, methylcellulose, mineral oil, monobasic sodium phosphate, monoethanolamine, oleic acid, polyy ethylene glycols (PEG 3350, PEG 4000, PEG 6000), polyoxy ethylene-polyoxypropylene copolymer (poloxamer), polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polysorbate, polyoxyethylene (20) sorbitan monolaurate (Tween 20, Polysorbate 20), polyoxyethylene (20) sorbitan monooleate (Tween 80, Polysorbate 80), povidone, propylene glycol alginate, saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium hydroxide, sodium lauryl sulfate, sodium phosphate monobasic, sodium phosphate dibasic, sorbitan esters, stearic acid, stearyl alcohol, sunflower oil, tragacanth, triethanolamine, vegetable oils, water, xanthan gum, or combinations thereof.

[0608] In certain embodiments, the at least one pharmaceutically acceptable excipient can be selected from the group consisting of acacia, animal oils, benzyl alcohol, benzyl benzoate, calcium stearate, carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol, cyclodextrins, dextrose, diethanolamine, emulsifying wax, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glycerol stearate,, glycery l monooleate, glyceryl monostearate, hydrous, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-P-cyclodextrin (HPBCD), hypromellose (hydroxypropyl methylcellulose (HPMC)), lanolin, lanolin alcohols, lecithin, medium-chain triglycerides, metallic soaps, methylcellulose, mineral oil, monobasic sodium phosphate, monoethanolamine, oleic acid, polyy ethylene glycols (PEG 3350, PEG 4000, PEG 6000), polyoxyethylene-poly oxypropylene copolymer (poloxamer), polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates.

[0609] -41- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0610] polysorbate, polyoxyethylene (20) sorbitan monolaurate (Tween 20, Polysorbate 20), polyoxyethylene (20) sorbitan monooleate (Tween 80, Polysorbate 80). povidone, propylene glycol alginate, saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium hydroxide, sodium lauryl sulfate, sodium phosphate monobasic, sodium phosphate dibasic, sorbitan esters, stearic acid, stearyl alcohol, sunflower oil, tragacanth, triethanolamine, vegetable oils, water, xanthan gum, and combinations thereof.

[0611] In certain embodiments, the pharmaceutically acceptable excipients can comprise dextrose, glycerin, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-P-cyclodextrin (HPBCD), hypromellose (hydroxypropyl methylcellulose (HPMC)), polyoxyethylene (20) sorbitan monolaurate (Tween 20, Polysorbate 20), polyyethylene glycols (PEG 400, PEG 3350, PEG 4000, PEG 6000), poly oxy ethylene-poly oxypropylene copolymer (Poloxamer 188, Pol oxamer 407), polyoxyethylene (20) sorbitan monooleate (Tween 80, Polysorbate 80), saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium lauryl sulfate, sodium phosphate monobasic, sodium phosphate dibasic, or a combination thereof.

[0612] In certain embodiments, the pharmaceutically acceptable excipients can be selected from the group consisting of dextrose, glycerin, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-P-cyclodextrin (HPBCD), hypromellose (hydroxypropyl methylcellulose (HPMC)), polyoxyethylene (20) sorbitan monolaurate (Tween 20, Polysorbate 20), polyyethylene glycols (PEG 400. PEG 3350, PEG 4000. PEG 6000), polyoxyethylene-polyoxypropylene copolymer (Poloxamer 188, Poloxamer 407), polyoxyethylene (20) sorbitan monooleate (Tween 80, Polysorbate 80), saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium lauryl sulfate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.

[0613] In certain embodiments, the pharmaceutical composition can comprise at least one of Compounds 3 — 71, or a combination thereof, and at least one pharmaceutically acceptable excipient in a weight ratio of the compounds to the pharmaceutically acceptable excipients in a range of from 1:100 to 100:1. In certain embodiments, the pharmaceutical composition can comprise a weight ratio of the compounds to at least one pharmaceutically acceptable excipient in a range of from 1:100, 1:80, 1:60, 1:50, 1:40, 1:30, 1:20, 1:15, 1:10, 1:5, 1:4, 1:3, 1:2, 1:1, 1:0.8, 1:0.6, 1:0.5, 1:0.4, 1:0.3, 1:0.2, 1:0.1, 1:0.05, and 1:0.01, with these ranges intended as a continuous range including every value between the minimum and maximum values. In certain embodiments, the pharmaceutical composition can comprise a weight ratio of the compounds to at least one pharmaceutically acceptable excipient in a range of from -42- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0614] 1:20. In certain embodiments, the pharmaceutical composition can comprise a weight ratio of the compounds to the at least one pharmaceutically acceptable excipient in a range of from 1:10. In certain embodiments, the pharmaceutical composition can comprise a weight ratio of the compounds to the at least one pharmaceutically acceptable excipient in a range of from 1:5.

[0615] In certain embodiments, the pharmaceutical composition disclosed herein can further comprise one or more additional active pharmaceutical ingredients. Traditional Active Pharmaceutical Ingredients (APIs) can be suitable. Drugs and APIs in the FDA’s Drug Approvals and Databases, developed or to be developed by those skilled in the art, can be suitable. Drugs and treatments known to have efficacy in treating or improving conditions of a subject having a disease selected from post-stroke brain ischemia-reperfusion injury (IRI), ischemia-reperfusion injury (IRI) not caused by post-stroke brain ischemia, ischemic heart diseases, lung injury related to a coronavirus infection, SARS-CoV infection, SARS-CoV-2 infection (COVID-19), Middle Eastern respiratory syndrome (MERS), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), kidney injury, respiratory illness due to alveolar damage, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, inflammatory bowel disease (IBD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), Sedaghatian-type spondylometaphyseal dysplasia (SSMD). organ injury due to vascular leakage during sepsis or heme release, iron-overloading diseases, neurodegenerative diseases. Huntington’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Chronic kidney disease (CKD), Kidney fibrosis, Traumatic brain injury, tumor, and a combination thereof, can be suitable.

[0616] In certain embodiments, the pharmaceutical composition can be formulated in dosage forms selected from tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration. Although some formulation and dosage forms are described here, the formulations, compositions and dosage forms that can be useful in the present disclosure are not limited to particular formulations, compositions and dosage forms that are described herein.

[0617] In certain embodiments, the pharmaceutical compositions can be formulated as tablets for oral intake. In certain embodiments, each single tablet can contain 0.1 mg, 0.5 mg, 1 mg.

[0618] 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, or 40 mg of the compound. Additional tablets can be -43- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0619] formulated similarly with different dosage. One or more tablets can form a single dosage for administering the pharmaceutical composition to a subject.

[0620] As used herein, “parenteral administration’’ of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In certain embodiments, parenteral administration can be contemplated to include, but is not limited to, intraocular, intravitreal, subcutaneous, intraperitoneal, intramuscular, intrastemal injection, intratumoral. and kidney dialytic infusion techniques.

[0621] Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier or excipients, such as sterile water or sterile isotonic saline. The pharmaceutically acceptable excipients disclosed herein can be suitable. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In certain embodiments of a formulation for parenteral administration, the active ingredient is provided in dry (i.e. powder or granular) form for reconstitution with a suitable vehicle (e.g. sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0622] In certain embodiments, this disclosure is directed to a method for treating, ameliorating, and / or preventing a disease or disorder in a subject in need thereof. The method can comprise administering an effective amount of the pharmaceutical composition disclosed herein, or a combination thereof, to the subject, wherein the disease or disorder can be selected from post-stroke brain ischemia-reperfusion injury (IRI), ischemia-reperfusion injury (IRI) not caused by post-stroke brain ischemia, ischemic heart diseases, lung injury related to a coronavirus infection, SARS-CoV infection. SARS-CoV-2 infection (COVID-19), Middle Eastern respiratory syndrome (MERS), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), kidney injury, respiratory illness due to -44- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0623] alveolar damage, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, inflammatory’ bowel disease (IBD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), Sedaghatian-type spondylometaphyseal dysplasia (SSMD), organ injury due to vascular leakage during sepsis or heme release, iron-overloading diseases, neurodegenerative diseases, Huntington’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Chronic kidney disease (CKD), Kidney fibrosis, Traumatic brain injury, tumor, and a combination thereof.

[0624] In certain embodiments, the pharmaceutical composition can be administered to the subject via oral, intracranial, nasal, intranasal, rectal, transrectal, parenteral, sublingual, transdermal, transmucosal (i.e., systemic delivery of drug through the mucous membrane of the oral cavity, e.g., sublingual or lingual, buccal or transbuccal administration), urethral, transurethral, vaginal (including trans- and perivaginal), intravesical, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous (IV), intrabronchial, inhalation, topical administration, intravenous (IV) injection, subcutaneous (SC) injection, intramuscular (IM) injection, intradermal (ID) injection, oral administration, aerosol administration, or a combination thereof.

[0625] In certain embodiments, the pharmaceutical composition can be administered to the subject via intravenous (IV) injection, subcutaneous (SC) injection, intramuscular (IM) injection, intradermal (ID) injection, oral administration, aerosol administration, or a combination thereof.

[0626] In certain embodiments, the pharmaceutical composition can be administered to a subject in combination with one or more additional medications, or treatments. Traditional medications, treatments suitable for the subject in need thereof can be suitable. Traditional surgical intervention, mechanical treatment, ventilator treatment, high or low oxygen treatment, dialysis, and other medications or treatments known to have effect in improving conditions of the subject can be suitable.

[0627] The present disclosure is further directed to a use of any one of Compounds 3 - 71. a salt, or solvate thereof, for manufacturing of a medicament for the treatment, ameliorating, and / or preventing a disease or disorder in a subject in need thereof, wherein said disease or disorder is selected from post-stroke brain ischemia-reperfusion injury (IRI), ischemia-reperfusion injury (IRI) not caused by post-stroke brain ischemia, ischemic heart diseases, lung injury related to a coronavirus infection, SARS-CoV infection, SARS-CoV-2 infection (COVID- 19), Middle Eastern respiratory syndrome (MERS), acute lung injury (ALI), acute -45- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0628] respiratory distress syndrome (ARDS), acute kidney injury (AKI), kidney injury, respiratory illness due to alveolar damage, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, inflammatory bowel disease (IBD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), Sedaghalian-type spondylometaphyseal dysplasia (SSMD), organ injury due to vascular leakage during sepsis or heme release, iron-overloading diseases, neurodegenerative diseases, Huntington’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Chronic kidney disease (CKD), Kidney fibrosis, Traumatic brain injury, tumor, or a combination thereof.

[0629] The present disclosure disclosed novel compounds that can be formulated in pharmaceutical compositions for treating diseases. Further detailed descriptions are provided in unlimited examples hereafter.

[0630] EXAMPLES

[0631] The present invention is further defined in the following Examples. It should be understood that these Examples, while indicating preferred embodiments of the invention, are given by way of illustration only. From the above discussion and these Examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various uses and conditions.

[0632] Example 1: Biological assay to access ferroptosis activity

[0633] The primary screen of activity is a cellular assay using 293T cell line. A 48-well plate was coated with Poly-lysine (Sigma-Aldrich) diluted in phosphate-buffered saline (PBS; Gibco) to a final concentration of 0.05 ng / pl. The plate was incubated at 37°C for 1 hour and rinsed with water twice. After that, 293T cells were seeded at a density of 0.12 million cells / ml (250 pl per well) and incubated at 37°C overnight. The ferroptosis inducer RSL-3 was added to the medium at a final concentration of 1 pM, and Compounds 3 (FIG. 3), 17 (FIG. 4). 5 (FIG. 5). 20 (FIG.6), were individually added at the indicated concentrations (e.g., 16 nM, 8 nM, 4 nM, 2 nM). The ATP detection was performed using the Luminescence ATP Detection Assay System kit (PerkinElmer, Waltham, MA, USA) according to the manufacturer's instructions. Briefly, cells were washed with 100 pl of PBS and lysed with 50 pl of mammalian cell lysis solution per well. The plate was then shaken for 5 min and 50 pl of substrate solution was added to each well and shaken for another 5 min. After a 10-min dark adaptation, luminescence was measured using a plate reader. Data are shown in FIG. 3 - -46- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0634] FIG. 6

[0635] GENERAL SYNTHETIC METHODS

[0636] The compounds of the invention may be prepared by the methods described below. In each of the schemes below, the groups R1 to R6 are as defined above for general formula unless noted. Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Typically, reaction progress may be monitored by thin layer chromatography (TLC) or HPLC-MS if desired. Intermediates and products may be purified by chromatography on silica gel, recrystallization, HPLC and / or reverse phase HPLC.

[0637] Starting materials and reagents are either commercially available or may be prepared by one skilled in the art using methods described in the chemical literature and in the Synthetic Examples section below.

[0638] Examples 2-9

[0639] Step 1.

[0640]

[0641] 4-fluoro-3-nitrobenzaldehyde (500 mg, 2.96mmol) was suspended in ethanol (4mL).

[0642] Benzylamine (379 mg, 3.55mmol) was added and the solution was stirred for 16 hours at 85°C. The Reaction was then concentrated and was stirred in 5mL of hexane for 15 minutes. Next the reaction was filtered and was washed with hexane (5 mL) to give product 4-(benzylamino)-3-nitro-benzaldehyde as an orange solid (92%).

[0643] Step 2.

[0644]

[0645] -47- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0646] 4-(benzylamino)-3-nitro-benzaldehyde (700 mg, 2.71mmol) and p-toluenesulfonylmethyl isocyanide (2.71 mmol) were suspended in MeOH (7 mL), then Potassium carbonate (6.78mmol) was added. The reaction was stirred at 65°C for 30 minutes and it was concentrated via vacuum. The residue was redissolved in 20 mL of CH2CI2. The solution was extracted with 20 mL of water. The combined organic layer w as dried with MgSO₄ (300 mg). The organic layer was then concentrated to give 729 mg of the product N-benzyl-2-nitro-4-oxazol-5-yl-aniline (80%) as a red solid.

[0647] Step 3.

[0648]

[0649] N-benzyl-2-nitro-4-oxazol-5-yl-aniline (729 mg, 2.47 mmol) was suspended in a 3:1 EtOH / H₂O solution (16 mL). Zinc (1.94 g) and ammonium chloride (1.58 g) were added, and the mixture was stirred for 1 hour at 70°C. The reaction was cooled down to room temperature and was filtered through Celite, then further rinsed with ethanol (2 mL) and the filtrate was concentrated via vacuum. The residue was redissolved in 20 mL of CH2CI2, and it was extracted with 20 mL of water. The combined organic layer was dried with MgSO₄ (300 mg). The mixture was filtered, and the filtrate was concentrated via vacuum to give 422 mg of product Nl-benzyl-4-oxazol-5-yl-benzene-l,2-diamine (64%) as atan solid.

[0650] Step 4.

[0651]

[0652] (Compound 4)

[0653] Nl-benzyl-4-oxazol-5-yl-benzene-l,2-diamine (200mg. 0.75mmol) was dissolved CH2CI2 (7 mL). To the solution was added cyclohexanone (78.4 mg, 0.8 mmol). Glacial acetic acid (286.2 mg, 4.77mmol) was added and the solution was stirred at 25°C for 1 hour. Sodium triacetoxyborohydride (237.3 mg, 1.12mmol) was added and the solution was stirred for additional Ihr at 25°C. IN NaOH aqueous solution (20 mL) was added, and the mixture was

[0654] -48- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0655] extracted with CH2CI2 (20 mL x 2). The combined organic layer was dried with MgSO₄ (500 mg) and filtered. The filtrate was concentrated via vacuum and the residue was purified by silica gel flash column chromatography with (0-20% EtOAc / Hexane) as the eluent to obtain the crude product contained traces of aliphatic impurities. The crude product was purified by suspension in ethanol (10 mL) at 65°C as Compound 4, and then cooling once homogenous and the solid was obtained by filtration. The solid obtained (32mg, 12%) as a white solid was confirmed as the title compound. LCMS (ESMS): m / z: 348.4 (M++l)

[0656] The following compounds were prepared in a similar manner:

[0657] N2-benzyl-Nl-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine (Compound 3);

[0658] Nl-benzyl-N2-(4-methoxycyclohexyl)-4-oxazol-5-yl-benzene-l,2-diamine (Compound 8); Nl-benzyl-N2-(4,4-difluorocyclohexyl)-4-oxazol-5-yl-benzene-l,2-diamine (Compound 9); Nl-benzyl-N2-(4-methylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-diamine (Compound 10); Nl-[(4-chlorophenyl)methyl]-N2-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine (Compound 11);

[0659] Nl-benzyl-N2-(4,4-dimethylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-diamine (Compound 12); and

[0660] N2-cyclohexyl-4-oxazol-5-yl-Nl-(l-phenylethyl)benzene-l,2-diamine (Compound 14).

[0661] Examples 10 - 19

[0662] Step 1

[0663]

[0664] To a suspension of 4-bromo-l-fluoro-2-nitrobenze (1 g. 4.54mmol) in EtOH (6 mL) was added cyclohexylamine (450 mg, 4.54 mmol). The reaction was stirred for 16 hours at 85°C. After completion, the reaction was concentrated, and the residue was stirred in 5 mL of hexane for 15 minutes. The solid was then filtered and rinsed with hexane (1 mL) to obtain the product 4-bromo-N-cyclohexyl-2-nitro-aniline (1.1 g, 81%) as an orange solid.

[0665] Step 2

[0666] -49- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0667]

[0668] Palladium Acetate (30 mg. 1%) and triphenylphosphine (50 mg, 2%) were added to DMF (8mL), followed by the 4-bromo-N-cyclohexyl-2-nitro-aniline (500 mg, 1.67 mmol), 1-fluoro-4-vinyl-benzene (244 mg, 2.00mmol) and triethylamine (202 mg, 2.00 mmol). The reaction was stirred at 130°C for 16 hours. Water (25 mL) was added, and the solution was extracted with EtOAc (25mL x 2). The combined organic layer was dried with MgSO₄ (500 mg) and was filtered. The filtrate was then concentrated, and the residue was purified by silica gel flash column chromatography with (0-20% CH₂Cl₂ / hexane) as the eluent to afford the product N-cy cl ohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-2-nitro-aniline as a red solid (280mg, 49%).

[0669] Step 3

[0670]

[0671] N-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-2-nitro-aniline (840 mg, 2.47 mmol) was suspended in a 3:1 EtOH / H₂O solution (16 mL). Zinc (1.94 g) and ammonium chloride (1.58 g) were added, and the mixture was stirred for 1 hour at 70°C. The reaction was cooled down to room temperature and was filtered through Celite, it was further rinsed with ethanol (2 mL) and the filtrate was concentrated via vacuum. The residue was redissolved in 20 mL of CH2CI2, and it was extracted with 20 mL of water. The combined organic layer was dried with MgSO₄ (300 mg). The mixture was filtered, and the filtrate was concentrated via vacuum to give 574 mg of product Nl-cy clohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-1,2-diamine (75%) as a tan solid.

[0672] Step 4

[0673] -50- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0674]

[0675] (Compound 6)

[0676] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-diamine (165mg, 0.53mmol) was dissolved in THF (5 mL) and potassium carbonate (73 mg, 0.53mmol) was added. A solution of Benzyl bromide (107 mg. 0.63 mmol) THF (2 mL) was then added dropwise. Upon completion, the reaction was stirred for 16 hours at 80°C. 15mL of water was added to the reaction and the mixture was extracted with EtOAc (15mL x 2). The combined organic layers were dried with MgSO4 (300 mg) and filtered. The residue was then concentrated, and the residue was purified by silica gel flash column chromatography with (0-20% EtOAc / hexane) as the eluent to afford the title compound (32mg, 15%) as a brown solid. LCMS (ESMS): m / z: 401.5 (M++l).

[0677] The following compounds were prepared in a similar manner:

[0678] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N, N-dimethyl-prop-2-enamide (Compound 5); N2-benzyl-Nl-cyclohexyl-4-[(E)-2-(4-methoxyphenyl)vinyl]benzene-l,2-diamine (Compound 7); (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N-isopropyl-prop-2-enamide (Compound 15); Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)benzene-l,2-diamine (Compound 17); N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl] phenyl] benzamide (Compound 18); Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(2 -methoxyphenyl)viny 1] benzene- 1,2-di amine (Compound 22); (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-l-morpholino-prop-2-en-l-one (Compound 20); N2-benzyl-4-[(E)-2-(2-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-l,2-diamine (Compound 21); andNl-benzyl-N2-cyclohexyl-4-[(E)-2-(4-pyridyl)vinyl]benzene-l,2-diamine (Compound 19).

[0679] Example 20

[0680] N2-benzyl-Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine (Compound 13) Step 1

[0681] -51- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0682]

[0683] Methyl 4-fluoro-3 -nitrobenzoate (500 mg, 2.51mmol) was suspended in EtOH (3mL), and cyclohexylamine (248.9 mg. 2.51mmol) was added. The reaction was stirred at 85°C for 16 hours and was then concentrated under vacuum. The residual crude solid was stirred in 3 mL of hexane for 15 minutes, then filtered yield the product methyl 4-(cyclohexylamino)-3-nitro-benzoate as an orange solid (545mg, 78%).

[0684] Step 2

[0685]

[0686] Methyl 4-(cyclohexylamino)-3-nitro-benzoate (300 mg. 1.08 mmol) was suspended in MeOH (5 mL), and hydrazine monohydrate (108 mg, 2.16mmol) was added dropwise. The reaction was stirred at 85°C for 16 hours and then concentrated. 10mL of CH2Cl2 was added to the residue and it was extracted with water (10 mL x 2). The combined organic layer was concentrated again to obtain the product 4-(cyclohexylamino)-3-nitro-benzohydrazide as an orange solid (270 mg, 90%).

[0687] Step 3

[0688]

[0689] 4-(cyclohexylamino)-3-nitro-benzohydrazide (252 mg, 0.92 mmol) was stirred in tri ethyl orthoformate (1. 3 g, 9.2mmol) at 100°C for 16 hours. The reaction cooled down and was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography with (0-30% EtOAc / hexane) as the eluent to afford the product N-cyclohexyl-2-nitro-4-(l,3,4-oxadiazol-2-yl)aniline as an orange solid (90mg, 34%).

[0690] Step 4

[0691] -52- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0692]

[0693] N-cyclohexyl-2-nitro-4-(1,3,4-oxadiazol-2-yl)aniline (864 mg, 3 mmol) was suspended in a 3:1 EtOH / H₂O solution (16 mL). Zinc (1.94 g) and ammonium chloride (1.58 g) were added, and the mixture was stirred for 1 hour at 70°C. The reaction was cooled down to room temperature and was filtered through Celite, it was further rinsed with ethanol (2 mL) and the filtrate was concentrated via vacuum. The residue was redissolved in 20 mL of CH2CI2, and it was extracted with 20 mL of water. The combined organic layer was dried with MgSO4 (300 mg). The mixture was filtered, and the filtrate was concentrated via vacuum to give the product Nl-cy cl ohexyl-4-(l, 3, 4-oxadiazol-2-yl)benzene-l,2-diamine as a tan solid (735 mg, 95%).

[0694] Step 5

[0695]

[0696] (Compound 13)

[0697] N1-cyclohexyl-4-(1,3,4-oxadiazol-2-yl)benzene-1,2-diamine (250 mg, 0.96 mmol) was dissolved in THF (5 mL) and potassium carbonate (132 mg, 0.96 mmol) was added. A solution of Benzyl bromide (188 mg, 1.1 mmol) THF (3 mL) was then added dropwise. Upon completion, the reaction was stirred for 16 hours at 80°C. 15 mL of water was added to the reaction and the mixture was extracted with EtOAc (15 mL x 2). The combined organic layers were dried with MgSO4(300 mg) and filtered. The residue was then concentrated, and the residue was purified by silica gel flash column chromatography with (0-15% EtOAc / hexane) as the eluent to afford the title compound (150 mg, 45%) as an off-white solid. LCMS (ESMS): m / z: 349.4 (M++l).

[0698] Example 21

[0699] Nl-benzyl-N2-cyclohexyl-4-[4-(p-tolyl)triazol-l-yl]benzene-l,2-diamine (Compound 16)

[0700] -53- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0701] Step 1

[0702]

[0703] OH

[0704] 4-Fluoro-3-nitrophenylboronic acid (300 mg, 1.62 mmol) was suspended in MeOH (25 mL), NaNs (127 mg, 1.95 mmol, 1.2 equiv.), and CuSCh (cat.) (26 mg, 0.16 mmol, 0.1 equiv.) were added while stirring suspension. The reaction mixture was left to stir at room temperature for 24 hours. An aqueous workup was performed, quenching the reaction mixture with H2O (30 mL) and extracting with EtOAc (30 mL) (3x). The organic phase layers were collected, combined, and then washed with H2O (30 mL) (2x). The washed organic phase was collected, dried with brine and MgSO4 (400 mg), and then filtered through a cotton funnel. The organic phase was concentrated to give the product, 4-azido-l-fluoro-2-nitro-benzene (277 mg, 93 %) as a brown solid.

[0705] Step 2

[0706]

[0707] 4-azi do- 1 -fl uoro-2 -nitro-benzene (277 mg, 1.50 mmol) was dissolved in THF (20 mL). 1-Ethynyl-4-methylbenzene (175 mg, 1.50 mmol. 1 equiv.). bromo-tris(triphenylphosphine)copper(I) (cat.) (31 mg, 0.03 mmol, 0.02 equiv.) and triethylamine (8.68 g, 85.75 mmol, 12 mL, 57 equiv.) were added to the reaction mixture. The mixture was stirred and refluxed at 65°C for 30 minutes and then quenched with 2N HC1 (43 mL). An aqueous workup was performed. H2O (30 mL) was added, and the mixture was extracted using EtOAc (40 mL) (3x). The organic phase layers were collected, combined, and then washed with brine. The organic phase was then dried with MgSO4(500 mg) and filtered through a cotton funnel. The resultant organic phase w as concentrated and the residue was purified by silica gel flash column chromatography with (0 -100 % EtOAc / Hexane) as the eluent to afford the product, l-(4-fluoro-3-nitro-phenyl)-4-(p-tolyl)triazole (141 mg, 32 %) as ayellow / orange solid crystal.

[0708] Step 3

[0709] -54- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0710]

[0711] l-(4-fluoro-3-nitro-phenyl)-4-(p-tolyl)triazole (141 mg, 0.47 mmol) was suspended in EtOH (10 mL). Benzylamine (61 mg, 0.57 mmol, 0.062 mL, 1.2 equiv.) was added dropwise while stirring. The reaction mixture was heated to 85°C and allowed to stir and reflux overnight (16 hours). The mixture was then cooled and concentrated to remove the EtOH. It was then slurred in hexane (10 mL) for an hour. The slurry was filtered through filter paper via vacuum filtration and the resultant solid was washed with hexane (5 mL) (2x) and allowed to dry under vacuo. The resultant crude product, N-benzyl-2-nitro-4-[4-(p-tolyl)triazol-l-y 1] aniline was then collected (210 mg) as an orange solid. The crude product was used in the next step of the synthesis without further purification.

[0712] Step 4

[0713]

[0714] N-benzyl-2-nitro-4-[4-(p-tolyl)triazol-l-yl]aniline (210 mg. 0.56 mmol) was suspended in a 3:1 solution of EtOH / H2O (12 mL / 4 mL). While stirring, solid NH4CI (369 mg, 6.77 mmol, 12 equiv.) and powdered Zinc (443 mg, 6.77 mmol, 12 equiv.) were added to the suspension mixture. The reaction mixture was then heated to 70°C and allowed to reflux for 1 hour. The solution was then filtered through celite powder under vacuo and washed with EtOH. The EtOH was concentrated, and the resultant crude residue was dissolved in CH2CI2 (20 mL). An aqueous workup was then performed with the addition of H2O (30 mL). The extraction was executed with CH2CI2 (20 mL) (3x), and the organic phase layers were collected and combined. The combined organic phase was then washed with H2O (30 mL) (2x) and recollected. The organic phase was dried using brine, followed by MgS04(500 mg), and then filtered through a cotton funnel. The filtrate was then concentrated to provide a -55- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0715] crude product, Nl-benzyl-4-[4-(p-tolyl)triazol-l-yl]benzene-l,2-diamine (115 mg, 60 %) as a brown oil. The crude product was carried on to the next step of the synthesis without further purification.

[0716] Step 5

[0717]

[0718] (Compound 16) Nl-benzyl-4-[4-(p-tolyl)triazol-l-yl]benzene-L2-diamine (115 mg. 0.34 mmol) was suspended in CH2Cl2(15 mL). The mixture was placed into an ice bath at 0°C.

[0719] Cyclohexanone (28.10 mg, 0.29 mmol, 0.03 mL, 0.85 equiv.) and Acetic acid (121.50 mg, 2.02 mmol, 0.12 mL, 6 equiv.) were added, both in a dropwise manner while stirring. The reaction mixture was allowed to stir at 0 °C and slowly come back up to room temperature while stirring over the course of 1 hour. After 1 hour, with the reaction mixture at room temperature, Sodium Triacetoxyborohydride (107.10 mg, 0.51 mmol, 1.5 equiv.) was added in small portions over a 15-minute period. The mixture was allowed to stir at room temperature for an additional hour.. After 1 hour of stirring, an aqueous workup was performed. The reaction mixture was quenched with IN NaOH (30 mL). An extraction was performed using CH2CI2 (25 mL) (3x). The organic phase layers were collected and combined. They were then washed with brine and dried using MgSO4 (500 mg). The resultant organic phase was filtered through a cotton funnel and concentrated. The crude residue purified by silica gel flash column chromatography with (0 - 15 % EtOAc / Hexane gradient) as the eluent to afford the title product (70 mg, 49 %) a greenish brown crystal solid. LCMS (ESMS): m / z: 438.5 (M++l).

[0720] CHEMICAL PROPERTY DATA

[0721] Chemical property data for Compounds 3 – 71 are also shown in Table 2 below.

[0722] Table 2. List of Compounds and Properties

[0723] -56- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0724] Ferroptosis LC-MS

[0725] Compound No. Structure Activity ICso (M++l)

[0726] (nM)

[0727] 3 348.4 1.32

[0728] \ / xX

[0729] < > z Z—

[0730] 4 348.4 0.72

[0731] \

[0732] 0

[0733] yy

[0734] 5 lEj 378.7 2.526

[0735] \ 4 Z Z —

[0736] 6 Y ji 401.53 14.77

[0737] 7 413.56 11.79

[0738] a.

[0739] 8 378.4 26.41

[0740] (J "

[0741] 0^

[0742] a,

[0743] H N'^sS

[0744] 9 384.4 10.34

[0745] 4?

[0746]

[0747] -57- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0748] 10 362.5 6.6

[0749] J JU*

[0750] o

[0751] CP

[0752] 11 o. 382.9 2.1

[0753] 0 'Z —

[0754] y

[0755] 'zJUo z^

[0756] 12 376.5 6.9

[0757] _ J \ _ / \ _ f \ i i I r \

[0758] 13 vJ> 349.4 8.7

[0759] 14 362.4 8.8 x l>

[0760] d

[0761] 15 392.5 44.3

[0762] 16 438.5 53.8

[0763]

[0764] -58- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0765] 17 402.5 8.03 18 T V 415.5 40.45

[0766] HN. - 19 YjL / i 413.5 12.86 y 0—

[0767] 6 y1L0

[0768] y^_

[0769] 20 _ _ \ \ _ _ / / z z I X \ \ > ( < zz— 420.5 16.79 vJ*

[0770] 21Cl417.9 32.55

[0771] (X

[0772] HN\ / \

[0773] 22 X I 384.5 12.62

[0774] QHN^x

[0775] 23 L 1 416.5 13.14

[0776] L /

[0777]

[0778] -59- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0779] 24 420.5 10.7

[0780] o —

[0781] 25 473.5 32.29

[0782] / \ \ I I

[0783] 'z z— \ /

[0784] 7 \

[0785] 7 \

[0786] 4

[0787] / 2= X 4

[0788] Q 4°z< /

[0789] 26 X 402.5 5.54

[0790] Q> AA M o kA

[0791] / \ x x ”

[0792] 4)

[0793] _ o

[0794] 27 431.5 20.9

[0795] 28 350.4 27

[0796] QHN'^X

[0797] 29 L 1 / 499.6 4

[0798] A'sx'J

[0799] 30 L 1 443.5 14.53

[0800]

[0801] coH

[0802] -60- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0803] 31 L 1 / 459.5 27.4 o J L JL

[0804] cXOx / NZr

[0805] Q HN. ^.

[0806] 32 -rM 434.5 10.84 z\ / w

[0807] JL r

[0808] 0 _ J

[0809] P °

[0810] Q

[0811] 33 433.4 16.33

[0812] F \ / \z z—N'N

[0813] F^ y PJ°o- / \ / ^L11^ I

[0814] o

[0815] \ o /

[0816] 34 379.4 8.5

[0817] Q

[0818] 35 447.3 4.17

[0819] N~N

[0820] L r

[0821] / N'P

[0822] 36 461.5 15.66

[0823]

[0824] -61- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0825] 37 417.5 <4

[0826] 19 < 9

[0827] ' / \ \ I I

[0828] 38 ( o z—

[0829] HN391.4 9.25 7 \I^V N~N>

[0830] OXJ A o

[0831] yj*

[0832] yyf> <

[0833] 4

[0834] 39 yj* 417.9 28.6 yj*

[0835] \ _ _ / X X \ \ / \z z—

[0836] X o

[0837] 40 T 1 i 451.5 88.61

[0838] QHN\^

[0839] 41 X 432.5 34.38 rv

[0840] 42 403.5 4.24

[0841] Q

[0842] 43 X 403.5 9.42 or

[0843]

[0844] -62- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0845] 44 387.5 26.32

[0846] 45 L 1 416.5 6.39

[0847] A

[0848] J 4>

[0849] ^7

[0850] 0^ 4

[0851] HN ■n

[0852] 46 Y o 1 401.5 4.46

[0853] ) Oz zy-— 4)

[0854] \ _ / \ / X X —

[0855] b 6 ‘xx

[0856] 47 404.4 <4

[0857] 48 402.5 2.02

[0858] QHN-^x

[0859] 49 L 1 410.5 8.58 y J.F

[0860]

[0861] 1

[0862] -63- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0863] Q

[0864] 50 JL JL O F F 417.4 9.26

[0865] Or1 F

[0866] Q HN

[0867] 51 r\. X JL O F F 418.4 18.06

[0868] HN^N^ y V

[0869] / \ \ X X

[0870] ' < > z z ——N-N F

[0871] M H> z

[0872] 52 503.6 9.22

[0873] 53 350.4 73.37

[0874] H

[0875] 0

[0876] 54 439.9 4.21

[0877] °< Y'

[0878] 0

[0879] 55 445.5 4.3

[0880] X

[0881] Q> XA

[0882]

[0883] -64- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0884] 56 0

[0885] 1 417.5 4.28 q P

[0886] A- r~\\ - i i

[0887] 57 ) ( °z~ 363.4 17.62

[0888] . YYY \7N~N

[0889] A

[0890] y Pyz

[0891] 58 397.4 14.97 y}

[0892] _ \ \ _ / / i r < o Vz—

[0893] o

[0894] QHN.

[0895] 59 349.4 11.52 60 417.5 13.99 61 1 402.5 39.87

[0896] 6 ^

[0897]

[0898] -65- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[0899] Q

[0900] 62 364.4 31.48

[0901] 6

[0902] o

[0903] CTJ^A r~\ * /

[0904] 63 400.9 68.47

[0905] - yy

[0906] 6

[0907] A 0A / M

[0908] \ _ / _ \ I X / \ ) \ Z Z z ——— ‘

[0909] Q

[0910] O

[0911] 64 312.3 35.51

[0912] J

[0913] J /

[0914] N

[0915] 65 436.5 35.43

[0916] 66 484.5 11.18

[0917]

[0918] -66- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0919] 67 454.5 4.34

[0920] o o

[0921] O - 7 - 7 - \ k < \ / \ T T / I z.

[0922] 'z z z— / — \ /

[0923] 68 452.5 25.14

[0924] - ^7

[0925] 4)

[0926] J o AV

[0927] Q Q M C>

[0928] ( ) Z z <z

[0929] C \ \ _ / _x / i r ——

[0930] ^

[0931] 69 o I ° 565.7 9.27

[0932] 70 551.7 8.09

[0933] 71 507.51 4.49

[0934]

[0935] Examples 22-41: Pharmaceutical Compositions

[0936] Compound 3 (5 mg) is mixed with 200 mg of Hydroxy lpropyl-0-cyclodextrin to form -67- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0937] a pharmaceutical composition of this disclosure.

[0938] Compound 4 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0939] Compound 5 (5 mg) is mixed with 200 mg of Hydroxy lpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0940] Compound 6 (5 mg) is mixed with 200 mg of Hydroxy lpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0941] Compound 7 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0942] Compound 8 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0943] Compound 9 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0944] Compound 10 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0945] Compound 11 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0946] Compound 12 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0947] Compound 13 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0948] Compound 14 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0949] Compound 15 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0950] Compound 16 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0951] Compound 17 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0952] Compound 18 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0953] Compound 19 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0954] Compound 20 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to -68- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0955] form a pharmaceutical composition of this disclosure.

[0956] Compound 21 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0957] Compound 22 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0958] At least one of Compounds 22-71 (5 mg) is mixed with 200 mg of Hydroxylpropyl-P-cyclodextrin to form a pharmaceutical composition of this disclosure.

[0959] Each of the pharmaceutical compositions is formulated for injection use.

[0960] Examples 42-61: Pharmaceutical Compositions

[0961] Each of the pharmaceutical composition is formulated as tablets with dosages indicated for oral intake.

[0962] Each of Compounds 3 - 71 is formulated into tablets, wherein each single tablet containing 1 mg, 5 mg, 10 mg or 20 mg of the compound. Additional tablets can be formulated similarly with different dosage.

[0963] Example 62: LPS-induced ALI model

[0964] 8-10 weeks old C57 / BL male and female mice were instilled with 50pg LPS (055-B5) at 2.5pl / bwg through orotracheal. Sixteen hours later, lOOpl of FITC-labeled albumin (lOmg / ml) was injected via retro-orbital. Mice were euthanized, and tissue samples were collected 18 hours after the induction of injury' to evaluate lung permeability and histology. Compound 6 was delivered through oral gavage at 10 mg / kg right before ALI induction and at 0.5hr, 2hr or 6hr with the optimal dose determined earlier after the induction of injury to test its therapeutic efficacy. Meanwhile, plasma and bronchoalveolar lavage (BAL) were collected after mice are euthanized.

[0965] Compound 6 demonstrated statistically significant efficacy in the dosing group compared with the vehicle control (FIG. 7).

[0966] Example 63: IRI-AKI model

[0967] Compound 6 was initially dosed of 1, 3, and 10 mg / kgbw for PO administration (via oral gavage). The bilateral IRI AKI model w as used in which both left, and right renal arteries are clamped for 30 min using vascular clamps (Fine Science Tools) through a midline abdominal incision under general anesthesia. The mice were euthanized 24 hours later. Blood samples were collected, and serum contents of creatinine were determined by DetectX serum -69- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0968] creatinine kit, whereas kidneys were sectioned and stained for the Periodic acid-Schiff (PAS) dye for detection of necrotic tissues.

[0969] Result showed that administering Compound 6 orally, at doses of 3mg / kg and 1 Omg / kg at kidney surgery, led to significant reductions in plasma creatinine levels (high creatinine content indicates kidney malfunction) compared to the vehicle control group (FIG.

[0970] 8A). Additionally, PAS staining revealed significant decreases in renal tissue injuries (the loss of the brush border, tubular necrosis, and cast formation) in mice subjected to 3mg / kg or 1 Omg / kg doses of compound 309 (FIGs. 8B-8C).

[0971] Example 64: Mice PK Procedure

[0972] 6 BALB / c mice (Female, 9-11 weeks old) are divided into 2 groups. The first group (1) will be dosed with 3 mg / kg of compound via IV injection. The second group (2) are dosed with 10 mg / kg of compound via oral gavage. Blood samples (25 uL) are taken in 8 time points (5 minutes, 15 minutes, 30 minutes, 1 hour, 2-hour, 4-hour, 8-hour, 24 hours). Plasma samples are analyzed using LC-MS / MS method using the parameter in Table 2. See also FIG. 9.

[0973] Table 2

[0974] Instrument Type Sciex Triple Quad 5500+

[0975] Ionization mode Electrospray, Positive

[0976] Column ACE Excel 5 C4 column (50 mm * 2.1 mm) Mobile Phases A: 5mM NH4OAc (with 0.05% FA )

[0977] Mobile Phase B: ACN (with 0.1% FA ) Column Temperature (°C) 25

[0978]

[0979] Table 3. PK parameter for SN-QX-309

[0980] Route Dose Formulation Tl / 2 AUClast AUClnf Vss CL F (mg / kg) (hour) (hr*ng / mL) (hr*ng / mL) (L / kg) (mL / min / kg) (%) IV 3 DMSO: 5.05 5633 5713 1.44 8.92

[0981] PEG400:

[0982] Aqueous

[0983] solution

[0984] with 20%

[0985] HP-P-CD

[0986]

[0987] -70- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[0988] (5:40:55,

[0989] v:v:v)) with

[0990] HC1

[0991] PO 10 DMSO: 4.49 3165 3226 16.9

[0992] PEG400:

[0993] Aqueous

[0994] solution

[0995] with 20%

[0996] HP-P-CD

[0997] (5:40:55,

[0998] v:v:v)) with

[0999] HC1

[1000]

[1001] Enumerated Embodiments

[1002] The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance:

[1003] R1

[1004] HN X HN^ XX 1^RS

[1005] R

[1006]

[1007] 2^ Embodiment!. A compound of formula (1): (1), wherein: each occurrence of X is independently N or CH;

[1008] Y is a bond, -CH2-, -C(=O), -CH(R4)-, -C(R4)2-, or a combination thereof;

[1009] R1 is C1-C12 alky l, C3-C 12 cycloalkyl, benzy l, Ce-Cio aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl, or a combination thereof;

[1010] R2 is C1-C12 alkyd, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, Ce-Cio aryl, 5- or 6- membered heteroaryl, 5- or 6-membered heterocyclyl, or a combination thereof; R3 is C1-C12 alky l, C2-C 12 alkenyl, C2-C12 alkynyl, Ce-Cio ary l, 5- or 6-membered heteroaryl, 5- or 6-membered heteroary l heterocycly 1, -CH=CHR6, or a combination thereof; each occurrence of R4 is independently C1-C12 alkyl, halogen, CN, or a combination thereof; each occurrence of R5 is independently C1-C12 alkyl, C3-C12 cycloalkyl, C1-C12 alkoxy, or a combination thereof; and

[1011] R6 is ary l, 5- or 6-membered heteroary 1 heteroary l, 5- or 6-membered heteroary 1, 5- or 6- membered heteroaryl heterocyclyl, carbocyclic, -C(=O)NR5R5, -C(=O)(N-linked heterocyclyl), or a combination thereof;

[1012] -71- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[1013] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, benzyl, ary l. heteroaryl, and heterocyclyl is independently optionally substituted;

[1014] a salt thereof, an isomer thereof, or an isotope containing derivative thereof.

[1015] Embodiment 2. The compound of Embodiment 1, wherein R3 is -CEI=CHR6,

[1016] R1

[1017] HN X.

[1018] Y

[1019]

[1020] and the compound has formula (2): (2).

[1021] Embodiments. The compound of any one of Embodiments 1-2, wherein R1 is selected from the group consisting of optionally substituted phenyl, optionally substituted benzy l, optionally substituted cyclohexyl, and optionally substituted heterocyclyl.

[1022] Embodiment 4. The compound of any one of Embodiments 1-3, wherein R1 is selected from the group consisting of:

[1023]

[1024] Embodiment 5. The compound of any one of Embodiments 1-4, wherein R2 is selected from the group consisting of optionally substituted phenyl, optionally substituted benzy l, optionally substituted cyclohexyl, optionally substituted pyridinyl, optionally substituted -CEh-pyridinyl, optionally substituted 1.4-benzodioxinyl, optionally substituted 2,3-dihydrobenzofuranyl, optionally substituted -(CH2)i-2C(=O)N(Ci-Ce alkyl)(Ci-Ce alkyl), optionally substituted -(CEl2)i-2C(=O)(N-linked heterocyclyl), optionally7substituted -(CH2)I-2C(=O)O(CI-C6 alkyl), optionally substituted -(CH2)i-2S(=O)2(Ci-C6 alkyl), optionally substituted -(CH2)i-2NEIC(=O)O(Ci-C6 alkyl), optionally substituted -(CH2)i-2C(=O)NH(heterocyclyl), optionally substituted -(CH2)I-2CN. optionally substituted -(CH2)i-2isoindolinyl-l, 3-dione, and optionally' substituted C2-C6 alkyny l.

[1025] -72- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[1026] Embodiment 6. The compound of any one of Embodiments 1-5, wherein R2 is selected from the group consisting of:

[1027]

[1028] Embodiment 7. The compound of any one of Embodiments 1-6, wherein R3 is selected from the group consisting of optionally substituted oxazolyl, optionally substituted triazolyl, and optionally substituted oxadiazolyl.

[1029] Embodiment 8. The compound of any one of Embodiments 1-6, wherein R3 is -CH=CEIR6, whereon R6 is selected from the group consisting of: -C(=O)NH2, -C(-O)NH(CI-C'6 alkyl), -C(=O)N(CI-C6alkyl)(Ci-C6alkyl), -C(=O)(N-heterocyclyl), and optionally substituted phenyl.

[1030] Embodiment 9. The compound of any one of Embodiments 1-8, wherein R3 is selected from the group consisting of:

[1031] -73- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[1032]

[1033] Embodiment 10. The compound of any one of Embodiments 1-9, wherein the compound is selected from the group consisting of:

[1034] N2-benzyl-Nl-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;

[1035] Nl-benzyl-N2-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;

[1036] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N, N-dimethyl-prop-2-enamide;

[1037] N2-benzyl-Nl-cy cl ohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-di amine;

[1038] N2-benzyl-Nl-cyclohexyl-4-[(E)-2-(4-methoxyphenyl)vinyl]benzene-l,2-diamine;

[1039] Nl-benzyl-N2-(4-methoxycyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[1040] Nl-benzyl-N2-(4,4-difluorocyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[1041] Nl-benzyl-N2-(4-methylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[1042] Nl-[(4-chlorophenyl)methyl]-N2-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;

[1043] Nl-benzyl-N2-(4,4-dimethylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[1044] N2-benzyl-Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-di amine;

[1045] N2-cyclohexyl-4-oxazol-5-yl-Nl-(l-phenylethyl)benzene-l,2-di amine;

[1046] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N-isopropyl-prop-2-enamide;

[1047] Nl-benzyl-N2-cyclohexyl-4-[4-(p-tolyl)triazol-l-yl]benzene-l,2-diamine;

[1048] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)benzene-l,2-diamine; N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]benzamide;

[1049] Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(2-methoxyphenyl)vinyl]benzene-l,2-diamine;

[1050] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-l-morpholino-prop-2-en-l-one;

[1051] N2-benzyl-4-[(E)-2-(2-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-l,2-diamine;

[1052] Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(4-pyridyl)vinyl]benzene-l,2-diamine;

[1053] N 1 -cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-methyl-2-pyridyl)methyl] benzene- -74- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[1054] 1,2-di amine;

[1055] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-fluoro-2-pyridyl)methyl]benzene-l,2-di amine;

[1056] N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]-2,3-dihydro-l,4-benzodioxine-6-carboxamide;

[1057] N2-benzyl-N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;

[1058] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]benzene-l,2-diamine;

[1059] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-(2-pyridylmethyl)benzene-l,2-diamine;

[1060] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[[4-(4-methylpiperazin-l-yl)phenyl]methyl]benzene-l,2-diamine;

[1061] Nl-cyclohexyl-N2-(2,3-dihydrobenzofuran-5-ylmethyl)-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-diamine;

[1062] Nl-cyclohexyl-N2-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-1.2-di amine;

[1063] Nl-cyclohexyl-N2-t(4-morpholinophenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-L2-diamine;

[1064] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[[4-(trifluoromethoxy)phenyl]methyl]benzene- 1,2-di amine;

[1065] Nl-cyclohexyl-N2-[(4-methoxyphenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine;

[1066] Nl-cyclohexyl-N2-[[4-(4-methylpiperazin-l-yl)phenyl]methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine;

[1067] Nl-cyclohexyl-N2-[(3,5-dimethoxyphenyl)methyl]-4-[(E)-2-(4-fluorophenyl)vinyl]benzene- 1,2-di amine;

[1068] 4-[[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]methyl]phenol;

[1069] N 1 -cyclohexyl-N2-(2,3-dihy drobenzofuran-6-ylmethyl)-4-( 1,3,4-oxadiazol-2-yl)benzene- 1,2-di amine;

[1070] N2-benzyl-4-[(E)-2-(3-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-L2-diamine;

[1071] N2-benzyl-Nl-cyclohexyl-4-[(E)-2-[3-(trifluoromethyl)phenyl]vinyl]benzene-l,2-di amine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]pyridine-2,3-diamine;

[1072] N2-benzyl-4-[(E)-2-(4-fluorophenyl)vinyl]-Nl-tetrahydropyran-4-yl-benzene-l,2-diamine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)pyridine-2,3-diamine;

[1073] -75- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[1074] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-phenyl-benzene-l,2-diamine;

[1075] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[2-(2-pyridyl)ethyl]benzene-1.2-di amine; Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-diamine;

[1076] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-tetrahydropyran-4-yl-pyridine-2,3-di amine; N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;

[1077] 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-N. N-dimethyl-propanamide; N2-benzyl-Nl-cyclohexyl-4-[5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl]benzene-l,2-diamine; N2-benzyl-N3-cy clohexyl-6-[5-(tri fluoromethyl)-!, 3, 4-oxadiazol-2-yl]pyridine-2,3-di amine; tert-butyl 4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]piperidine-l-carboxylate;

[1078] N2-benzyl-N3-cyclohexyl-6-(l,3,4-oxadiazol-2-yl)pyridine-2,3-diamine;

[1079] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(4-piperidyl)pyridine-2,3-diamine;hydrochloride;

[1080] 1-[4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-l-piperidyl]ethenone;

[1081] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(l-methyl-4-piperidyl)pyridine-2,3-diamine; N2-benzyl-Nl-cyclohexyl-4-(5-methyl-l,3,4-oxadiazol-2-yl)benzene-l,2-diamine; methyl 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoate;

[1082] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-prop-2-ynyl-benzene-l,2-di amine;

[1083] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-methylsulfonylethyl)benzene-1.2-diamine;

[1084] N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;

[1085] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-l,2-diamine;

[1086] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-1.2-diamine;hydrochloride;

[1087] 3-[2-(cyclohexylamino)-5-(l,3,4-oxadiazol-2-yl)anilino]propanenitrile;

[1088] 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-l-pyrrolidin-l-yl-propan-l-one;

[1089] 2-[2-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]ethyl]isoindoline- 1,3-dione;

[1090] tert-butyl N-[2-[2-(cyclohexylamino)-5-[(E)-2-(4-fluoropheny l)vinyl] anilino] ethyl] carbamate:

[1091] 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-l-morpholino-propan-l-one; tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4- -76- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[1092] fluorophenyl)vinyl]anilino]propanoylamino]piperidine-l -carboxylate;

[1093] tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoyl]piperazine-l-carboxylate;

[1094] [4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-l-piperidyl]-phenyl-methanone;

[1095] N2-benzyl-Nl-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;

[1096] N 1 -benzyl-N2-cy clohexyl-4-oxazol-5-yl-benzene- 1,2-diamine;

[1097] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N, N-dimethyl-prop-2-enamide;

[1098] N2-benzyl-Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-diamine;

[1099] N2-benzyl-Nl-cyclohexyl-4-[(E)-2-(4-methoxyphenyl)vinyl]benzene-l,2-diamine;

[1100] N 1 -benzyl-N2-(4-methoxy cyclohexyl)-4-oxazol-5-yl-benzene- 1,2-diamine;

[1101] N1 -benzyl-N2-(4,4-difluorocy cl ohexyl)-4-oxazol-5-yl-benzene- 1,2-di amine;

[1102] Nl-benzyl-N2-(4-methylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[1103] N 1 - [(4-chloropheny l)methyl] -N2-cy clohexyl-4-oxazol-5-yl-benzene- 1,2-diamine;

[1104] Nl-benzyl-N2-(4,4-dimethylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[1105] N2-benzyl-Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-di amine;

[1106] N2-cyclohexyl-4-oxazol-5-yl-Nl-(l-phenylethyl)benzene-l,2-di amine;

[1107] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N-isopropyl-prop-2-enamide;

[1108] N 1 -benzyl-N2-cy clohexyl-4-[4-(p-tolyl)triazol- 1 -yl]benzene- 1,2-diamine;

[1109] Nl-cy cl ohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)benzene-1.2-di amine; N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]benzamide;

[1110] Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(2-methoxyphenyl)vinyl]benzene-l,2-diamine;

[1111] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-l-morpholino-prop-2-en-l-one;

[1112] N2-benzyl-4-[(E)-2-(2-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-l,2-diamine;

[1113] Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(4-pyridyl)vinyl]benzene-l,2-diamine;

[1114] Nl-cy clohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-methyl-2-pyridyl)methyl]benzene-1,2-di amine;

[1115] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-fluoro-2-pyridyl)methyl]benzene-l,2-diamine;

[1116] N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]-2,3-dihydro-l,4-benzodioxine-6-carboxamide;

[1117] N2-benzyl-N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;

[1118] Nl-cy clohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]benzene- 1,2-di amine;

[1119] -77- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[1120] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-(2-pyridylmethyl)benzene-l,2-diamine;

[1121] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[[4-(4-methylpiperazin-l-yl)phenyl]methyl]benzene-l,2-diamine;

[1122] Nl-cyclohexyl-N2-(2,3-dihydrobenzofuran-5-ylmethyl)-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-di amine;

[1123] Nl-cyclohexyl-N2-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-4-[(E)-2-(4-fluorophenyl)vinyl]benzene- 1,2-di amine;

[1124] Nl-cyclohexyl-N2-[(4-morpholinophenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine;

[1125] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[[4-(trifluoromethoxy)phenyl]methyl]benzene-1,2-di amine;

[1126] Nl-cyclohexyl-N2-[(4-methoxyphenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-L2-diamine;

[1127] Nl-cyclohexyl-N2-[[4-(4-methylpiperazin-l-yl)phenyl]methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine;

[1128] Nl-cyclohexyl-N2-t(3,5-dimethoxyphenyl)methyl]-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-1,2-di amine;

[1129] 4-[[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]methyl]phenol;

[1130] Nl-cyclohexyl-N2-(2,3-dihydrobenzofuran-6-ylmethyl)-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine;

[1131] N2-benzyl-4-[(E)-2-(3-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-l,2-diamine;

[1132] N2-benzyl-Nl-cyclohexyl-4-[(E)-2-[3-(trifluoromethyl)phenyl]vinyl]benzene-l,2-di amine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]pyridine-2,3-di amine;

[1133] N2-benzyl-4-[(E)-2-(4-fluorophenyl)vinyl]-Nl-tetrahydropyran-4-yl-benzene-l,2-di amine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)pyridine-2,3-diamine; Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-phenyl-benzene-l,2-diamine;

[1134] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[2-(2-pyridyl)ethyl]benzene-l,2-diamine; Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-diamine;

[1135] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-tetrahydropyran-4-yl-pyridine-2,3-di amine; N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;

[1136] 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-N, N-dimethyl-propanamide; N2-benzyl-Nl-cyclohexyl-4-[5-(trifluoromethyl)-1.3.4-oxadiazol-2-yl]benzene-l,2-diamine; N2-benzyl-N3-cyclohexyl-6-[5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl]pyridine-2,3-diamine;

[1137] -78- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[1138] tert-butyl 4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]piperidine-l-carboxylate;

[1139] N2-benzyl-N3-cyclohexyl-6-(l,3,4-oxadiazol-2-yl)pyridine-2,3-diamine;

[1140] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(4-piperidyl)pyridine-2,3-diamine;hydrochloride;

[1141] 1-[4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-l-piperidyl]ethenone;

[1142] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(l-methyl-4-piperidyl)pyridine-2,3-diamine; N2-benzyl-Nl-cyclohexyl-4-(5-methyl-l,3,4-oxadiazol-2-yl)benzene-l,2-diamine; methyl 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoate;

[1143] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-prop-2-ynyl-benzene-l,2-diamine;

[1144] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-methylsulfonylethyl)benzene-l,2-diamine;

[1145] N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;

[1146] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-1.2-diamine;

[1147] N1-cyclohexyl-4-(1,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-1,2-diamine;hydrochloride;

[1148] 3-[2-(cyclohexylamino)-5-(l,3,4-oxadiazol-2-yl)anilino]propanenitrile;

[1149] 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-l-pyrrolidin-l-yl-propan-l-one;

[1150] 2-[2-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]ethyl]isoindoline- 1,3-dione;

[1151] tert-butyl N-[2-[2-(cyclohexylamino)-5-[(E)-2-(4-fluoropheny l)vinyl] anilino] ethyl] carbamate:

[1152] 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-l-morpholino-propan-l-one; tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoylamino]piperidine-l -carboxylate;

[1153] tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoyl]piperazine-1-carboxylate;

[1154] [4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-l-piperidyl]-phenyl-methanone;

[1155] a salt thereof, an isomer thereof, or an isotope containing derivative thereof.

[1156] Embodiment 11. A pharmaceutical composition comprising a compound of any one of Embodiments 1-10, a salt thereof, an isomer thereof, or an isotope containing

[1157] -79- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[1158] derivative thereof, and at least one pharmaceutically acceptable excipient.

[1159] Embodiment 12. The pharmaceutical composition of Embodiment 11. wherein R1 HN., X..x

[1160]

[1161] R3 is -CH=CHR6, and the compound has formula (2): (2).

[1162] Embodiment 13. The pharmaceutical composition of any one of Embodiments 11-12, wherein the compound is selected from the group consisting of:

[1163] N2-benzyl-Nl-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;

[1164] Nl-benzyl-N2-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;

[1165] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N, N-dimethyl-prop-2-enamide;

[1166] N2-benzyl-Nl-cy cl ohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-di amine;

[1167] N2-benzyl-Nl-cyclohexyl-4-[(E)-2-(4-methoxyphenyl)vinyl]benzene-l,2-diamine;

[1168] N1 -benzyl-N2-(4-methoxycy cl ohexy l)-4-oxazol-5-yl-benzene- 1,2-di amine;

[1169] Nl-benzyl-N2-(4,4-difluorocyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[1170] Nl-benzyl-N2-(4-methylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[1171] Nl-[(4-chlorophenyl)methyl]-N2-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;

[1172] Nl-benzyl-N2-(4,4-dimethylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;

[1173] N2-benzyl-Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-di amine;

[1174] N2-cyclohexyl-4-oxazol-5-yl-Nl-(l-phenylethyl)benzene-l,2-di amine;

[1175] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N-isopropyl-prop-2-enamide;

[1176] Nl-benzyl-N2-cyclohexyl-4-[4-(p-tolyl)triazol-l-yl]benzene-l,2-diamine;

[1177] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)benzene-l,2-diamine; N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]benzamide;

[1178] Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(2-methoxyphenyl)vinyl]benzene-l,2-diamine;

[1179] (E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-l-morpholino-prop-2-en-l-one;

[1180] N2-benzyl-4-[(E)-2-(2-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-l,2-diamine;

[1181] N1 -benzyl-N2-cyclohexyl-4-[(E)-2-(4-pyridyl)vinyl]benzene-l,2-diamine;

[1182] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-methyl-2-pyridyl)methyl]benzene-1,2-di amine;

[1183] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-fluoro-2-pyridyl)methyl]benzene-l,2-diamine;

[1184] -80- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[1185] N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]-2,3-dihydro-l,4-benzodioxine-6-carboxamide;

[1186] N2-benzyl-N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;

[1187] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]benzene-l,2-di amine;

[1188] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-(2-pyridylmethyl)benzene-l,2-diamine;

[1189] N1 -cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[[4-(4-methylpiperazin-l -yl)phenyl]methyl]benzene-l,2-diamine;

[1190] Nl-cyclohexyl-N2-(2,3-dihydrobenzofuran-5-ylmethyl)-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-di amine;

[1191] Nl-cyclohexyl-N2-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-4-[(E)-2-(4-fluorophenyl)vinyl]benzene- 1,2-di amine;

[1192] Nl-cyclohexyl-N2-[(4-morpholinophenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine;

[1193] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[[4-(trifluoromethoxy)phenyl]methyl]benzene- 1,2-di amine;

[1194] Nl-cyclohexyl-N2-[(4-methoxyphenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-di amine;

[1195] N1 -cy clohexyl-N2- [ [4-(4-methy Ipiperazin- 1 -yl)phenyl]methy l]-4-( 1,3,4-oxadiazol-2-yl)benzene-l,2-diamine;

[1196] Nl-cyclohexyl-N2-[(3,5-dimethoxyphenyl)methyl]-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-1,2-di amine;

[1197] 4-[[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]methyl]phenol;

[1198] Nl-cyclohexyl-N2-(2,3-dihydrobenzofuran-6-ylmethyl)-4-(1.3.4-oxadiazol-2-yl)benzene-l,2-diamine;

[1199] N2-benzyl-4-[(E)-2-(3-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-l,2-di amine;

[1200] N2-benzyl-Nl-cyclohexyl-4-[(E)-2-[3-(trifluoromethyl)phenyl]vinyl]benzene-l,2-di amine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]pyridine-2,3-diamine;

[1201] N2-benzyl-4-[(E)-2-(4-fluorophenyl)vinyl]-Nl-tetrahydropyran-4-yl-benzene-l,2-diamine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)pyridine-2,3-diamine; Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-phenyl-benzene-l,2-diamine;

[1202] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[2-(2-pyridyl)ethyl]benzene-1.2-di amine; Nl-benzyl-N2-cy cl ohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene- 1,2-di amine;

[1203] -81- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[1204] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-tetrahydropyran-4-yl-pyridine-2,3-di amine; N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;

[1205] 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-N, N-dimethyl-propanamide: N2-benzyl-Nl-cyclohexyl-4-[5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl]benzene-l,2-diamine; N2-benzyl-N3-cyclohexyl-6-[5-(tri fluoromethyl)-!, 3, 4-oxadiazol-2-yl]pyridine-2,3-di amine; tert-butyl 4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]piperidine-l-carboxylate;

[1206] N2-benzyl-N3-cyclohexyl-6-(l,3,4-oxadiazol-2-yl)pyridine-2,3-diamine;

[1207] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(4-piperidyl)pyridine-2,3-diamine;hydrochloride;

[1208] 1-[4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-l-piperidyl]ethenone;

[1209] N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(l-methyl-4-piperidyl)pyridine-2,3-diamine; N2-benzyl-Nl-cyclohexyl-4-(5-methyl-l,3,4-oxadiazol-2-yl)benzene-l,2-diamine; methyl 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoate;

[1210] Nl-cyclohexyl-4-t(E)-2-(4-fluorophenyl)vinyl]-N2-prop-2-ynyl-benzene-l,2-diamine;

[1211] Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-methylsulfonylethyl)benzene-l,2-diamine;

[1212] N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-!luorophenyl)vinyl]pyridine-2,3-diamine;

[1213] Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-1.2-diamine;

[1214] N1 -cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-l,2-diamine;hydrochloride;

[1215] 3-[2-(cyclohexylamino)-5-(l,3,4-oxadiazol-2-yl)anilino]propanenitrile;

[1216] 3- [2-(cy clohexylamino)-5 - [(E)-2-(4-fluorophenyl) vinyl] anilino] - 1 -pyrrolidin- 1 -y 1-propan- 1 -one;

[1217] 2-[2-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]ethyl]isoindoline-l,3-dione;

[1218] tert-butyl N-[2-[2-(cyclohexylamino)-5-[(E)-2-(4-fluoropheny 1 ) v iny 1 ] anilino] ethyl] carbamate:

[1219] 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-l-morpholino-propan-l-one; tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoylamino]piperidine-l -carboxylate;

[1220] tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoyl]piperazine-l-carboxylate;

[1221] -82- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[1222] [4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-l-piperidyl]-phenyl-methanone;

[1223] a salt thereof, an isomer thereof, an isotope containing derivative thereof, and combinations thereof.

[1224] Embodiment 14. The pharmaceutical composition of any one of Embodiments 11-13, wherein the pharmaceutical composition is formulated for injection administration, oral administration, inhalational administration, topical administration, or combinations thereof.

[1225] Embodiment 15. The pharmaceutical composition of any one of Embodiments 11-14, wherein the pharmaceutical composition is formulated for an administration route selected from the group consisting of oral, intracranial, nasal, intranasal, rectal, transrectal. parenteral, sublingual, transdermal, transmucosal, urethral, transurethral, vaginal, intravesical, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous (IV), intrabronchial, inhalation, and topical.

[1226] Embodiment 16. The pharmaceutical composition of any one of Embodiments 11-1, wherein the pharmaceutical composition is formulated for treatment of post-stroke brain ischemia-reperfusion injury (IRI), ischemia-reperfusion injury (IRI) not caused by poststroke brain ischemia, ischemic heart diseases, lung injury related to a coronavirus infection, SARS-CoV infection, SARS-CoV-2 infection (COVID-19), Middle Eastern respiratory syndrome (MERS), acute lung injury (ALT), acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), kidney injury', respiratory' illness due to alveolar damage, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, inflammatory bowel disease (IBD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), Sedaghatian-type spondylometaphyseal dysplasia (SSMD), organ injury due to vascular leakage during sepsis or heme release, iron-overloading diseases, neurodegenerative diseases, Huntington’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), chronic kidney disease (CKD), kidney fibrosis, traumatic brain injury, tumor, or combinations thereof.

[1227] Embodiment 17. The pharmaceutical composition of any one of Embodiments 11-16, wherein the at least one pharmaceutically acceptable excipient comprises acacia, animal oils, benzyl alcohol, benzyl benzoate, calcium stearate, carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol, cyclodextrins, dextrose, diethanolamine, emulsifying wax, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glycerol stearate, glyceryl -83- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[1228] monooleate, glyceryl monostearate, hydrous, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-P-cyclodextrin (HPBCD). hypromellose (hydroxypropyl methylcellulose (HPMC)), lanolin, lanolin alcohols, lecithin, medium-chain triglycerides, metallic soaps, methyl cellulose, mineral oil, monobasic sodium phosphate, monoethanolamine, oleic acid, polyy ethylene glycols (PEG 3350, PEG 4000, PEG 6000), polyoxyethylene-polyoxypropylene copolymer (poloxamer), polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polysorbate, polyoxyethylene (20) sorbitan monolaurate (Tween 20, Polysorbate 20), polyoxyethylene (20) sorbitan monooleate (Tween 80, Polysorbate 80), povidone, propylene glycol alginate, saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium hydroxide, sodium lauryl sulfate, sodium phosphate monobasic, sodium phosphate dibasic, sorbitan esters, stearic acid, stearyl alcohol, sunflower oil, tragacanth, triethanolamine, vegetable oils, water, xanthan gum, or combinations thereof.

[1229] Embodiment 18. The pharmaceutical composition of Embodiment 17, wherein the at least one pharmaceutically acceptable excipient comprises dextrose, glycerin, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-P-cyclodextrin (HPBCD), hypromellose (hydroxypropyl methylcellulose (HPMC)), polyoxyethylene (20) sorbitan monolaurate (Tween 20, Polysorbate 20), polyy ethylene glycols (PEG 400, PEG 3350, PEG 4000, PEG 6000), poly oxy ethylene-poly oxypropylene copolymer (Poloxamer 188.

[1230] Poloxamer 407). polyoxyethylene (20) sorbitan monooleate (Tween 80, Polysorbate 80). saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium lauryl sulfate, sodium phosphate monobasic, sodium phosphate dibasic, or combinations thereof.

[1231] Embodiment 19. The pharmaceutical composition of any one of Embodiments 11-18, further comprising at least one active pharmaceutical ingredient.

[1232] Embodiment 20. A method for treating, ameliorating, and / or preventing a disease or disorder in a subject in need thereof, the method comprising administering an effective amount of a pharmaceutical composition of any one of Embodiments 11-19 to the subject,

[1233] wherein the disease or disorder comprises post-stroke brain ischemia-reperfusion injury (IRI), ischemia-reperfusion injury (IRI) not caused by post-stroke brain ischemia, ischemic heart diseases, lung injury related to a coronavirus infection, SARS-CoV infection, SARS-CoV-2 infection (COVID- 19), Middle Eastern respiratory syndrome (MERS), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), kidney injury, respiratory illness due to alveolar damage, chronic obstructive pulmonary -84- 56802210 1 Attorney Docket No. 047162-7600W01(02785)

[1234] disease (COPD), asthma, cystic fibrosis, inflammatory bowel disease (IBD), idiopathic pulmonary fibrosis (IPF), pulmonary’ arterial hypertension (PAH), Sedaghatian-type spondylometaphyseal dysplasia (SSMD), organ injury due to vascular leakage during sepsis or heme release, iron-overloading diseases, neurodegenerative diseases, Huntington’s disease, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), chronic kidney disease (CKD), kidney fibrosis, traumatic brain injury, tumor, or combinations thereof.

[1235] Embodiment 21. The method of Embodiment 20, wherein the pharmaceutical composition is administered to the subject via an administration route comprising oral, intracranial, nasal, intranasal, rectal, transrectal, parenteral, sublingual, transdermal, transmucosal, urethral, transurethral, vaginal, intravesical, intravesical, intrapulmonary, intraduodenal, intragastrical. intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous (IV), intrabronchial, inhalation, topical, intravenous (IV) injection, subcutaneous (SC) injection, intramuscular (IM) injection, intradermal (ID) injection, oral, aerosol or combinations thereof.

[1236] Embodiment 22. The method of Embodiment 21, wherein the pharmaceutical composition is administered to the subject in combination with at least one additional medication or treatment.

[1237] Embodiment 23. Use of a compound of any one of Embodiments 1-10, or a salt thereof, an isomer thereof, an isotope containing derivative thereof, and combinations thereof, for manufacturing of a medicament for the treatment, ameliorating, and / or preventing a disease or disorder in a subject in need thereof, wherein the disease or disorder is selected from post-stroke brain ischemia-reperfusion injury (IRI), ischemia-reperfusion injury' (IRI) not caused by post-stroke brain ischemia, ischemic heart diseases, lung injury related to a coronavirus infection, SARS-CoV infection, SARS-CoV-2 infection (COVID-19). Middle Eastern respiratory syndrome (MERS), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), kidney injury, respiratory illness due to alveolar damage, chronic obstructive pulmonary disease (COPD), asthma, cy stic fibrosis, idiopathic pulmonary’ fibrosis (IPF), pulmonary arterial hypertension (PAH), Sedaghatian-type spondylometaphyseal dysplasia (SSMD). organ injury due to vascular leakage during sepsis or heme release, iron-overloading diseases, neurodegenerative diseases, Huntington’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), chronic kidney disease (CKD), kidney fibrosis, traumatic brain injury, tumor, or combinations thereof.

[1238] The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding -85- 56802210 1 Attomey Docket No. 047162-7600W01(02785)

[1239] any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application.

[1240] -86- 56802210 1

Claims

Attomey Docket No. 047162-7600W01(02785)CLAIMSWhat is claimed is:

1. A compound of formula (1):R1wherein:each occurrence of X is independently N or CH;Y is a bond, -CH2-. -C(=O), -CH(R4)-. -C(R4)2-, or a combination thereof; R1 is Ci-C 12 alkyl, C3-C12 cycloalkyl, benzyl, Ce-Cio and, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl;R2 is C1-C12 alky l, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, Ce-Cio aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl; R3 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Ce-Cio aryl, 5- or 6- membered heteroaryl, 5- or 6-membered heteroaryl heterocyclyl, or - CH=CHR6;each occurrence of R4 is independently C1-C12 alkyl, halogen, or CN; each occurrence of R5 is independently C1-C12 alkyl, C3-C12 cycloalkyl, or Ci- C12 alkoxy; andR6 is aryl, 5- or 6-membered heteroaryl heteroaryl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroaryl heterocyclyl, carbocyclic, - C(=O)NR5R5, or -C(=O)(N-linked heterocyclyl);wherein each alkyl, alkenyl, alkynyl, cycloalkyl, benzyl, aryl, heteroaryl, and heterocyclyl is independently optionally substituted;a salt thereof, an isomer thereof, or an isotope containing derivative thereof.

2. The compound of claim 1, wherein R3 is -CH=CHR6, and the compound has formula (2):-87- 56802210 1Attorney Docket No. 047162-7600W01(02785)R1HN XR2(2).

3. The compound of any one of claims 1-2. wherein R1 is selected from the group consisting of optionally substituted phenyl, optionally substituted benzy l, optionally substituted cyclohexyl, and optionally substituted heterocyclyl.

4. The compound of any one of claims 1-3. wherein R1 is selected from the group consisting of:

5. The compound of any one of claims 1-4. wherein R2 is selected from the group consisting of optionally substituted phenyl, optionally substituted benzy l, optionally substituted cyclohexyl, optionally substituted pyridinyl, optionally substituted -CH2- pyridinyl, optionally substituted 1,4-benzodioxinyl, optionally substituted 2,3- dihydrobenzofuranyl, optionally substituted -(CH2)i-2C(=O)N(Ci-Ce alkyl)(Ci-C6 alkyl), optionally substituted -(CH2)i-2C(=O)(N-linked heterocyclyl), optionally substituted -(CH2)i-2C(=O)O(Ci-Ce alkyl), optionally substituted - (CH2)i-2S(=O)2(Ci-Ce alky l), optionally substituted -(CH2)I-2NHC(=O)O(CI-C6 alkyl), optionally substituted -(CH2)i-2C(=O)NH(heterocyclyl), optionally substituted -(CH2)I-2CN. optionally substituted -(CH2)i-2isoindolinyl-l, 3-dione, and optionally substituted C2-C6 alkynyl.-88- 56802210 1Attorney Docket No. 047162-7600W01(02785)6. The compound of any one of claims 1-5. wherein R2 is selected from the group consisting of:

7. The compound of any one of claims 1-6. wherein R3 is selected from the group consisting of optionally substituted oxazolyl, optionally substituted triazolyL and optionally substituted oxadiazolyl.

8. The compound of any one of claims 1-6. wherein R3 is -CH=CHR6, whereon R6 is selected from the group consisting of: -C(=O)NH2, -C(=O)NH(Ci-Ce alkyl). - C(=O)N(CI-C6 alkyl)(Ci-C6 alkyl), -C(=O)(N-heterocyclyl), and optionally substituted phenyl.-89- 56802210 1Attorney Docket No. 047162-7600W01(02785)9. The compound of any one of claims 1-8. wherein R3 is selected from the group consisting of:Cl10. The compound of any one of claims 1-9. wherein the compound is selected from the group consisting of:N2-benzyl-Nl-cyclohexyl-4-oxazol-5-yl-benzene-E2-diamine;Nl-benzyl-N2-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;(E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N, N-dimethyl-prop-2-enamide;N2-benzyl-Nl-cy cl ohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-di amine;N2-benzyl-Nl-cyclohexyl-4-L(E)-2-(4-methoxyphenyl)vinylJbenzene-l,2-diamine;Nl-benzyl-N2-(4-methoxycyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;Nl-benzyl-N2-(4,4-difluorocyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;Nl-benzyl-N2-(4-methylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;Nl-[(4-chlorophenyl)methyl]-N2-cyclohexyl-4-oxazol-5-yl-benzene-1.2-diamine;N1 -benzyl-N2-(4,4-dimethylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;N2-benzyl-Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine;N2-cy clohexyl-4-oxazol-5 -y 1-N 1 -( 1 -pheny lethy l)benzene- 1,2-di amine;(E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N-isopropyl-prop-2-enamide;Nl-benzyl-N2-cy cl ohexyl-4-[4-(p-tolyl)tri azol- 1-yl] benzene- 1,2-di amine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)benzene-l,2-diamine; N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]benzamide;Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(2-methoxyphenyl)vinyl]benzene-l,2-diamine;(E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-l-morpholino-prop-2-en-l-one;-90- 56802210 1Attomey Docket No. 047162-7600W01(02785)N2-benzyl-4-[(E)-2-(2-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-l,2-diamine;Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(4-pyridyl)vinyl]benzene-l,2-diamine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-methyl-2-pyridyl)methyl]benzene- 1,2-di amine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-fluoro-2-pyridyl)methyl]benzene-l,2-di amine;N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]-2,3-dihydro-l,4-benzodioxine-6-carboxamide;N2-benzyl-N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]benzene-l,2-diamine;Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-(2-pyridylmethyl)benzene-l,2-diamine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[[4-(4-methylpiperazin-l-yl)phenyl]methyl]benzene-l,2-diamine;Nl-cyclohexyl-N2-(2,3-dihydrobenzofuran-5-ylmethyl)-4-[(E)-2-(4-fluorophenyl)vinyl]benzene- 1,2-di amine;Nl-cyclohexyl-N2-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-di amine;Nl-cyclohexyl-N2-[(4-morpholinophenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine;N1 -cyclohexyl-4-( 1,3, 4-oxadiazol-2-yl)-N2-[[4-(tri fluoromethoxy )ph enyl] methyl] benzene- 1,2-di amine;Nl-cyclohexyl-N2-[(4-methoxyphenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine;Nl-cyclohexyl-N2-[[4-(4-methylpiperazin-l-yl)phenyl]methyl]-4-(l,3,4-oxadiazol-2-yl)benzene- 1,2-diamine;Nl-cyclohexyl-N2-[(3,5-dimethoxyphenyl)methyl]-4-[(E)-2-(4-fluorophenyl)vinyl]benzene- 1,2-di amine;4-[[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]methyl]phenol;Nl-cyclohexyl-N2-(2,3-dihydrobenzofuran-6-ylmethyl)-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine;N2-benzyl-4-[(E)-2-(3-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-l,2-diamine;N2-benzyl-Nl-cyclohexyl-4-[(E)-2-[3-(trifluoromethyl)phenyl]vinyl]benzene-l,2-di amine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]pyridine-2,3- -91- 56802210 1Attomey Docket No. 047162-7600W01(02785)diamine;N2-benzyl-4-[(E)-2-(4-fluorophenyl)vinyl]-Nl-tetrahydropyran-4-yl-benzene-l,2-diamine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)pyridine-2,3-diamine; Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-phenyl-benzene-l,2-diamine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[2-(2-pyridyl)ethyl]benzene-l,2-di amine; N1-benzyl-N2-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-1,2-diamine;N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-tetrahydropyran-4-yl-pyridine-2 -di amine; N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-N, N-dimethyl-propanamide; N2-benzyl-Nl-cyclohexyl-4-[5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl]benzene-l,2-diamine; N2-benzyl-N3-cyclohexyl-6-[5-(tri fluoromethyl)-!.3.4-oxadiazol-2-yl]pyridine-2,3-di amine; tert-butyl 4- [[2-(benzylamin o)-6-[(E)-2-(4-fluorophenyl)vinyl] -3 -pyridyl] amino] piperidine- 1-carboxylate;N2-benzyl-N3-cyclohexyl-6-(l,3,4-oxadiazol-2-yl)pyridine-2,3-diamine;N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(4-piperidyl)pyridine-2,3-diamine;hydrochloride;1-[4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-l-piperidyl] ethenone;N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(l-methyl-4-piperidyl)pyridine-2,3-di amine; N2-benzyl-Nl-cyclohexyl-4-(5-methyl-l,3,4-oxadiazol-2-yl)benzene-l,2-diamine; methyl 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoate;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-prop-2-ynyl-benzene-l,2-di amine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-methylsulfonylethyl)benzene-l,2-di amine;N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-l,2-diamine;Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-l,2-diamine;hydrochloride;3-[2-(cyclohexylamino)-5-(l,3,4-oxadiazol-2-yl)anilino]propanenitrile;3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-l-pyrrolidin-l-yl-propan-l-one;2-[2-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]ethyl]isoindoline-l,3-dione;tert-butyl N-[2-[2-(cyclohexylamino)-5-[(E)-2-(4- -92- 56802210 1Attomey Docket No. 047162-7600W01(02785)fluoropheny l)vinyl] anilino] ethyl] carbamate:3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]- 1 -morpholino-propan- 1-one; tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoylamino]piperidine-l -carboxylate;tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)viny 1] anilino] propanoyl]piperazine- 1 -carboxylate;[4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-l-piperidyl]-phenyl-methanone;N2-benzyl-Nl-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;Nl-benzyl-N2-cyclohexyl-4-oxazol-5-yl-benzene-l,2-di amine;(E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N, N-dimethyl-prop-2-enamide;N2-benzyl-Nl-cy cl ohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-di amine;N2-benzyl-Nl-cyclohexyl-4-[(E)-2-(4-methoxyphenyl)vinyl]benzene-l,2-diamine;Nl-benzyl-N2-(4-methoxycyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;Nl-benzyl-N2-(4,4-difluorocyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;Nl-benzyl-N2-(4-methylcyclohexyl)-4-oxazol-5-yl-benzene-L2-di amine;Nl-[(4-chlorophenyl)methyl]-N2-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;Nl-benzyl-N2-(4,4-dimethylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;N2-benzyl-Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-di amine;N2-cyclohexyl-4-oxazol-5-yl-Nl-(l-phenylethyl)benzene-l,2-di amine;(E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N-isopropyl-prop-2-enamide;Nl-benzyl-N2-cyclohexyl-4-[4-(p-tolyl)triazol-l-yl]benzene-l,2-diamine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)benzene-l,2-diamine; N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]benzamide;Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(2-methoxyphenyl)vinyl]benzene-l,2-diamine;(E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-l-morpholino-prop-2-en-l-one;N2-benzyl-4-[(E)-2-(2-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-l,2-diamine;Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(4-pyridyl)vinyl]benzene-l,2-diamine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-methyl-2-pyridyl)methyl]benzene-1,2-di amine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-fluoro-2-pyridyl)methyl]benzene-l,2-diamine;N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]-2.3-dihydro-l,4-benzodioxine-6-carboxamide;-93- 56802210 1Attomey Docket No. 047162-7600W01(02785)N2-benzyl-N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]benzene-l,2-di amine;Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-(2-pyridylmethyl)benzene-l,2-diamine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[[4-(4-methylpiperazin-l-yl)phenyl]methyl]benzene-l,2-diamine;Nl-cyclohexyl-N2-(2,3-dihydrobenzofuran-5-ylmethyl)-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-diamine;Nl-cyclohexyl-N2-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-di amine;Nl-cyclohexyl-N2-[(4-morpholinophenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-di amine;Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[[4-(trifluoromethoxy)phenyl]methyl]benzene-1,2-di amine;Nl-cyclohexyl-N2-[(4-methoxyphenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine;Nl-cyclohexyl-N2-[[4-(4-methylpiperazin-l-yl)phenyl]methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine;Nl-cyclohexyl-N2-[(3,5-dimethoxyphenyl)methyl]-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-1,2-di amine;4-[[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]methyl]phenol;Nl-cyclohexyl-N2-(2,3-dihydrobenzofuran-6-ylmethyl)-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-di amine;N2-benzyl-4-[(E)-2-(3-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-l,2-diamine;N2-benzyl-Nl-cyclohexyl-4-[(E)-2-[3-(trifluoromethyl)phenyl]vinyl]benzene-l,2-di amine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]pyridine-2,3-diamine;N2-benzyl-4-[(E)-2-(4-fluorophenyl)viny 1] -N 1 -tetrahy dropyran-4-yl-benzene- 1,2-diamine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)pyridine-2,3-diamine; Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-phenyl-benzene-l,2-diamine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[2-(2-pyridyl)ethyl]benzene-l,2-di amine; N1 -benzyl -N2-cy cl ohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene- 1,2-di amine;N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-tetrahydropyran-4-yl-pyridine-2,3-di amine; N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;-94- 56802210 1Attomey Docket No. 047162-7600W01(02785)3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-N, N-dimethyl-propanamide; N2-benzyl-Nl-cyclohexyl-4-[5-(trifluoromethyl)-1.3.4-oxadiazol-2-yl]benzene-l,2-diamine; N2-benzyl-N3-cy clohexyl-6-[5-(tri fluoromethyl)-!, 3, 4-oxadiazol-2-yl]pyridine-2,3-di amine; tert-butyl 4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]piperidine-l-carboxylate;N2-benzyl-N3-cyclohexyl-6-(l,3,4-oxadiazol-2-yl)pyridine-2,3-diamine;N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(4-piperidyl)pyridine-2,3-diamine;hydrochloride;1-[4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-1-piperidyl]ethenone;N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(l-methyl-4-piperidyl)pyridine-2,3-diamine; N2-benzyl-Nl-cyclohexyl-4-(5-methyl-l,3,4-oxadiazol-2-yl)benzene-l,2-diamine; methyl 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoate;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-prop-2-ynyl-benzene-l,2-di amine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-methylsulfonylethyl)benzene-1.2-diamine;N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-l,2-diamine;Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-1.2-diamine;hydrochloride;3-[2-(cyclohexylamino)-5-(l,3,4-oxadiazol-2-yl)anilino]propan enitrile;3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-l-pyrrolidin-l-yl-propan-l-one;2-[2-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]ethyl]isoindoline-1.3-dione;tert-butyl N-[2-[2-(cyclohexylamino)-5-[(E)-2-(4-fluoropheny l)vinyl] anilino] ethyl] carbamate;3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]- 1 -morpholino-propan- 1-one; tert-butyl 4- [3 -[2-(cy clohexy lamino)-5 - [(E)-2-(4-fluorophenyl)vinyl]anilino]propanoylamino]piperidine-l -carboxylate;tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl] anilino] propanoyl]piperazine- 1 -carboxylate;[4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-l-piperidyl]-phenyl-methanone;-95- 56802210 1Attomey Docket No. 047162-7600W01(02785)a salt thereof, an isomer thereof, or an isotope containing derivative thereof.

11. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound of any one of claims 1-10, a salt thereof, an isomer thereof, or an isotope containing derivative thereof.

12. The pharmaceutical composition of claim 11, wherein R3 is -CH=CHR6, and the compound has formula (2):R1HN.!HN" 1 X ' 1 R613. The pharmaceutical composition of any one of claims 11-12, wherein the compound is selected from the group consisting of:N2-benzyl-Nl-cyclohexyl-4-oxazol-5-yl-benzene-l,2-diamine;Nl-benzyl-N2-cyclohexyl-4-oxazol-5-yl-benzene-l, 2-diamine;(E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N, N-dimethyl-prop-2-enamide;N2-benzyl-Nl-cy cl ohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l, 2-diamine;N2-benzyl-Nl-cyclohexyl-4-[(E)-2-(4-methoxyphenyl)vinyl]benzene-l, 2-diamine;Nl-benzyl-N2-(4-methoxycyclohexyl)-4-oxazol-5-yl-benzene-l, 2-diamine;Nl-benzyl-N2-(4,4-difluorocy cl ohexyl)-4-oxazol-5-yl-benzene-l, 2-diamine;Nl-benzyl-N2-(4-methylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;N 1 - [(4-chloropheny l)methyl] -N2-cy clohexyl-4-oxazol-5-yl-benzene- 1.2-diamine;Nl-benzyl-N2-(4,4-dimethylcyclohexyl)-4-oxazol-5-yl-benzene-l,2-di amine;N2-benzyl-Nl-cy clohexyl-4-(l, 3, 4-oxadiazol-2-yl)benzene-l, 2-diamine;N2-cy clohexyl-4-oxazol-5 -yl-N 1 -( 1 -pheny lethy l)benzene- 1, 2-diamine;(E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-N-isopropyl-prop-2-enamide;N 1 -benzyl-N2-cy clohexyl-4-[4-(p-tolyl)triazol- 1 -yl]benzene- 1,2-di amine;Nl-cy cl ohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)benzene-l, 2-diamine; N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]benzamide;Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(2-methoxyphenyl)vinyl]benzene-l, 2-diamine;-96- 56802210 1Attomey Docket No. 047162-7600W01(02785)(E)-3-[3-(benzylamino)-4-(cyclohexylamino)phenyl]-l-morpholino-prop-2-en-l-one;N2-benzyl-4- [(E)-2-(2-chloropheny l)viny 1] -N 1 -cy clohexy 1-benzene- 1,2-diamine;Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(4-pyridyl)vinyl]benzene-E2-diamine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-methyl-2-pyridyl)methyl]benzene- 1,2-di amine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(6-fluoro-2-pyridyl)methyl]benzene-l,2-diamine;N-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]phenyl]-2,3-dihydro-l,4-benzodioxine-6-carboxamide;N2-benzyl-N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-di amine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]benzene-l,2-diamine;Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-(2-pyridylmethyl)benzene-l,2-diamine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[[4-(4-methylpiperazin-l-yl)phenyl]methyl]benzene-l,2-diamine;Nl-cyclohexyl-N2-(2,3-dihydrobenzofuran-5-ylmethyl)-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-diamine;Nl-cyclohexyl-N2-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-1.2-di amine;Nl-cyclohexyl-N2-[(4-morpholinophenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine;Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[[4-(trifluoromethoxy)phenyl]methyl]benzene- 1,2-di amine;Nl-cyclohexyl-N2-[(4-methoxyphenyl)methyl]-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-diamine;N 1 -cyclohexyl-N2-[[4-(4-methylpiperazin- 1 -yl)phenyl]methyl]-4-( 1,3,4-oxadiazol-2-yl)benzene-l,2-diamine;Nl-cyclohexyl-N2-[(3,5-dimethoxyphenyl)methyl]-4-[(E)-2-(4-fluorophenyl)vinyl]benzene- 1,2-di amine;4-[[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]methyl]phenol;Nl-cyclohexyl-N2-(2,3-dihydrobenzofuran-6-ylmethyl)-4-(l,3,4-oxadiazol-2-yl)benzene-l,2-di amine;N2-benzyl-4-[(E)-2-(3-chlorophenyl)vinyl]-Nl-cyclohexyl-benzene-l,2-diamine;N2-benzyl-Nl-cyclohexyl-4-[(E)-2-[3-(trifluoromethyl)phenyl]vinyl]benzene-l,2-di amine;-97- 56802210 1Attomey Docket No. 047162-7600W01(02785)N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-[(4-methoxyphenyl)methyl]pyridine-2,3-di amine;N2-benzyl-4-[(E)-2-(4-fluorophenyl)vinyl]-Nl-tetrahydropyran-4-yl-benzene-l,2-di amine; N3-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-pyridylmethyl)pyridine-2,3-diamine; Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-phenyl-benzene-l,2-diamine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-[2-(2-pyridyl)ethyl]benzene-l,2-diamine; Nl-benzyl-N2-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]benzene-l,2-diamine;N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-tetrahydropyran-4-yl-pyridine-2,3-di amine; N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-N, N-dimethyl-propanamide; N2-benzyl-Nl-cyclohexyl-4-[5-(trifluoromethyl)-1.3.4-oxadiazol-2-yl]benzene-l,2-diamine; N2-benzyl-N3-cy clohexyl-6-[5-(tri fluoromethyl)-!, 3, 4-oxadiazol-2-yl]pyridine-2,3-di amine; tert-butyl 4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]piperidine-l-carboxylate;N2-benzyl-N3-cyclohexyl-6-(l,3,4-oxadiazol-2-yl)pyridine-2,3-diamine;N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(4-piperidyl)pyridine-2,3-diamine;hydrochloride;1-[4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-l-piperidyl]ethenone;N2-benzyl-6-[(E)-2-(4-fluorophenyl)vinyl]-N3-(l-methyl-4-piperidyl)pyridine-2,3-diamine; N2-benzyl-NI-cyclohexyl-4-(5-methyl-l,3,4-oxadiazol-2-yl)benzene-l,2-diamine; methyl 3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoate;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-prop-2-ynyl-benzene-l,2-di amine;Nl-cyclohexyl-4-[(E)-2-(4-fluorophenyl)vinyl]-N2-(2-methylsulfonylethyl)benzene-1.2-diamine;N3-benzyl-N2-cyclohexyl-6-[(E)-2-(4-fluorophenyl)vinyl]pyridine-2,3-diamine;Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-l,2-diamine;Nl-cyclohexyl-4-(l,3,4-oxadiazol-2-yl)-N2-[2-(2-pyridyl)ethyl]benzene-1.2-diamine;hydrochloride;3-[2-(cyclohexylamino)-5-(l,3,4-oxadiazol-2-yl)anilino]propanenitrile;3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-l-pyrrolidin-l-yl-propan-l-one;2-[2-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]ethyl]isoindoline-1.3-dione;-98- 56802210 1Attomey Docket No. 047162-7600W01(02785)tert-butyl N-[2-[2-(cyclohexylamino)-5-[(E)-2-(4-fluoropheny l)vinyl] anilino] ethyl] carbamate:3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]-l-morpholino-propan-l-one; tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoylamino]piperidine-l -carboxylate;tert-butyl 4-[3-[2-(cyclohexylamino)-5-[(E)-2-(4-fluorophenyl)vinyl]anilino]propanoyl]piperazine-l-carboxylate;[4-[[2-(benzylamino)-6-[(E)-2-(4-fluorophenyl)vinyl]-3-pyridyl]amino]-l-piperidyl]-phenyl-methanone;a salt thereof, an isomer thereof, an isotope containing derivative thereof, and combinations thereof.

14. The pharmaceutical composition of any one of claims 11-13, wherein the pharmaceutical composition is formulated for injection administration, oral administration, inhalational administration, topical administration, or combinations thereof.

15. The pharmaceutical composition of any one of claims 11-14, wherein the pharmaceutical composition is formulated for an administration route selected from the group consisting of oral, intracranial, nasal, intranasal, rectal, transrectal, parenteral, sublingual, transdermal, transmucosal, urethral, transurethral, vaginal, intravesical, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous (IV), intrabronchial, inhalation, and topical.

16. The pharmaceutical composition of any one of claims 11-15, wherein the pharmaceutical composition is formulated for treatment of post-stroke brain ischemiareperfusion injury’ (IRI), ischemia-reperfusion injury’ (IRI) not caused by post-stroke brain ischemia, ischemic heart diseases, lung injury related to a coronavirus infection, SARS-CoV infection, SARS-CoV-2 infection (COVID- 19), Middle Eastern respiratory’ syndrome (MERS), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), acute kidney injury' (AKI), kidney injury', respiratory illness due to alveolar damage, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, inflammatory bowel disease (IBD), idiopathic pulmonary fibrosis (IPF), -99- 56802210 1Attomey Docket No. 047162-7600W01(02785)pulmonary arterial hypertension (PAH), Sedaghatian-type spondylometaphyseal dysplasia (SSMD). organ injury due to vascular leakage during sepsis or heme release, iron-overloading diseases, neurodegenerative diseases. Huntington’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), chronic kidney disease (CKD), kidney fibrosis, traumatic brain injury, tumor, or combinations thereof.

17. The pharmaceutical composition of any one of claims 11-16, wherein the at least one pharmaceutically acceptable excipient comprises acacia, animal oils, benzy l alcohol, benzyl benzoate, calcium stearate, carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol, cyclodextrins, dextrose, diethanolamine, emulsifying wax, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glycerol stearate, glycery l monooleate, glyceryl monostearate, hydrous, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl- -cyclodextrin (HPBCD), hypromellose (hydroxypropyl methylcellulose (HPMC)), lanolin, lanolin alcohols, lecithin, medium-chain triglycerides, metallic soaps, methylcellulose, mineral oil, monobasic sodium phosphate, monoethanolamine, oleic acid, polyy ethylene glycols (PEG 3350, PEG 4000, PEG 6000), polyoxyethylene-polyoxypropylene copolymer (poloxamer), polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polysorbate, polyoxyethylene (20) sorbitan monolaurate (Tween 20, Polysorbate 20), polyoxyethylene (20) sorbitan monooleate (Tween 80, Polysorbate 80), povidone, propylene glycol alginate, saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium hydroxide, sodium lauryl sulfate, sodium phosphate monobasic, sodium phosphate dibasic, sorbitan esters, stearic acid, stearyl alcohol, sunflower oil, tragacanth, triethanolamine, vegetable oils, water, xanthan gum, or combinations thereof.

18. The pharmaceutical composition of claim 17, wherein the at least one pharmaceutically acceptable excipient comprises dextrose, glycerin, histidine, hydrochloric acid, hydroxypropyl cellulose, hydroxypropyl-P-cyclodextrin (HPBCD), hypromellose (hydroxypropyl methylcellulose (HPMC)), polyoxyethylene (20) sorbitan monolaurate (Tween 20, Polysorbate 20). polyyethylene glycols (PEG 400, PEG 3350, PEG 4000, PEG 6000), polyoxy ethylene-polyoxypropylene copolymer -100- 56802210 1Attomey Docket No. 047162-7600W01(02785)(Poloxamer 188, Poloxamer 407), polyoxyethylene (20) sorbitan monooleate (Tween 80, Polysorbate 80), saline, sodium chloride, sodium citrate, sodium citrate dihydrate, sodium lauryl sulfate, sodium phosphate monobasic, sodium phosphate dibasic, or combinations thereof.

19. The pharmaceutical composition of any one of claims 11-18, further comprising at least one active pharmaceutical ingredient.

20. A method for treating, ameliorating, and / or preventing a disease or disorder in a subject in need thereof, the method comprising administering an effective amount of a pharmaceutical composition of any one of claims 11-19 to the subject,wherein the disease or disorder comprises post-stroke brain ischemiareperfusion injury (IRI), ischemia-reperfusion injury' (IRI) not caused by post-stroke brain ischemia, ischemic heart diseases, lung injury related to a coronavirus infection, SARS-CoV infection, SARS-CoV-2 infection (COVID- 19), Middle Eastern respiratory syndrome (MERS), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), kidney injury, respiratory illness due to alveolar damage, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, inflammatory bowel disease (IBD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), Sedaghatian-type spondylometaphyseal dysplasia (SSMD), organ injury due to vascular leakage during sepsis or heme release, iron-overloading diseases, neurodegenerative diseases, Huntington’s disease, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), chronic kidney disease (CKD). kidney fibrosis, traumatic brain injury, tumor, or combinations thereof.

21. The method of claim 20, wherein the pharmaceutical composition is administered to the subject via an administration route comprising oral, intracranial, nasal, intranasal, rectal, transrectal, parenteral, sublingual, transdermal, transmucosal, urethral, transurethral, vaginal, intravesical, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous (IV), intrabronchial, inhalation, topical, intravenous (IV) injection, subcutaneous (SC) injection, intramuscular (IM) injection, intradermal (ID) injection, oral, aerosol or combinations thereof.-101- 56802210 1Attomey Docket No. 047162-7600W01(02785)22. The method of claim 21, wherein the pharmaceutical composition is administered to the subject in combination with at least one additional medication or treatment.

23. Use of a compound of any one of claims 1-10, or a salt thereof, an isomer thereof, an isotope containing derivative thereof, and combinations thereof, for manufacturing of a medicament for the treatment, ameliorating, and / or preventing a disease or disorder in a subject in need thereof, wherein the disease or disorder is selected from poststroke brain ischemia-reperfusion injury (IRI), ischemia-reperfusion injury (IRI) not caused by post-stroke brain ischemia, ischemic heart diseases, lung injury related to a coronavirus infection, SARS-CoV infection. SARS-CoV-2 infection (COVID- 19), Middle Eastern respiratory syndrome (MERS), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), kidney injury, respiratory illness due to alveolar damage, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, inflammatory’ bowel disease (IBD), idiopathic pulmonary fibrosis (IPF), pulmonary- arterial hypertension (PAH), Sedaghatian-type spondylometaphyseal dysplasia (SSMD), organ injury due to vascular leakage during sepsis or heme release, iron-overloading diseases, neurodegenerative diseases, Huntington’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), chronic kidney disease (CKD). kidney fibrosis, traumatic brain injury, tumor, or combinations thereof.-102- 56802210 1

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