Sulfonamides, compositions comprising said sulfonamides, methods for the preparation of said sulfonamides, and said sulfonamides for use as medicament and in a method for the treatment or prevention of an ocular disease or condition, or idiopathic intracranial hypertension

Abstract

Disclosed are sulfonamides, compositions comprising said sulfonamides, methods for the preparation of said sulfonamides, and said sulfonamides for use as medicament and in a method for the treatment or prevention of an ocular disease or condition, or idiopathic intracranial hypertension.

Description

[0001]SULFONAMIDES, COMPOSITIONS COMPRISING SAID SULFONAMIDES, METHODS FOR THE PREPARATION OF SAID SULFONAMIDES, AND SAIDSULFONAMIDES FOR USE AS MEDICAMENT AND IN A METHOD FOR THETREATMENT OR PREVENTION OF AN OCULAR DISEASE OR CONDITION, OR IDIOPATHIC INTRACRANIAL HYPERTENSION. TECHNICAL FIELD The present disclosure relates to sulfonamides and in particular to new derivatives of 4-hydrazineylbenzenesulfonamides and 4-(aminooxy)benzenesulfonamides. Further, the presentdisclosure relates to compositions comprising said sulfonamides, to said sulfonamides for use as a medicament, to said sulfonamides for use in methods for the treatment or prevention of an ocular disease or condition, or idiopathic intracranial hypertension, in particular for the treatment of glaucoma and macular edema (ME), and to a method for the preparation of said compounds. BACKGROUND Carbonic anhydrase inhibitors (CAIs) are a class of drugs that inhibit the activity of the enzyme carbonic anhydrase. Carbonic anhydrase plays a role in many physiological processes, including fluid and electrolyte balance, acid-base balance, and cell signaling. CAIs are used to treat a variety of ocular diseases and conditions, including glaucoma,idiopathic intracranial hypertension (IIH), and macular edema (ME). In the eye, carbonic anhydrase is involved in the production of aqueous humor, the fluid that fills the front of the eye (European Journal of Medicinal Chemistry (2021):209;112923). Aqueous humor is constantly produced and drained from the eye to maintain a normal intraocular pressure (IOP). If the drainage of aqueous humor is impaired, IOP can increase, leading to glaucoma. CAIs reduce the production of aqueous humor, thereby lowering IOP. This makes them a valuable treatment for glaucoma. CAIs can be used as monotherapy or in combination with other glaucoma medications. In addition to their use in glaucoma, CAIs are also used to treat IIH and ME. IIH is a condition in which the pressure in the cerebrospinal fluid is elevated. This can cause headaches, vision problems, and other symptoms. CAIs are used to lower the pressure in the cerebrospinal fluid and improve symptoms in patients with IIH. ME is a condition in which fluid accumulates in the retina, the light-sensitive tissue at the back of the eye. This can cause blurred vision, distortion, and other vision problems. CAIs are used to reduce fluid accumulation in the retina and improve vision in patients with ME. CAIs are available in both topical and oral formulations. Topical CAIs are applied directly to the eye in the form of drops or ointments. Oral CAIs are taken by mouth and are more effective at lowering IOP than topical CAIs. Specific uses of CAIs in ocular diseases and conditions include: 1. GlaucomaCAIs are a first-line treatment for most types of glaucoma. They are particularly effective in patients with chronic open-angle glaucoma, the most common type of glaucoma. CAIs can also be used to treat other types of glaucoma, such as (acute) angle-closure glaucoma,open angle glaucoma, pediatric glaucoma and pseudoexfoliative glaucoma.2. Idiopathic Intracranial HypertensionCAIs are the mainstay treatment for IIH. They are effective in lowering the pressure inthe cerebrospinal fluid and improving symptoms in most patients with IIH.3. Macular EdemaCAIs are used to treat ME secondary to a variety of causes, including diabetes, retinal vein occlusion, and uveitis. CAIs are effective in reducing fluid accumulation in the retina and improving vision in most patients with ME. CAIs are a valuable class of medications for the treatment of a variety of ocular diseases. They are effective in lowering IOP, reducing fluid accumulation in the retina, and improving symptoms in patients with glaucoma, IIH, and ME. SUMMARY This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter. An object of the present invention is to provide compounds useful in treating or preventing an ocular disease or condition, in particular glaucoma and macular edema (ME), or idiopathic intracranial hypertension (IIH). The invention is based on the realization that the compounds are novel melanin-bindingCAI inhibitors that reduce IOP and may be used for the treatment or prevention of glaucomaand related ocular diseases, including IIH, and ME. The inhibitors apply a novel hybrid design,connecting a CAI moiety to a melanin-binding aromatic or heteroaromatic moiety through a hydrazone or oxime linker. The combination of melanin-binding aromatic or heteroaromatic moiety and hydrazone / oxime linker may allow for a tuning of drug action over very wide range in the acidic pH of the cellular melanosomes. The objects of the invention are achieved by compounds and said compounds for use as a medicament that are characterized by what is stated in the independent claims. The preferred embodiments of the invention are disclosed in the dependent claims.In one aspect is provided a compound of formula (I): formula (I), wherein R1and R2are each independently selected from the group consisting of H, C1-8-alkyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substituted with one or more halogen; each Z is independently selected from the group consisting of C(R), and N;each R is independently selected from the group consisting of H, halogen, preferably F,Cl, or Br; hydroxy, C1-8-alkoxy, C1-8-alkylthio, C1-8-carboxamide group, C1-8-ester group, C1-8-urea group, C1-8-carbamate group, C1-8-alkyl, C6-10-aryl, C5-10-heteroaryl, and derivatives thereofbeing substituted with one or more halogen; Y is N(R) or O; Xis a 5-10 membered aliphatic, aromatic or heterocyclic ring comprising 0-5heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-5 substituents each independently selected from R’; each R’ is independently selected from the group consisting of halogen, preferably F,Cl, or Br; hydroxy, C1-8-alkoxy, C1-8-alkylthio, C1-8-carboxamide group, C1-8-ester group, C1-8-urea group, C1-8-carbamate group, C1-8-alkyl, C6-10-aryl, C5-10-heteroaryl, and derivatives thereofbeing substituted with one or more halogen; R3 is H, C(R4)(R5)(R6), or R’’, wherein R’’, together with X and the carbon they areattached to, forms a bi- or tricyclic 8-13 membered heterocyclic ring comprising an unsaturated5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-memberedheterocyclic ring being fused with X and being optionally substituted with N(R7)(R8); andR4, R5, R6, R7, and R8are each independently selected from the group consisting of H,halogen, C1-8-alkyl, C1-8-alkyl-N(R9)(R10), C1-6-alkyl-C1-6-cycloalkyl, C1-6-alkyl-C1-6-heterocyclyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substituted with one ormore halogen, or two of R4, R5, and R6, together with the carbon they are attached to, form a C3-8-cycloalkyl and the rest of R4, R5, and R6is H, wherein R9and R10are each independentlyselected from the group consisting of H, and C1-8-alkyl; provided that if Y is NH, both Z areCH, both R are H, and X is pyridinyl, 2-furanyl, 2-thiophenyl, phenyl or phenyl substituted with1-3 substituents each independently selected from R’, then R3 is not CH3 or CH2CH3; or astereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof.In another aspect is provided a composition comprising the compound as defined in the presentdisclosure, or a stereoisomer, the pharmaceutically acceptable salt, solvate, or hydrate thereof.In another aspect is provided a compound as defined in the present disclosure, or a stereoisomer,the pharmaceutically acceptable salt, solvate, or hydrate thereof, for use as a medicament.In another aspect is provided a compound of formula (I) as defined in the present disclosure, ora stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof, for use in amethod for the treatment or prevention of an ocular disease or condition, or idiopathic intracranial hypertension (IIH). In another aspect is provided a method for the preparation of a compound as defined in the present disclosure; wherein the method comprises:- providing a compound of formula (X) or a salt thereof: formula (X), and a compound of formula (XI´): formula (XI´) or a compound of formula (XI´´): formula (XI´´), wherein both X´, together with the carbons they are attached to, together form a 5-10 memberedaliphatic, aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’, each dotted line represents an optional bond, and R1, R2, R3, R, R’, X, Y, and Z are as defined in the present disclosure; and- reacting the compound of formula (X) or a salt thereof with the compound of formula(XI´) or the compound of formula (XI´´), optionally in the presence of a base, thereby forming a compound as defined in the present disclosure. DETAILED DESCRIPTION The following explanations of terms and methods are provided to better describe the present compounds, compositions and methods, and to guide those of ordinary skill in the art inthe practice of the present disclosure. It is also to be understood that the terminology used in thedisclosure is for the purpose of describing particular embodiments and examples only and is not intended to be limiting. “Acyl” refers to a group having the structure –C(O)R, where R may be, for example, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. “Lower acyl” groups are those that contain one to six carbon atoms. “Acyloxy” refers to a group having the structure –OC(O)R-, where R may be, for example, optionally substituted alkyl, optionally substituted aryl, or optionally substitutedheteroaryl. “Lower acyloxy” groups contain one to six carbon atoms.“Administration” as used herein is inclusive of administration by another person to the subject or self-administration by the subject. The term "aliphatic" is defined as including alkyl, alkenyl, alkynyl, halogenated alkyland cycloalkyl groups. A "lower aliphatic" group is a branched or unbranched aliphatic grouphaving from 1 to 10 carbon atoms. “Alkanediyl,” “cycloalkanediyl,” “aryldiyl,” “alkanearyldiyl” refers to a divalent radical derived from aliphatic, cycloaliphatic, aryl, and alkanearyl hydrocarbons. “Alkenyl” refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and contains one or more double bonds that may or may not be conjugated.Alkenyl groups may be unsubstituted or substituted. “Lower alkenyl” groups contain one to sixcarbon atoms. The term “alkoxy” refers to a straight, branched or cyclic hydrocarbon configuration and combinations thereof, including from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms (referred to as a “lower alkoxy”), more preferably from 1 to 4 carbon atoms, that include anoxygen atom at the point of attachment. An example of an “alkoxy group” is represented by theformula –OR, where R can be an alkyl group, optionally substituted with an alkenyl, alkynyl,aryl, aralkyl, cycloalkyl, halogenated alkyl, alkoxy or heterocycloalkyl group. Examples ofalkoxy groups and lower alkoxy and C1-8-alkoxy include, but are not limited to, methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, cyclopropoxy,cyclohexyloxy, and the like. The term “alkylthio” refers to a straight, branched or cyclic hydrocarbon configurationand combinations thereof, including from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms (referred also to as a “lower alkylthio”), more preferably from 1 to 4 carbon atoms, thatinclude a sulphur atom at the point of attachment. Examples of alkylthio groups and loweralkylthio and C1-8- alkylthio include, but are not limited to, methylthio, ethylthio, n-propylthio,i-propylthio, n-butylthio, i-butylthio, sec-butylthio, tert-butylthio, and the like. “Alkoxycarbonyl” refers to an alkoxy substituted carbonyl radical, –C(O)OR, wherein R represents an optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl or similar moiety. The term “alkyl” refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl,hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. A “loweralkyl” group is a saturated branched or unbranched hydrocarbon having from 1 to 8 carbonatoms. Preferred alkyl groups have 1 to 4 carbon atoms. Alkyl groups may be “substitutedalkyls” wherein one or more hydrogen atoms are substituted with a substituent such as halogen,cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl. For example, a lower alkyl or(C1-C8)alkyl or C1-8-alkyl can be, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl; (C3-C6)cycloalkyl(C1-C8)alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2- cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl; (C1-C8)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C2-C8)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C2-C8)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl; (C1-C8)alkanoyl can be acetyl, propanoyl or butanoyl; halo(C1-C8)alkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl; hydroxy(C1-C8)alkyl can be hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3- hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl, 5-hydroxypentyl, 1- hydroxyhexyl, or 6-hydroxyhexyl; (C1-C8)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (C1-C8)alkylthio can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio; (C2-C6)alkanoyloxy can be acetoxy,propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy. Examples of “C1-8-alkyl derivatives thereof being substituted with one or more halogen” include, but are not limited to, trifluoromethyl. “Alkynyl” refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and unless otherwise mentioned typically contains one to twelve carbon atoms,and contains one or more triple bonds. Alkynyl groups may be unsubstituted or substituted.“Lower alkynyl” groups are those that contain one to six carbon atoms. The term “amine” or “amino” refers to a group of the formula –NRR', where R and R' can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl,halogenated alkyl, heterocycloalkyl, or carboxyl group. For example, an “alkylamino” or“alkylated amino” refers to –NRR', wherein at least one of R or R' is an alkyl. A suitable amineor amino group is acetamido. The term "aminoalkyl" refers to alkyl groups as defined above where at least one hydrogen atom is replaced with an amino group (e.g, -CH2-NH2). “Aminocarbonyl” alone or in combination, means an amino substituted carbonyl(carbamoyl) radical, wherein the amino radical may optionally be mono- or di-substituted, suchas, for example, with alkyl, aryl, acyl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl,alkoxycarbonyl, aralkoxycarbonyl and the like. For example, an aminocarbonyl may berepresented by the formula –C(O)NRR', where R and R' independently can be, for example, a hydrogen, alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group. An “analog” is a molecule that differs in chemical structure from a parent compound, for example a homolog (differing by an increment in the chemical structure or mass, such as a difference in the length of an alkyl chain or the inclusion of one of more isotopes), a molecular fragment, a structure that differs by one or more functional groups, or a change in ionization. An analog is not necessarily synthesized from the parent compound. A derivative is a molecule derived from the base structure. An “animal” refers to living multi-cellular vertebrate organisms, a category thatincludes, for example, mammals and birds. The term mammal includes both human and non-human mammals. Similarly, the term “subject” includes both human and non-human subjects,including birds and non-human mammals. Illustrative non-human mammals include animal models (such as mice), non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats.The term subject applies regardless of the stage in the organism’s life-cycle. Thus, the termsubject applies to an organism in utero or in ovo, depending on the organism (that is, whetherthe organism is a mammal or a bird, such as a domesticated or wild fowl). The term "aralkyl" refers to an alkyl group wherein an aryl group is substituted for ahydrogen of the alkyl group. An example of an aralkyl group is a benzyl group.“Aryl” and “aromatic ring” refer to a monovalent or polyvalent unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthylor anthryl), which can optionally be unsubstituted or substituted. Examples of “C6-10-aryl” or“6-10 membered aromatic ring” include, but are not limited to, phenyl, indanyl, and naphthyl.A “heteroaryl” and a “heteroaryl group” is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Therefore, it is to be understoodthat an “aromatic ring comprising 0-5 heteroatoms” may be an aryl or an heteroaryl. It is also tobe understood that the terms “heterocyclic ring” as used in the present disclosure may includeboth aromatic and non-aromatic monovalent and polyvalent radicals derived from heterocycliccompounds and, therefore, may be a heteroaryl (such as, but not limited to, pyridinyl andindolyl) or a heterocyclic ring (such as, but not limited to, imidazolidinyl). Examples ofheteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorous. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like. The arylor heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy, or the aryl or heteroaryl group can be unsubstituted. “Aryloxy” or “heteroaryloxy” refers to a group of the formula –OAr, wherein Ar is an aryl group or a heteroaryl group, respectively. "Bicyclic" or "bicyclyl" as used herein refers to a ring assembly of two rings where thetwo rings may be fused together, linked by a single bond or linked by two or more bridgingatoms. The rings may be selected from carbocyclyls, and heterocyclyls, or a mixture thereof.Compounds having bicyclic rings include, but are not limited to, spiro compounds,fused / condensed bicyclic compounds, and bridged bicyclic compounds. Examples of bicyclic8-13 membered heterocyclic rings include, but are not limited to, 1H-isoindol-3-ylamine, 1H- isoindole, 1H-2,4,7-triazainden-3-ylamine, 1H-2,4-diazainden-3-ylamine, and 2-quinoxalinyl. Examples of bicyclic 8-13 membered heterocyclic ring comprising an unsaturated 5-memberedheterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ringis fused with X include, but are not limited to, 1H-isoindol-3-ylamine, 1H-isoindole, 1H-2,4,7- triazainden-3-ylamine, 1H-2,4-diazainden-3-ylamine. “Tricyclic” as used herein refers to a ring assembly of three rings where the three ringsmay be fused together, linked by single bonds or linked by two or more bridging atoms. Therings may be selected from carbocyclyls, and heterocyclyls, or a mixture thereof. As for bicycliccompounds, tricyclic compounds may have spiro atoms, and may share two or more atoms. An example of a tricyclic ring includes, but is not limited to, 2,5,8-triazatricyclo[7.4.0.03,7]trideca- 1(9),2,4,7,10,12-hexaene. An example of a tricyclic 8-13 membered heterocyclic ringcomprising an unsaturated 5-membered heterocyclic ring comprising 1 nitrogen, wherein theunsaturated 5-membered heterocyclic ring is fused with X includes, but is not limited to, 2,5,8-triazatricyclo[7.4.0.03,7]trideca-1(9),2,4,7,10,12-hexaene. A“carbonylamino” group and a “carboxamide group” may be –N(R)-C(O)-R (whereineach R is independently a substitution group such as, for example, alkyl, alkenyl, alkynyl, acyl,aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group, or H). A suitablecarbonylamino group is acetamido. The term “carboxylate” or “carboxyl” refers to the group -COO- or -COOH. Thecarboxyl group can form a carboxylic acid. “Substituted carboxyl” refers to -COOR where R isalkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group.For example, a substituted carboxyl group could be a carboxylic acid ester or a salt thereof (e.g., a carboxylate). The term “co-administration” or “co-administering” refers to administration of a compound disclosed herein with at least one other therapeutic agent or therapy within the same general time period, and does not require administration at the same exact moment in time (although co-administration is inclusive of administering at the same exact moment in time). Thus, co-administration may be on the same day or on different days, or in the same week or in different weeks. In some embodiments, the co-administration of two or more agents or therapies is concurrent. In other embodiments, a first agent / therapy is administered prior to a second agent / therapy. Those of skill in the art understand that the formulations and / or routes of administration of the various agents or therapies used may vary. The appropriate dosage for co- administration can be readily determined by one skilled in the art. In some embodiments, when agents or therapies are co-administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent and / or lowers the frequency of administering the potentially harmful (e.g., toxic) agent. “Co-administration” or “co-administering” encompass administration of two or more active agents to a subject so that both the active agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration atdifferent times in separate compositions, or administration in a composition in which two or more active agents are present. The terms “cycloalkyl” and “aliphatic ring” refer to a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptanyl, and thelike. The terms “heterocycloalkyl group”, “heterocyclic ring” and “heterocycle” is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with aheteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorous. Therefore, theterms “aliphatic ring comprising 0-5 heteroatoms” as used herein and hereafter may include both cycloalkyls and heterocycloalkyl groups (heterocyclic rings, heterocycles), and may be amonovalent or polyvalent saturated or partially unsaturated aliphatic ring having a single ring(e.g., cyclohexyl) or multiple condensed rings (e.g., perhydronaphth-2-yl). The term “ester” refers to a carboxyl group-containing moiety having the hydrogen replaced with, for example, a C1-6alkyl group (“carboxylC1-6alkyl” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on. CO2C1-3alkyl groups are preferred, such as for example, methylester (CO2Me), ethylester (CO2Et) and propylester (CO2Pr) and includes reverse esters thereof (e.g. –OCOMe, -OCOEt and –OCOPr). The terms “each dotted line represents an optional bond” as used herein and hereafterrefers one or more bonds that may or may not be present. It is to be understood that when adotted line is present then it forms, together with the single bond next to it, a double bond.Therefore, e.g., the compound of formula (III) is equal to a compound of formula (IIIa) orformula (IIIb) when one or more dotted lines are present: formula (IIIa), formula (IIIb),and when a dotted line is not present, the compound of formula (I) is equal to a compound offormula (IIIc): formula (IIIc), wherein R1, R2, R7, R8, R, X´, Y, and Z are as defined in the present disclosure. "Halo" or "halogen", as used herein, refers to fluoro, chloro, bromo, and iodo.The terms “haloalkyl”, "halogenated alkyl" and "haloalkyl group" refer to an alkyl group withone or more hydrogen atoms present on these groups substituted with a halogen (F, Cl, Br, I).Examples of haloalkyl groups include without limitation chloromethyl, fluoromethyl, -CH2CF3,trifluoromethyl (-CF3) and trichloromethyl (-CCl3). The terms “heterocyclic”, “heterocycle” and “heterocyclic ring” refer to a closed-ringcompound, or radical thereof as a substituent bonded to another group, particularly other organic groups, where at least one atom in the ring structure is other than carbon, and typically is oxygen,sulfur and / or nitrogen. It is to be understood that the terms “heterocyclic ring”, “heterocyclic”,and “heterocycle” as used in the present disclosure may include both aromatic and non-aromaticmonovalent and polyvalent radicals derived from heterocyclic compounds and, therefore, mayrefer to a heteroaryl group, a non-aromatic heterocycloalkyl group and heterocyclic ring. A “5-10 membered heterocyclic ring” may have a single ring (e.g., pyridinyl) or multiple condensedrings (e.g., indolyl). It is to be understood that the terms “bi- or tricyclic 8-13 memberedheterocyclic ring” refer in the present disclosure to 8-13 membered heterocycles having two(bicyclic) or three (tricyclic) condensed rings, wherein at least one of the condensed rings is aheterocyclic ring, typically two or three of the condensed rings are heterocyclic rings. The term “hydroxyl” is represented by the formula –OH. The term "hydroxyalkyl" refers to an alkyl group that has at least one hydrogen atomsubstituted with a hydroxyl group. The term "alkoxyalkyl group" is defined as an alkyl groupthat has at least one hydrogen atom substituted with an alkoxy group described above. “Inhibiting” refers to inhibiting the full development of a disease or condition. “Inhibiting” also refers to any quantitative or qualitative reduction in biological activity or binding, relative to a control. “N-Heterocyclic” refers to mono- or bicyclic rings or ring systems that include at leastone nitrogen heteroatom. The rings or ring systems generally include 1 to 9 carbon atoms in addition to the heteroatom(s) and may be saturated, unsaturated or aromatic (including pseudoaromatic). The term "pseudoaromatic" refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings. Aromatic includes pseudoaromatic ring systems, such as pyrrolyl rings. An example of a group of “two of R4, R5, and R6, together with the carbon they are attached to, form a C3-8-cycloalkyl and the rest of R4, R5, and R6is H” is cyclopropyl, i.e., e.g., R4and R5, together with the carbon they are attached to, form the cyclopropyl and R6is H. In another words, R3is cyclopropyl. Examples of 5-membered monocyclic N-heterocycles include pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls) isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls), and dithiazolyl. Examples of 6-membered monocyclic N- heterocycles include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and triazinyl. The heterocycles may be optionally substituted with a broad range of substituents, and preferably with C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C1-6alkyl)amino. The N-heterocyclic group may be fused to a carbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl. Examples of 8-, 9- and 10-membered bicyclic heterocycles include 1H thieno[2,3-c]pyrazolyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, and the like. These heterocycles may be optionally substituted, for example with C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C1-6alkyl)amino. Unless otherwise defined optionally substituted N-heterocyclics includespyridinium salts and the N-oxide form of suitable ring nitrogens. The terms “R’’, together with X and the carbon they are attached to, forms a bi- ortricyclic 8-13 membered heterocyclic ring comprising an unsaturated 5-membered heterocyclicring comprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ring is fused withX” as used herein and hereafter may refer to a group comprising a first ring fused to a secondring, wherein the first ring may be an unsaturated 5-membered heterocyclic ring comprising 1nitrogen, and the second ring is X, i.e., a 5-10 membered aliphatic, aromatic or heterocyclic ringcomprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring is optionally substituted with 1-5 substituents each independently selected from R’. Therefore, it is to be understood that groupR’’, group X and the carbon they are both attached to (i.e., the carbon that X and R3 are attachedto in the compound of formula (I)) together form an 8-13 membered polycyclic (bi- or tricyclic)group comprising the unsaturated 5-membered heterocyclic ring, which comprises 1 nitrogenand is fused with the 5-10 membered aliphatic, aromatic or heterocyclic ring comprising the 0-5 heteroatoms each independently selected from the group consisting of N, O, and S. Therefore,it is to be understood that the terms “X is a 5-10 membered aliphatic, aromatic or heterocyclicring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionallysubstituted with 1-5 substituents each independently selected from R’ ” may also include thepossible alternatives of (substituted) rings that have the unsaturated 5-membered heterocyclicring comprising 1 nitrogen fused to said rings, i.e., X. Therefore, X may be considered amonovalent or polyvalent radical. Examples of bicyclic 8-13 membered heterocyclic ringcomprising an unsaturated 5-membered heterocyclic ring comprising 1 nitrogen, wherein theunsaturated 5-membered heterocyclic ring is fused with X include, but are not limited to, 1H-2,4-diazainden-1-yl, 1H-2,4,7-triazainden-1-yl, and 1H-isoindol-1-yl. Examples of tricyclic 8-13 membered heterocyclic ring comprising an unsaturated 5-membered heterocyclic ringcomprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ring is fused with X include, but are not limited to, 2,5,8-triazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7,10,12-hexaen-4- yl. The term “subject” includes both human and non-human subjects, including birds andnon-human mammals, such as non-human primates, companion animals (such as dogs and cats),livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats.The term subject applies regardless of the stage in the organism’s life-cycle. Thus, the termsubject applies to an organism in utero or in ovo, depending on the organism (that is, whetherthe organism is a mammal or a bird, such as a domesticated or wild fowl). “Substituted” or “substitution” refers to replacement of a hydrogen atom of a moleculeor an R-group with one or more additional R-groups. Unless otherwise defined, the term“optionally-substituted” or “optional substituent” as used herein refers to a group which may or may not be further substituted with 1, 2, 3, 4 or more groups, preferably 1, 2 or 3, morepreferably 1 or 2 groups. The substituents may be selected, for example, from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, hydroxyl, oxo, C1-6alkoxy, aryloxy, C1-6alkoxyaryl, halo, C1-6alkylhalo (such as CF3 and CHF2), C1-6alkoxyhalo (such as OCF3 and OCHF2), carboxyl, esters, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketones, amides, aminoacyl, substituted amides, disubstituted amides, thiol, alkylthio, thioxo, sulfates, sulfonates, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonylamides, substituted sulfonamides, disubstituted sulfonamides, aryl, C1-6alkyl, heterocyclyl and heteroaryl wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl and groupscontaining them may be further optionally substituted. Optional substituents in the case N-heterocycles may also include but are not limited to C1-6alkyl i.e. N-C1-3alkyl, more preferably methyl, particularly N-methyl. A "therapeutically effective amount" refers to a quantity of a specified agent sufficientto achieve a desired effect in a subject being treated with that agent. Ideally, a therapeuticallyeffective amount of an agent is an amount sufficient to inhibit or treat the disease or conditionwithout causing a substantial cytotoxic effect in the subject. The therapeutically effectiveamount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition. The terms “treatment”, “treating”, “prevention”, and “preventing” as used herein andhereafter includes prophylaxis, or prevention of, as well as lowering the individual's risk of falling ill with the named disease, disorder or condition, or alleviation, amelioration,elimination, or cure of the said disease, disorder or condition once it has been established.Therefore, “treatment” may refer to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop. As used herein, the term “ameliorating,” with reference to a disease or condition, refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters wellknown in the art that are specific to the particular disease. The phrase “treating a disease” mayrefer to inhibiting at least partially the development, preferably the full development, of adisease, for example, in a subject who is at risk for a disease. A “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing a pathology or condition, or diminishing the severity of a pathology or condition. “Pharmaceutical compositions” are compositions that include an amount (for example, a unit dosage) of one or more of the disclosed compounds together with one or more non-toxic pharmaceutically acceptable additives, including carriers, diluents, and / or adjuvants, and optionally other biologically active ingredients. Such pharmaceutical compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA (19th Edition). The terms “pharmaceutically acceptable salt or ester” refers to salts or esters prepared by conventional means that include salts, e.g., of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelicacid and the like. “Pharmaceutically acceptable salts” of the presently disclosed compounds alsoinclude those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine,tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may beprepared by standard procedures, for example by reacting the free acid with a suitable organicor inorganic base. Any chemical compound recited in this specification may alternatively beadministered as a pharmaceutically acceptable salt thereof. “Pharmaceutically acceptable salts”are also inclusive of the free acid, base, and zwitterionic forms. Descriptions of suitablepharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts,Properties, Selection and Use, Wiley VCH (2002). When compounds disclosed herein includean acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline,alkaline earth, ammonium, quaternary ammonium cations and the like. Such salts are known tothose of skill in the art. For additional examples of “pharmacologically acceptable salts,” seeBerge et al., J. Pharm. Sci. 66:1 (1977).“Pharmaceutically acceptable esters” includes those derived from compounds describedherein that are modified to include a carboxyl group. An in vivo hydrolysable ester is an ester,which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Representative esters thus include carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl, optionally substituted by, for example, halogen, C.sub.1-4 alkyl, orC.sub.1-4 alkoxy) or amino); sulphonate esters, such as alkyl- or aralkylsulphonyl (for example,methanesulphonyl); or amino acid esters (for example, L-valyl or L-isoleucyl). A“pharmaceutically acceptable ester” also includes inorganic esters such as mono-, di-, or tri- phosphate esters. In such esters, unless otherwise specified, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms. Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group, optionally substituted as shown in the definition ofcarbocyclyl above. Pharmaceutically acceptable esters thus include C1-C22 fatty acid esters, suchas acetyl, t-butyl or long chain straight or branched unsaturated or omega-6 monounsaturatedfatty acids such as palmoyl, stearoyl and the like. Alternative aryl or heteroaryl esters include benzoyl, pyridylmethyloyl and the like any of which may be substituted, as defined in carbocyclyl above. Additional pharmaceutically acceptable esters include aliphatic L-amino acid esters such as leucyl, isoleucyl and especially valyl. For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted bytreatment with an appropriate base into the free base form. The compounds containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. The term “addition salt” as used hereinabove also comprises the solvates which the compounds described herein are able to form. Such solvates are for example hydrates, alcoholates and the like. The term “quaternary amine” as used herein before defines the quaternary ammoniumsalts which the compounds are able to form by reaction between a basic nitrogen of a compound and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins. Prodrugs of the disclosed compounds also are contemplated herein. A prodrug is anactive or inactive compound that is modified chemically through in vivo physiological action,such as hydrolysis, metabolism and the like, into an active compound following administrationof the prodrug to a subject. The term “prodrug” as used throughout this text means thepharmacologically acceptable derivatives such as esters, amides and phosphates, such that theresulting in vivo biotransformation product of the derivative is the active drug as defined in thecompounds described herein. Prodrugs preferably have excellent aqueous solubility, increasedbioavailability and are readily metabolized into the active inhibitors in vivo. Prodrugs of acompounds described herein may be prepared by modifying functional groups present in thecompound in such a way that the modifications are cleaved, either by routine manipulation orin vivo, to the parent compound. The suitability and techniques involved in making and usingprodrugs are well known by those skilled in the art. F or a general discussion of prodrugsinvolving esters see Svensson and Tunek, Drug Metabolism Reviews 165 (1988) andBundgaard, Design of Prodrugs, Elsevier (1985). The term “prodrug” also is intended to include any covalently bonded carriers thatrelease an active parent drug of the present invention in vivo when the prodrug is administeredto a subject. Since prodrugs often have enhanced properties relative to the active agentpharmaceutical, such as, solubility and bioavailability, the compounds disclosed herein can bedelivered in prodrug form. Thus, also contemplated are prodrugs of the presently disclosedcompounds, methods of delivering prodrugs and compositions containing such prodrugs. Prodrugs of the disclosed compounds typically are prepared by modifying one or morefunctional groups present in the compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to yield the parent compound. Prodrugs may includecompounds having a phosphonate, hydroxy, thio and / or amino group functionalized with anygroup that is cleaved in vivo to yield the corresponding amino, hydroxy, thio and / or phosphonategroup, respectively. Examples of prodrugs can include, without limitation, compounds havingan acylated amino group and / or a phosphonate ester or phosphonate amide group. Protected derivatives of the disclosed compounds also are contemplated. A variety of suitable protecting groups for use with the disclosed compounds are disclosed in Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999. In general, protecting groups are removed under conditions that will not affect theremaining portion of the molecule. These methods are well known in the art and include acidhydrolysis, hydrogenolysis and the like. One preferred method involves the removal of an ester,such as cleavage of a phosphonate ester using Lewis acidic conditions, such as in TMS-Brmediated ester cleavage to yield the free phosphonate. A second preferred method involvesremoval of a protecting group, such as removal of a benzyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like ormixtures thereof. A t-butoxy-based group, including t-butoxy carbonyl protecting groups can beremoved utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as water, dioxane and / or methylene chloride. Another exemplaryprotecting group, suitable for protecting amino and hydroxy functions amino is trityl. Otherconventional protecting groups are known and suitable protecting groups can be selected by those of skill in the art in consultation with Greene and Wuts, Protective Groups in OrganicSynthesis; 3rd Ed.; John Wiley & Sons, New York, 1999. When an amine is deprotected, theresulting salt can readily be neutralized to yield the free amine. Similarly, when an acid moiety,such as a phosphonic acid moiety is unveiled, the compound may be isolated as the acid compound or as a salt thereof. Particular examples of the presently disclosed compounds may include one or more asymmetric centers; thus the compounds described can exist in different stereoisomeric forms. Accordingly, compounds and compositions may be provided as individual pure enantiomers oras stereoisomeric mixtures, including racemic mixtures. In certain embodiments the compoundsdisclosed herein may be synthesized in or may be purified to be in substantially enantiopure form, such as in a 90% enantiomeric excess, a 95% enantiomeric excess, a 97% enantiomeric excess or even in greater than a 99% enantiomeric excess, such as in enantiopure form. The presently disclosed compounds can have one or more asymmetric centers orgeometric centers, cis-trans centers (C=C, C=N). All chiral, diasteromeric, racemic, meso, rotational, conformational and geometric isomers of the structures are intended unless otherwise specified. The compounds can be isolated as a single isomer or as mixture of isomers by methods utilizing specific chiral resolving agents like quinine, Chiral HPLC, SFC (super critical fluid chromatography) etc. All tautomers of the compounds are also considered part of the disclosure. The presently disclosed compounds also include all isotopes of atoms present in the compounds, which can include, but are not limited to, deuterium, tritium,13C,18F, stable and radioisotope, etc. In one aspect is disclosed a compound of formula (I): formula (I), wherein R1and R2are each independently selected from the group consisting of H, C1-8-alkyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substituted with one or more halogen; each Z is independently selected from the group consisting of C(R), and N;each R is independently selected from the group consisting of H, halogen, preferably F,Cl, or Br; hydroxy, C1-8-alkoxy, C1-8-alkylthio, C1-8-carboxamide group, C1-8-ester group, C1-8-urea group, C1-8-carbamate group, C1-8-alkyl, C6-10-aryl, C5-10-heteroaryl, and derivatives thereofbeing substituted with one or more halogen; Y is N(R) or O; Xis a 5-10 membered aliphatic, aromatic or heterocyclic ring comprising 0-5heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-5 substituents each independently selected from R’; each R’ is independently selected from the group consisting of halogen, preferably F,Cl, or Br; hydroxy, C1-8-alkoxy, C1-8-alkylthio, C1-8-carboxamide group, C1-8-ester group, C1-8-urea group, C1-8-carbamate group, C1-8-alkyl, C6-10-aryl, C5-10-heteroaryl, and derivatives thereofbeing substituted with one or more halogen; R3 is H, C(R4)(R5)(R6), or R’’, wherein R’’, together with X and the carbon they areattached to, forms a bi- or tricyclic 8-13 membered heterocyclic ring comprising an unsaturated5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-memberedheterocyclic ring is fused with X and is optionally substituted with N(R7)(R8); andR4, R5, R6, R7, and R8are each independently selected from the group consisting of H,halogen, C1-8-alkyl, C1-8-alkyl-N(R9)(R10), C1-6-alkyl-C1-6-cycloalkyl, C1-6-alkyl-C1-6-heterocyclyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substituted with one ormore halogen, or two of R4, R5, and R6, together with the carbon they are attached to, form a C3-8-cycloalkyl and the rest of R4, R5, and R6is H, wherein R9and R10are each independentlyselected from the group consisting of H, and C1-8-alkyl; provided that if Y is NH, both Z areCH, both R are H, and X is pyridinyl, 2-furanyl, 2-thiophenyl, phenyl or phenyl substituted with1-3 substituents each independently selected from R’, then R3 is not CH3 or CH2CH3; or astereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. Additionally, or alternatively, X is a 5-6 membered aliphatic, aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-5 substituents each independently selected from R’.Additionally, or alternatively, R3 is C(R4)(R5)(R6) or R’’, wherein R’’, together with X and thecarbon they are attached to, forms a bicyclic 8-9 membered heterocyclic ring comprising anunsaturated 5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ring is fused with X and is optionally substituted with N(R7)(R8).Additionally, or alternatively, X is a 5-6 membered aromatic or heterocyclic ring comprising 0- 2 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aromatic and the heterocyclic ring being optionally substituted with 1-2 substituents each independently selected from R’; R3 is R’’, wherein R’’, together with X and the carbon they are attached to, forms abicyclic 8-9 membered heterocyclic ring comprising an unsaturated 5-membered heterocyclicring comprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ring is fusedwith X and is substituted with N(R7)(R8); and each R’ and R7, and R8 are as defined in the present disclosure;or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.Additionally, or alternatively, the compound has formula (II): formula (II), wherein R1, R2, R4R5, R6, R, X, Y, and Z are as defined in the present disclosure; or astereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.Additionally, or alternatively, the compound has formula (III): formula (III), wherein each dotted line represents an optional bond; R1, R2, R7, R8, R, Y, and Z are as defined in the present disclosure; andboth X´, together with the carbons they are attached to, together form a 5-10 membered aliphatic,aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’; and R’is as defined in the present disclosure; or a stereoisomer, pharmaceutically acceptable salt,solvate, or hydrate thereof.Additionally, or alternatively, both X´, together with the carbons they are attached to, togetherform a 5-6 membered aliphatic, aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’; and R’ is as defined in the present disclosure; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.Additionally, or alternatively, both X´, together with the carbons they are attached to, togetherform a 5-6 membered aromatic heterocyclic ring comprising 1-3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aromatic heterocyclic ring being optionally substituted with 1-3 substituents each independently selectedfrom R’; and R’ is as defined in the present disclosure; or a stereoisomer, pharmaceuticallyacceptable salt, solvate, or hydrate thereof.Additionally, or alternatively, both X´, together with the carbons they are attached to, togetherform a 6 membered aromatic ring, wherein the aromatic ring being optionally substituted with1-3 substituents each independently selected from R’; and R’ is as defined in the presentdisclosure; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.Additionally, or alternatively, X is a 5-6 membered aromatic heterocyclic ring comprising 1-3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aromatic heterocyclic ring being optionally substituted with 1-3 substituents each independentlyselected from R’; and R’ is as defined in the present disclosure; or a stereoisomer,pharmaceutically acceptable salt, solvate, or hydrate thereof. Additionally, or alternatively, X is a 5-6 membered aromatic heterocyclic ring comprising 2-3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aromatic heterocyclic ring being optionally substituted with 1-3 substituents each independently selected from R’; andR’ is as defined in the present disclosure; or a stereoisomer, pharmaceutically acceptable salt,solvate, or hydrate thereof. Additionally, or alternatively, R4, R5, and R6are each independently selected from the groupconsisting of H, halogen, C1-8-alkyl, C1-8-alkyl-N(R9)(R10), C1-6-alkyl-C1-6-cycloalkyl, C1-6-alkyl-C1-6-heterocyclyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substitutedwith one or more halogen, or two of R4, R5, and R6, together with the carbon they are attached to, form a C3-8-cycloalkyl and the rest of R4, R5, and R6is H, wherein R9and R10are each independently selected from the group consisting of H, and C1-8-alkyl;R7, and R8 are each independently selected from the group consisting of H, and C1-8-alkyl,preferably H, methyl, and ethyl;provided that if Y is NH, both Z are CH, both R are H, and X is pyridinyl, 2-furanyl, 2-thiophenyl, phenyl or phenyl substituted with 1-3 substituents each independently selected fromR’, then R3 is not CH3 or CH2CH3; or a stereoisomer, pharmaceutically acceptable salt, solvate,or hydrate thereof. Additionally, or alternatively, X is a 6 membered aromatic ring, wherein the aromatic ring being optionally substituted with 1-3 substituents each independently selected from R’; wherein each R’ is independently selected from the group consisting of C1-8-alkylthio, C1-8-carboxamide group, C1-8-ester group, C1-8-urea group, C1-8-carbamate group, C6-10-aryl, C5-10-heteroaryl, and derivatives thereof being substituted with one or more halogen; or astereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.Additionally, or alternatively, R1and R2are each independently selected from the group consisting of H, C1-8-alkyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substitutedwith one or more halogen, wherein the C1-10-heteroaryl comprises 1-4 heteroatoms eachindependently selected from the group consisting of N, O, and S, preferably R1and R2are both H. Additionally, or alternatively, R1and R2are H; zero, one, or two Z are N and the rest of Z are C(R); Yis NH; andR is as defined in the present disclosure; or a stereoisomer, pharmaceutically acceptablesalt, solvate, or hydrate thereof. Additionally, or alternatively, R1and R2are H; X is a 5-6 membered aliphatic, aromatic or heterocyclic ring comprising 0-2 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-5 substituents each independently selected from R’, or both X´, together with the carbons they are attached to, together form a 5-6 memberedaliphatic, aromatic or heterocyclic ring comprising 0-2 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’; and R’ is as defined in the present disclosure; and Yis NH; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.Additionally, or alternatively, Y is NH; both Z are CH; both R are H; and at least one of R4, R5 and R6 is each independently selected from the group consisting ofC2-8-alkyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substituted with one or more halogen, and the rest of R4, R5and R6is each independently selected from the group consisting of H, C1-8-alkyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substitutedwith one or more halogen; or a stereoisomer, pharmaceutically acceptable salt, solvate, orhydrate thereof. Additionally, or alternatively, Y is NH; and R3 is t-Bu; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydratethereof. Additionally, or alternatively, R1and R2are H; both Z are CH; Y is NH; and R3 is t-Bu; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydratethereof. Additionally, or alternatively, R1and R2are H; zero, one, or two Z are N and the rest of Z are C(R);Y is O; and Ris as defined in the present disclosure; or a stereoisomer, pharmaceutically acceptablesalt, solvate, or hydrate thereof. Additionally, or alternatively, R3 is selected from H, trifluoromethyl, t-butyl, cyclopropyl, and -CH2CH2N(Me)2, or R3is methyl, provided that X is a 5-10 membered aliphatic, aromatic or heterocyclic ring comprising 2-3 heteroatoms each independently selected from the group consisting of N, O, and S, preferably 2 N, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-5 substituents each independently selected from R’. Additionally, or alternatively, provided that if X is pyridinyl, 2-furanyl, 2-thiophenyl, phenyl orphenyl substituted with 1-3 substituents each independently selected from R’, Y is NH, both Zare CH, and both R are H, then R3 is not CH3 or CH2CH3; and R and R’ are as defined in thepresent disclosure.Additionally, or alternatively, R4, R5, and R6 are each independently selected from the groupconsisting of H, halogen, C1-8-alkyl, C1-8-alkyl-N(R9)(R10), C1-6-alkyl-C1-6-cycloalkyl, C1-6-alkyl-C1-6-heterocyclyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substituted with one or more halogen, or two of R4, R5, and R6, together with the carbon they are attachedto, form a C3-8-cycloalkyl and the rest of R4, R5, and R6 is H, wherein R9 and R10 are eachindependently selected from the group consisting of H, and C1-8-alkyl, preferably selected from the group consisting of H, methyl, and ethyl; and R7, and R8are each independently selected from the group consisting of H, and C1-8-alkyl, preferably H, methyl, and ethyl; provided that if Y is NH, both Z are CH, both R are H, and X is pyridinyl, 2-furanyl, 2-thiophenyl, phenyl or phenyl substituted with 1-3 substituents each independently selected fromR’, then at least one of R4, R5, and R6 is each independently selected from the group consistingof halogen, preferably F, C1-8-haloalkyl, C2-8-alkyl, C1-8-alkyl-N(R9)(R10), C1-6-alkyl-C1-6-cycloalkyl, C1-6-alkyl-C1-6-heterocyclyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereofbeing substituted with one or more halogen, and the rest of R4, R5, and R6is each independentlyselected from the group consisting of H, halogen, preferably F, C1-8-alkyl, C1-8-haloalkyl, C1-8-alkyl-N(R9)(R10), C1-6-alkyl-C1-6-cycloalkyl, C1-6-alkyl-C1-6-heterocyclyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substituted with one or more halogen. Additionally, or alternatively, X is a 6-10 membered aromatic heterocycle comprising 2-5heteroatoms each independently selected from the group consisting of N, O, and S, wherein thearomatic heterocycle being optionally substituted with 1-3 substituents each independentlyselected from R’; andR3 is H, C(R4)(R5)(R6), or R’’, wherein R’’, together with X and the carbon they areattached to, forms a bi- or tricyclic 8-13 membered heterocyclic ring comprising an unsaturated5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-memberedheterocyclic ring is fused with X and is substituted with N(R7)(R8);wherein R4, R5, R6, R7, R8, R’, and R’’ are as defined in the present disclosure.Additionally, or alternatively, R1and R2are H; X is a 5-6 membered aliphatic, aromatic or heterocyclic ring comprising 0-2 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-5 substituents each independently selected from R’, orboth X´, together with the carbons they are attached to, together form a 5-6 memberedaliphatic, aromatic or heterocyclic ring comprising 0-2 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’; and R’ is as defined in the present disclosure; and Yis O; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.Additionally, or alternatively, the compound has formula (IV): formula (IV), wherein R1, R2, R7, R8, R, Y, and Z are as defined in the present disclosure; andeach X´´ is independently selected from the group consisting of C(R’), and N; and R´ isas defined in the present disclosure; or a stereoisomer, pharmaceutically acceptable salt, solvate,or hydrate thereof.Additionally, or alternatively, 1-2 of X´´ is / are N and 2-3 of X´´ are C(R´); and R´ is as definedin the present disclosure; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydratethereof. Additionally, or alternatively, 1-2 of X´´ is / are N and 2-3 of X´´ are CH; or astereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.Additionally, or alternatively, the compound is selected from: 4-(2-(2,2-dimethyl-1-(pyridin-3-yl)propylidene)hydrazineyl)benzenesulfonamide;(Z)-4-(2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethylidene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(1-(5-bromopyridin-3-yl)ethylidene)hydrazineyl)benzenesulfonamid; (E)-4-(2-(cyclopropyl(5-fluoropyridin-3-yl)methylene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(1-(quinoxalin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(pyridin-3-ylmethylene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(1-(pyrazin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(1-(3-methylpyrazin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(1-(3,5-dimethylpyrazin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(3-(dimethylamino)-1-(pyrazin-2-yl)propylidene)hydrazineyl)benzenesulfonamide; 4-(((1-(pyridin-3-yl)ethylidene)amino)oxy)benzenesulfonamide; 4-(2-(3-amino-1H-isoindol-1-ylidene)hydrazineyl)benzenesulfonamide;4-(2-(7-amino-5H-pyrrolo[3,4-b]pyridin-5-ylidene)hydrazineyl)benzenesulfonamide; and4-(2-(7-amino-5H-pyrrolo[3,4-b]pyrazin-5-ylidene)hydrazineyl)benzenesulfonamide;or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.Additionally, or alternatively, the compound is selected from: or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.It is to be understood that the compounds of the present disclosure may be in different tautomer forms, i.e., there may be two or more tautomers of the same compound. E.g., tautomers ofcompound A12 (4-(2-(3-amino-1H-isoindol-1-ylidene)hydrazineyl)benzenesulfonamide and 4-[(Z)-(3-iminoisoindolin-1-ylidene)hydrazino]benzenesulfonamide) may have the following structures: Therefore, even though some of the compounds presented in the present disclosure is presentedonly with one structure (with one tautomeric form), it is to be understood that the compoundsof the present invention also include the other possible tautomeric form(s) of the compounds.Therefore, the terms ”unsaturated 5-membered heterocyclic ring comprising 1 nitrogen, whereinthe unsaturated 5-membered heterocyclic ring is fused with X and is optionally substituted withN(R7)(R8)” should be understood such that the unsaturated 5-membered heterocyclic ring comprising 1 nitrogen may be unsaturated due to one of the tautomeric forms it may have.In one aspect is disclosed a composition comprising the compound, or a stereoisomer,pharmaceutically acceptable salt, solvate, or hydrate thereof, as defined in the presentdisclosure. Additionally, or alternatively, the composition as defined in the present disclosure comprising one or more compounds as defined in the present disclosure in combination with one or more other active ingredients. Additionally, or alternatively, the one or more other active ingredients are each independently selected from active ingredients for use in the treatment orprevention of an ocular disease or condition, such as glaucoma, macular edema (ME), and adegenerative retinal disease, such as retinitis pigmentosa and AMD; or idiopathic intracranial hypertension (IIH). Additionally, or alternatively, the one or more other active ingredients are eachindependently selected from latanoprost and timolol.In one aspect is disclosed a compound, or a stereoisomer, pharmaceutically acceptablesalt, solvate, or hydrate thereof, or a composition as defined in the present disclosure for use asa medicament. In one aspect is disclosed a compound of formula (I), or a stereoisomer,pharmaceutically acceptable salt, solvate, or hydrate thereof, or a composition as defined in thepresent disclosure for use in a method for the treatment or prevention of an ocular disease orcondition, or idiopathic intracranial hypertension (IIH).Additionally, or alternatively, the compound, or a stereoisomer, pharmaceutically acceptablesalt, solvate, or hydrate thereof, or the composition as defined in the present disclosure for usein the method as defined in the present disclosure, wherein the ocular disease or condition isselected from glaucoma, macular edema (ME), and a degenerative retinal disease.Additionally, or alternatively, the compound, or a stereoisomer, pharmaceutically acceptablesalt, solvate, or hydrate thereof, or the composition as defined in the present disclosure for usein the method as defined in the present disclosure, wherein the glaucoma is selected from acuteangle-closure glaucoma, angle-closure glaucoma, open angle glaucoma, pediatric glaucoma andpseudoexfoliative glaucoma.Additionally, or alternatively, the compound, or a stereoisomer, pharmaceutically acceptablesalt, solvate, or hydrate thereof, or the composition as defined in the present disclosure for usein the method as defined in the present disclosure, wherein the degenerative retinal disease isselected from retinitis pigmentosa and AMD (Age-Related Macular Degeneration). CAIs havebeen shown to have retinoprotective effects (Graefes Arch Clin Exp Ophthalmol. 2005Feb;243(2):163-8; Expert Opinion on Therapeutic Patents, 2019; 29:10, 761-767; Int. J. Mol. Sci. 2019, 20(3), 467).Additionally, or alternatively, the compound, or a stereoisomer, pharmaceutically acceptablesalt, solvate, or hydrate thereof, as defined in the present disclosure for use in the method asdefined in the present disclosure, wherein the method comprises administering to a subject inneed thereof a therapeutically effective amount of the compound, or the stereoisomer,pharmaceutically acceptable salt, solvate, or hydrate thereof. In one aspect is disclosed a use of a compound of formula (I), or a stereoisomer,pharmaceutically acceptable salt, solvate, or hydrate thereof, as defined in the present disclosurein a method for the treatment or prevention of an ocular disease or condition, or idiopathic intracranial hypertension (IIH). Additionally, or alternatively, the ocular disease or condition is selected from glaucoma, macular edema (ME), serous retinal detachment and a degenerative retinal disease. Additionally, or alternatively, the glaucoma is selected from acute angle-closure glaucoma,angle-closure glaucoma, open angle glaucoma, pediatric glaucoma and pseudoexfoliativeglaucoma. Additionally, or alternatively, the method comprises administering to a subject in need thereofa therapeutically effective amount of the compound, or a stereoisomer, pharmaceuticallyacceptable salt, solvate, or hydrate thereof, as defined in the present disclosure. In one aspect is disclosed a method for the preparation of a compound as defined in the present disclosure; wherein the method comprises:- providing a compound of formula (X) or a salt thereof: formula (X), and a compound of formula (XI´): formula (XI´) or a compound of formula (XI´´): formula (XI´´), wherein both X´, together with the carbons they are attached to, together form a 5-10 memberedaliphatic, aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’, each dotted line represents an optional bond, and R1, R2, R3, R, R’, X, Y, and Z are as defined in the present disclosure; and- reacting the compound of formula (X) or a salt thereof with the compound of formula(XI´) or the compound of formula (XI´´), optionally in the presence of a base, thereby forming a compound as defined in the present disclosure.Additionally, or alternatively, the compound of formula (XI´´): formula (XI´´), wherein both X´, together with the carbons they are attached to, together form a 5-6 memberedaliphatic, aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’, and each dotted line represents an optional bond. Additionally, or alternatively, the compound of formula (XI´´) is prepared by reacting a compound of formula (XIII): formula (XIII), with NH3, wherein both X´ are as defined in the present disclosure. CompoundsHerein are disclosed novel melanin-binding CAI inhibitors that reduce IOP and may be used forthe treatment or prevention of glaucoma and related ocular diseases, including IIH, and ME.The inhibitors apply a novel hybrid design, connecting a CAI moiety to a melanin-bindingaromatic or heteroaromatic moiety through a hydrazone or oxime linker. The combination ofmelanin-binding aromatic or heteroaromatic moiety and hydrazone / oxime linker may allow fora tuning of drug action over very wide range in the acidic pH of the cellular melanosomes. Illustrative example compounds include compounds A1-A14: , and stereoisomers, pharmaceutically acceptablesalts, solvates, or hydrates thereof.Pharmaceutical Compositions and Methods of Use The compounds disclosed herein may be used for treating glaucoma, idiopathic intracranial hypertension (IIH), and macular edema (ME). In some embodiments, the methods disclosed herein involve administering to a subject in need of treatment a pharmaceutical composition, for example a composition that includes a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of thecompounds disclosed herein. The compounds may be administered orally, parenterally(including subcutaneous injections (SC or depo-SC), intravenous (IV), intramuscular (IM or depo-IM), intrasternal injection or infusion techniques), sublingually, intranasally (inhalation),intrathecally, topically, ophthalmically, or rectally. The pharmaceutical composition may beadministered in dosage unit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants, and / or vehicles. The compounds are preferably formulated intosuitable pharmaceutical preparations such as tablets, capsules, or elixirs for oral administrationor in sterile solutions or suspensions for parenteral administration. Typically, the compoundsdescribed above are formulated into pharmaceutical compositions using techniques and procedures well known in the art. In some embodiments, one or more of the disclosed compounds are mixed or combined with a suitable pharmaceutically acceptable carrier to prepare a pharmaceutical composition. Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to be suitable for the particular mode of administration. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21stEdition (2005), describes exemplary compositions and formulations suitable for pharmaceutical delivery of thecompounds disclosed herein. In addition, the compounds may be formulated as the solepharmaceutically active ingredient in the composition or may be combined with other active ingredients. Upon mixing or addition of the compound(s) to a pharmaceutically acceptable carrier,the resulting mixture may be a solution, suspension, emulsion, or the like. Liposomalsuspensions may also be suitable as pharmaceutically acceptable carriers. These may beprepared according to methods known to those skilled in the art. The form of the resultingmixture depends upon a number of factors, including the intended mode of administration andthe solubility of the compound in the selected carrier or vehicle. Where the compounds exhibitinsufficient solubility, methods for solubilizing may be used. Such methods are known andinclude, but are not limited to, using cosolvents such as dimethylsulfoxide (DMSO), usingsurfactants such as Tween®, and dissolution in aqueous sodium bicarbonate. Derivatives of thecompounds, such as salts or prodrugs may also be used in formulating effective pharmaceuticalcompositions. The disclosed compounds may also be prepared with carriers that protect themagainst rapid elimination from the body, such as time-release formulations or coatings. Suchcarriers include controlled release formulations, such as, but not limited to, microencapsulated delivery systems. The disclosed compounds and / or compositions can be enclosed in multiple or singledose containers. The compounds and / or compositions can also be provided in kits, for example,including component parts that can be assembled for use. For example, one or more of thedisclosed compounds may be provided in a lyophilized form and a suitable diluent may beprovided as separated components for combination prior to use. In some examples, a kit mayinclude a disclosed compound and a second therapeutic agent (such as an anti-retroviral agent)for co-administration. The compound and second therapeutic agent may be provided as separatecomponent parts. A kit may include a plurality of containers, each container holding one or moreunit dose of the compound. The containers are preferably adapted for the desired mode ofadministration, including, but not limited to tablets, gel capsules, sustained-release capsules, and the like for oral administration; depot products, pre-filled syringes, ampoules, vials, and the like for parenteral administration; and patches, medipads, creams, and the like for topical administration. The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on thesubject treated. A therapeutically effective concentration may be determined empirically bytesting the compounds in known in vitro and in vivo model systems for the treated disorder. Insome examples, a therapeutically effective amount of the compound is an amount that lessens or ameliorates at least one symptom of the disorder for which the compound is administered.Typically, the compositions are formulated for single dosage administration. The concentrationof active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the active compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. In some examples, about 0.1 mg to 1000 mg of a disclosed compound, a mixture of such compounds, or a physiologically acceptable salt or ester thereof, is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor,etc., in a unit dosage form. The amount of active substance in those compositions or preparationsis such that a suitable dosage in the range indicated is obtained. The term “unit dosage form”refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In some examples, the compositions are formulated in a unit dosage form, each dosage containing from about 1 mg to about 1000 mg (for example, about 2 mg to about 500 mg, about 5 mg to 50 mg, about 10 mg to 100 mg, or about 25 mg to 75 mg) of the one or more compounds. In other examples, the unit dosage form includes about 0.1 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, or more of the disclosed compound(s). The disclosed compounds or compositions may be administered as a single dose, or maybe divided into a number of smaller doses to be administered at intervals of time. The therapeuticcompositions can be administered in a single dose delivery, by continuous delivery over an extended time period, in a repeated administration protocol (for example, by a multi-daily, daily,weekly, or monthly repeated administration protocol). It is understood that the precise dosage,timing, and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage values may also vary with theseverity of the condition to be alleviated. In addition, it is understood that for a specific subject,dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only. When administered orally as a suspension, these compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners / flavoring agents. As immediaterelease tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and / or other excipients, binders, extenders, disintegrants,diluents and lubricants. If oral administration is desired, the compound is typically provided ina composition that protects it from the acidic environment of the stomach. For example, thecomposition can be formulated in an enteric coating that maintains its integrity in the stomachand releases the active compound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient. Oral compositions will generally include an inert diluent or an edible carrier and may becompressed into tablets or enclosed in gelatin capsules. For the purpose of oral therapeuticadministration, the active compound or compounds can be incorporated with excipients andused in the form of tablets, capsules, or troches. Pharmaceutically compatible binding agentsand adjuvant materials can be included as part of the composition. The tablets, pills, capsules,troches, and the like can contain any of the following ingredients or compounds of a similar nature: a binder such as, but not limited to, gum tragacanth, acacia, corn starch, or gelatin; an excipient such as microcrystalline cellulose, starch, or lactose; a disintegrating agent such as, but not limited to, alginic acid and corn starch; a lubricant such as, but not limited to, magnesium stearate; a gildant, such as, but not limited to, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and a flavoring agent such as peppermint, methyl salicylate, or fruit flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of theabove type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain variousother materials, which modify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administered as a component of anelixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition tothe active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors. When administered orally, the compounds can be administered in usual dosage formsfor oral administration. These dosage forms include the usual solid unit dosage forms of tabletsand capsules as well as liquid dosage forms such as solutions, suspensions, and elixirs. Whenthe solid dosage forms are used, it is preferred that they be of the sustained release type so thatthe compounds need to be administered only once or twice daily. In some examples, an oraldosage form is administered to the subject 1, 2, 3, 4, or more times daily. In additional examples,the compounds can be administered orally to humans in a dosage range of 1 to 1000 mg / kg bodyweight in single or divided doses. One illustrative dosage range is 0.1 to 200 mg / kg body weightorally (such as 0.5 to 100 mg / kg body weight orally) in single or divided doses. For oraladministration, the compositions may be provided in the form of tablets containing about 1 to 1000 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200,250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of the active ingredient. It will beunderstood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion,drug combination, the severity of the particular condition, and the host undergoing therapy.Injectable solutions or suspensions may also be formulated, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer’s solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspendingagents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fattyacids, including oleic acid. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, and the like, or a synthetic fatty vehicle such as ethyl oleate, and the like, polyethylene glycol, glycerine, propylene glycol, or other synthetic solvent; antimicrobial agents such as benzyl alcohol and methyl parabens; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, and phosphates; andagents for the adjustment of tonicity such as sodium chloride and dextrose. Parenteralpreparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made ofglass, plastic, or other suitable material. Buffers, preservatives, antioxidants, and the like can beincorporated as required. Where administered intravenously, suitable carriers include physiological saline, phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agentssuch as glucose, polyethylene glycol, polypropyleneglycol, and mixtures thereof. Liposomalsuspensions including tissue-targeted liposomes may also be suitable as pharmaceutically acceptable carriers. The compounds can be administered parenterally, for example, by IV, IM, depo-IM, SC,or depo-SC. When administered parenterally, a therapeutically effective amount of about 0.1 toabout 500 mg / day (such as about 1 mg / day to about 100 mg / day, or about 5 mg / day to about 50mg / day) may be delivered. When a depot formulation is used for injection once a month or onceevery two weeks, the dose may be about 0.1 mg / day to about 100 mg / day, or a monthly dose of from about 3 mg to about 3000 mg. The compounds can also be administered sublingually. When given sublingually, thecompounds should be given one to four times daily in the amounts described above for IM administration. The compounds can also be administered intranasally. When given by this route, theappropriate dosage forms are a nasal spray or dry powder. The dosage of the compounds forintranasal administration is the amount described above for IM administration. Whenadministered by nasal aerosol or inhalation, these compositions may be prepared according totechniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents. The compounds can be administered intrathecally. When given by this route, theappropriate dosage form can be a parenteral dosage form. The dosage of the compounds forintrathecal administration is the amount described above for IM administration. The compounds can be administered topically. When given by this route, the appropriatedosage form is a cream, ointment, or patch. When administered topically, an illustrative dosageis from about 0.5 mg / day to about 200 mg / day. Because the amount that can be delivered by apatch is limited, two or more patches may be used. The compounds can be administered rectally by suppository. When administered bysuppository, an illustrative therapeutically effective amount may range from about 0.5 mg toabout 500 mg. When rectally administered in the form of suppositories, these compositions maybe prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and / or dissolve in the rectal cavity to release the drug. It should be apparent to one skilled in the art that the exact dosage and frequency of administration will depend on the particular compounds administered, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular subject, and other medication the individual may be taking as is well known to administering physicians or other clinicians who are skilled in therapy of retroviral infections, diseases, and associated disorders. ExamplesBiological screens for assessing CAI inhibitors that reduce IOP and are promisingcandidates for the treatment of glaucoma and related ocular disease, including IIH, and ME. Assay 1. PROFILING OF THE SYNTHESIZED COMPOUNDS VIA ESTERASE ACTIVITY ASSAYThe protocol was based on a literature method described in J. Enz. Inhib. Med. Chem. 30:6, 955-960 (2015). Synthesized compounds A1-14 were evaluated for their inhibitory activity against carbonic anhydrase II using the established 4-nitrophenylacetate (NPA) esterase assay. Human carbonic anhydrase II (hCA II), commercially sourced (C6165-5MG, Sigma-Aldrich St. Louis,USA), was used as a model enzyme, and acetazolamide, subsequently denoted as AAZ (A6011-10G, Sigma-Aldrich St. Louis, USA), served as a reference compound. The assay setup included a final concentration of 70 nM hCA II and 0.5 mM NPA (N8130-10G, Sigma-Aldrich St. Louis,USA) in an assay buffer of 200 µL (comprising of 1 % dimethyl sulfoxide, 0.5 mMethylenediaminetetraacetic acid, 20 mM Tris buffer, and 33 mM sodium sulfate, pH 7.4). The optimal concentration of hCA II for the assay was determined by titration; NPA substrate concentration of 0.5 mM was chosen based on observed Km-value for the hCA II esterase activity, 10.4 mM (SEM 1.8 mM). The range of inhibitor concentrations chosen based onapparent IC50-value of AAZ (11.8 nM) and followed 10-fold dilution with 3 concentrationsabove and below the said value. With the initial estimate of the IC50-value, the concentration range was adjusted accordingly, and the assay was performed again with 3-fold dilution. All measurements were performed as triplicates. For the inhibition experiments, hCA II was pre-incubated with potential inhibitors for 10 minutes at 25 °C before initiating the reaction with NPA. Enzymatic activity was determined by tracking the formation of the colored compound, 4-nitrophenol (4-NP), measuring its absorbance at 405 nm at 0.5-minute intervals over a span of 10 minutes at 25°C. To ensure accuracy in determining enzyme activity, ethylenediaminetetraacetic acid was added to the assay buffer to suppress the spontaneous hydrolysis of the substrate. The initial rate of the enzymatic reaction was derived from the slope obtained by plotting the absorbance (405 nm) as a function of time. This rate was subsequently utilized to compute the enzyme activity as a percentage. The degree of inhibition rendered by the compounds was estimated by benchmarking against the enzyme's activity in an inhibitor-free environment, set at 100%. IC50values were deduced using a non-linear least-squares method via PRISM 5 / 10 (Graphpad Software Inc., La Jolla, CA). These IC50values were then translated to Ki values utilizing the equation (i): i. Ki= IC50 / (1+([S] / Km))The results are presented in Table 1.Table 1. IC50 and Ki values of compounds A1-A14 and AAZ measured in an esterase activityassay against human carbonic anhydrase II.CA II Compound IC50 (nM) 95% CI Ki (nM)inhibitory activity AAZ 11.8 10.62 - 13.03 11.26 +++A1 430.2 341.4 - 533.1 410.41 ++A2 149.1 127.2 - 172.7 142.24 +++A3 450.5 406.1 - 497.0 429.78 ++A4 136.7 120.1 - 154.2 130.41 +++A5 156.4 144.7 - 168.5 149.21 +++A6 295 274.2 - 316.4 281.43 +++A7 284.8 254.6 - 316.6 271.70 +++A8 98.42 85.06 - 112.4 93.89 +++A9 124.2 104.5 - 145.4 118.49 +++A10 763.9 662.6 - 871.5 728.76 ++A11 116.8 104.8 - 129.7 111.43 +++A12 95.29 85.55 - 105.5 90.91 +++A13 142.1 125.8 - 159.5 135.56 +++A14 97.77 84.46 - 112.5 93.27 +++Based on these assay results, A1, A3 and A10 were classified as an intermediate hCA IIinhibitors, whereas A2, A4-9 and A11-14 were classified as potent hCA II inhibitors.Assay 2. MEASURING MELANIN BINDING OF THE SYNTHESIZED COMPOUNDSThe method was based on literature protocol described in Int. J. Toxicol. 37:4, 296-307, (2018).Melanin (Melanin M8631-1G Sigma-Aldrich St Louis, MO, USA) was mixed with 100 mM potassium phosphate buffer pH 7.4 to yield a 2 mg / mL suspension, and subsequently sonicated for 5 minutes. Incubation solutions for the test compound were produced by diluting 10 mM, previously prepared in DMSO, 50-fold in 100 mM potassium phosphate buffer pH 7.4 resulting in solutions with 200 µM drug concentration containing 2% DMSO. Both the melaninsuspensions and the test compound solutions were prepared no more than 4 hours before thestart of the incubations. For the assay, 200 µL of melanin suspension was mixed with 200 µL of the test compound solution, prepared in triplicate. Control samples (incubated, non-incubated, and filtered) were also made in triplicate by mixing 200 µL of the test compound solution with 200 µL of 100 mM potassium phosphate buffer pH 7.4. Melanin samples and incubation controls were incubated at room temperature with gentle shaking for 24 hours. Post-incubation, samples were centrifuged at 16,000g for 30 min. 300 µL of melanin sample supernatants and filtration controls weretransferred into centrifugal filters (Amicon Ultra Centrifugal Filter – 0,5 mL, RegeneratedCellulose 3,000 Da MWCO, UFC5003 Merck Millipore Ltd.) and centrifuged 10,000g for 60 min. For the analysis the samples were diluted by mixing 100 µL of sample solution or filtrate with 400 µL of MilliQ H2O and 500 µL of acetonitrile. All diluted samples were vortex-mixedbefore transferring 100 µL of each into 96-well plates for autosampler.Brimonidine (Brimonidine tartrate PHR2795-500MG Sigma-Aldrich St. Louis, MO, USA) and amitriptyline (Amitriptyline hydrochloride A8404-10G Sigma-Aldrich St Louis, MO, USA)were chosen as control compounds with varying affinities towards melanin. Brimonidine hashigh binding affinity towards melanin while amitriptyline is an intermediate melanin binder, asreported in Drug Metab. Dispos. 23:7, 708-12, (1995), and J. Pharm. Sci. 104:12;3997-4001(2015). The analysis was conducted using an Agilent UHPLC-QTOF-MS system (Agilent Technologies 1290 LC, 6540 MS, Agilent Technologies, Santa Clara, CA, USA). Column used was InfinityLab Poroshell 120 SB-C18 (50 mm × 2.1 mm, 2.7 µm, Agilent Technologies). The column temperature was set to 40 °C, flow rate 0.5 mL / min, injection volume 2 µL, and gradient elution was used for the analysis with water (eluent A) and acetonitrile (eluent B). Both eluentscontained 0.1% v / v of formic acid. The following eluent gradient was used: 0-9.80 min: 2 →95% B; 9.80-10.20 min: 95% B; 10.20-10.21 min: 95 → 2% B; 10.21-12.50 min: 2% B. The samples underwent ionization and were subsequently introduced into the time-of-flight mass analyzer. Data acquisition, processing, and interpretation were managed using Agilent MassHunter Quantitative Analysis for Q-TOF software (Version B.09.00, Agilent Technologies). For the in vitro experiments, test compound concentrations were measured using this QTOF-MS system, setting the corresponding non-incubated reference controls as 100%.The results are summarized in Table 2.Table 2. Determination of the fraction unbound (Fu) for compounds A1-14, brimonidine, andamitriptyline in a suspension of synthetic melanin.Compound Fu, % SD, % Melanin binderAffinity to melanin classification Brimonidine 8.5 0.1 High binder +++Amitriptyline 13.3 1.1 Intermediate binder ++A1 94.4 1.8 Low binder +A2 22.5 2.0 Intermediate binder ++A3 1.2 1.8 High binder +++A4 14.1 1.5 Intermediate binder ++A6 6.3 0.3 High binder +++A7 26.9 0.6 Intermediate binder ++A8 25.5 3.2 Intermediate binder ++A9 5.2 2.0 High binder +++A10 0.3 3.8 High binder +++A11 9.8 0.8 High binder ++A12 2.5 0.2 High binder +++A13 4.6 3.5 High binder +++A14 4.5 0.1 High binder +++Based on the experiment results, A1 was classified as a low melanin binder, while A2, A4, A7,and A8 were categorized as intermediate melanin binders, and A3, A6, A9-14 were classifiedas high melanin binders.To confirm the observed structure-property relationship trends, the discovered high melaninbinders were further profiled via an orthogonal assay, namely microscale thermophoresisagainst melanin nanoparticles. The protocol was based on the method described inPharmaceutics, 12:6; 554, (2020). A dilution series with concentrations of 1000 µM, 200 µM,100 µM, 10 µM, 1 µM, 0.1 µM, 0.01 µM and 0 µM were prepared in 1xPBS for the compound analyzed, on a PCR-plate (96 Well semi-skirted PCR plates, #4ti0760, 4titude Ltd, Wotton,Surrey, U.K.). Equal volumes (10 µL) of both compound dilutions and MNP (1 mg / mL) solutionwere transferred to PCR tube strips (8-well PCR Tube strips, Nippon Genetics GmbH, Germany), the melanin solution pipetted with low-binding pipette tips (Maximum Recovery pipet tips, #T-200C-L-R, Corning Incorporated, Salt Lake City, UT, USA) to prevent aggregation and adsorption. PCR strips containing the samples were left on a shaker (Heidolph Titramax 101, Heidolph Instruments GmbH, Germany) to incubate in room temperature for at least 2 hours before analysis. Following adequate incubation, the samples containing the melanin-compound solution were drawn into glass capillaries (Monolith NT.115 Premium Capillaries, #MO-K025, NanoTemper Technologies GmbH, München, Germany), placed on the tray and inserted into the Monolith NT.115Pico (NanoTemper Technologies GmbH, München, Germany). The built-in MO.Control Software was configured with the following settings: activated expert mode,enabled nano-blue fluorescence channel, 60% excitation power, high infrared laser power, anda capillary heating duration of 30 seconds. The measurements were performed in triplicates. Theresults are provided in Table 3.Table 3. MST profiling of high melanin binders A3, A6, and A9-A14, brimonidine, andamitriptyline against melanin nanoparticles.Affinity to MST Kd (µM) Kd confidenceCompound Classification melanin (µM) nanoparticles Brimonidine 109 136 High binder +++Intermediate Amitriptyline 265 149++ binder Intermediate A3 340 164++ binder A6 216 325 High binder +++A9 23 19 High binder +++A10 45 41 High binder +++A11 158 65 High binder +++A12 97 48 High binder +++A13 147 43 High binder +++A14 174 91 High binder +++Based on the results from the orthogonal assay, A3 was classified as an intermediate binder,whereas A6, A9, and A11-14 were classified as high melanin binders.EXAMPLE 1. SYNTHESIS OF POTENTIAL MELANIN BINDING CARBONICANHYDRASE INHIBITORS ACCORDING TO THE INVENTIONGeneral Synthetic Methods. All reaction solvents were dried prior to use. THF was freshly distilled from a sodium / benzophenone radical anion solution and CH2Cl2, acetonitrile, and toluene were freshly distilled over (CaH2). Et3N, DIPEA, and pyridine were distilled (CaH2. When necessary, degassed solvents were prepared by freeze-pump-thaw techniques. Unless stated otherwise, all reactions were performed under an atmosphere of N2 that was passed through a short cartridge (10 × 2 cm) of drierite®. All glassware and stir bars were flame-dried prior to use. Reactions were monitored by TLC analysis (pre-coated silica gel 60 F254) and spots were visualized (UV lamp 254 nm and 395 nm). IR spectra were obtained using a PerkinElmer 100 IR-ATR spectrometer. Melting points were obtained using a Mel-Temp instrument and are uncorrected.1H / 13C NMR spectra were recorded on a Bruker Avance HD III 600 spectrometer. All NMR experiments were measured at 298 K. High resolution mass spectrawere obtained on an Agilent 1260 Infinity LC system coupled with an Agilent 6410 triplequadrupole mass spectrometer with an electrospray ionization source (Agilent Technologies, Palo Alto, CA). Chemical shifts were reported in parts per million (ppm) with the residual solvent peak (CDCl3: 7.26 ppm for1H, 77.16 ppm for13C; DMSO-d6: 2.50 ppm for1H, 39.52 ppm for13C) used as the internal standard. Chemical shifts were tabulated as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, h = sextet, dd = doublet of doublet, dt = doublet of triplet, ddd = doublet of doublet of doublet, tt = triplet of triplet, dtd = double of triplet of doublet, dddd = doublet of doublet of doublet of doublet, dddt = doublet of doublet of doublet of triplet, dtdd = doublet of triplet of doublet of doublet, ddtd = doublet of doublet of triplet of doublet, dtt = doublet of doublet of triplet, m = multiplet, brs = broad singlet, AB = second order AB spin system doublet of doublet, app = apparent), coupling constant(s), and integration. The purity of final products was assessed using a UHPLC-qTOF- MS system (1290 UHPLC, Jetstream ESI source, 6540 UHD qTOF-MS, Agilent Technologies, Waldbronn, Karlsruhe, Germany). Data acquisition software was MassHunter Acquisition B.04.00 (Agilent Technologies). All final assay samples showed a purity >95% by LCMS analysis with UV (220 nm) and ELS detection. The following examples are set forth below to illustrate the methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results.These examples are not intended to exclude equivalents and variations of the present invention,which are apparent to a person of ordinary skill in the art. Procedure A. Synthesis of 4-(2-(2,2-dimethyl-1-(pyridin-3- yl)propylidene)hydrazineyl)benzenesulfonamide (A1) 2,2-Dimethyl-1-(pyridin-3-yl)propan-1-one (100 mg, and 4-hydrazineylbenzenesulfonamide hydrochloride (114 mg, 0.61 mmol) were dissolved in aceticacid (2mL). The mixture was then refluxed for 4 hours. After cooling to room temperature, the resulting precipitate was collected by filtration. The precipitate was subsequently washed withcooled ethanol (2 mL) and dried in vacuo to provide 4-(2-(2,2-dimethyl-1-(pyridin-3-yl)propylidene)hydrazineyl)benzenesulfonamide (A1) in a yield of 180 mg (88%): 1H NMR(600 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.99 (dd, J = 5.7, 1.1 Hz, 1H), 8.84 (d, J = 1.1 Hz, 1H), 8.33 (d, J = 7.8 Hz, 1H), 8.11 (dd, J = 7.8, 5.7 Hz, 1H), 7.62 (d, J = 8.9 Hz, 2H), 7.14 (d, J = 8.9Hz, 2H), 7.07 (s, 2H), 1.18 (s, 9H); 13C NMR (150 MHz, DMSO-d6) δ 149.1, 148.4, 145.3,143.1, 142.7, 133.8, 132.6, 127.3, 127.1 (2C), 111.7 (2C), 37.9, 28.3 (3C). HRMS (ESI / Q-TOF)m / z [M+H]+ Calcd for C16H21N4O2S+ 333.1380; Found 333.1382.Procedure B. Synthesis of compounds A2-A104-Hydrazineylbenzenesulfonamide hydrochloride (94 mg, 0.5 mmol) and corresponding ketone(0.5 mmol) were dissolved in EtOH (4 mL). Acetic acid (20 µL) was added and the mixture washeated at reflux for 4 h. After cooling to room temperature, the resulting precipitate was collected by filtration. The precipitate was subsequently washed with cooled ethanol (2 mL) anddried in vacuo. Where necessary, the purification was performed by column chromatography toprovide compounds (A2-A10) in the yields ranging between 19 and 88%.(Z)-4-(2-(2,2,2-Trifluoro-1-(pyridin-3-yl)ethylidene)hydrazineyl)benzenesulfonamide (A2) 2,2,2-Trifluoro-1-(pyridin-3-yl)ethan-1-one (88 mg, 0.5 mmol) was used as a starting material.(Z)-4-(2-(2,2,2-Trifluoro-1-(pyridin-3-yl)ethylidene)hydrazineyl)benzenesulfonamide wasobtained in a yield of 64 mg (37%): 1H NMR (600 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.79 (dd,J = 4.9, 1.6 Hz, 1H), 8.67 (d, J = 1.8 Hz, 1H), 7.94 (dt, J = 7.9, 1.8 Hz, 1H), 7.73 (d, J = 8.9 Hz,2H), 7.64 (ddd, J = 7.9, 4.9, 0.8 Hz, 1H), 7.32 (d, J = 8.9 Hz, 2H), 7.18 (s, 2H). 13C NMR (150MHz, DMSO-d6) δ 151.8, 150.0, 146.9, 137.9, 137.0, 129.1 (q, J = 34.5 Hz), 127.7, 125.0,124.5, 121.9 (q, J = 272.4 Hz), 113.8. HRMS (ESI / Q-TOF) m / z [M+H]+ Calcd forC13H12F3N4O2S+345.0628; Found 345.0628. (E)-4-(2-(1-(5-Bromopyridin-3-yl)ethylidene)hydrazineyl)benzenesulfonamide (А3) 1-(5-Bromopyridin-3-yl)ethan-1-one (100 mg, 0.5 mmol) was used as a starting material. (E)- 4-(2-(1-(5-bromopyridin-3-yl)ethylidene)hydrazineyl)benzenesulfonamide was obtained in ayield of 156 mg (84%).1H NMR (600 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.04 (d, J = 1.9 Hz,1H), 8.73 (d, J = 1.9 Hz, 1H), 8.48 (s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H),7.15 (s, 2H), 2.34 (s, 3H) ppm. 13C NMR (150 MHz, DMSO-d6) δ 148.4, 147.8, 144.3, 139.3,137.3, 136.7, 135.0, 127.7 (2С), 121.1, 113.0 (2С), 13.6. HRMS (ESI / Q-TOF) m / z [M+H]+Calcd for C13H14BrN4O2S+369.0015; Found 369.0015. (E)-4-(2-(Cyclopropyl(5-fluoropyridin-3-yl)methylene)hydrazineyl)benzenesulfonamide (A4) Cyclopropyl(5-fluoropyridin-3-yl)methanone (83 mg, 0.5 mmol) was used as a starting material. (E)-4-(2-(Cyclopropyl(5-fluoropyridin-3-yl)methylene)hydrazineyl)benzenesulfonamide was obtained in a yield of 131 mg (78%): 1HNMR (600 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.89 (t, J = 1.5 Hz, 1H), 8.58 (d, J = 2.6 Hz, 1H),8.12 – 8.08 (m, 1H), 7.71 – 7.69 (m, 2H), 7.47 – 7.43 (m, 2H), 7.13 (s, 2H), 1.85 – 1.74 (m, 1H),1.23 – 1.18 (m, 2H), 0.58 – 0.48 (m, 2H).13C NMR (150 MHz, DMSO-d6) δ 160.4, 158.7, 147.9,143.3 (d, J = 3.6 Hz), 142.1, 135.2, 127.6 (2C), 113.2 (2C), 8.3, 7.7(2C) ppm. HRMS (ESI / Q-TOF) m / z [M+H]+ Calcd for C15H16FN4O2S+ 335.0973; Found 335.0976. (E)-4-(2-(1-(Quinoxalin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide (A5) 1-(Quinoxalin-2-yl)ethan-1-one (86 mg, 0.5 mmol) was used as a starting material. (E)-4-(2-(1-(quinoxalin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide was obtained in a yield of 32 mg(19%): 1H NMR (600 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.75 (s, 1H), 8.08 (dd, J = 8.2, 1.3 Hz,1H), 8.06 (dd, J = 8.2, 1.3 Hz, 1H), 7.84 (ddd, J = 8.2, 7.0, 1.5 Hz, 1H), 7.80 (ddd, J = 8.2, 7.0,1.5 Hz, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.16 (s, 2H), 2.49 (s, 3H). 13CNMR (150 MHz, DMSO-d6) δ 150.8, 147.9, 144.2, 142.9, 141.3, 141.2, 135.7, 130.8, 130.0,129.4, 129.3, 127.8 (2C), 113.4 (2C), 11.4. HRMS (ESI / Q-TOF) m / z [M+H]+ Calcd forC16H16N5O2S+342.1019; Found 342.1020. (E)-4-(2-(Pyridin-3-ylmethylene)hydrazineyl)benzenesulfonamide (A6) Nicotinaldehyde (54 mg, 0.5 mmol) was used as a starting material. (E)-4-(2-(Pyridin-3-ylmethylene)hydrazineyl)benzenesulfonamide was obtained in a yield of 100 mg (72%): 1HNMR (600 MHz, DMSO-d6) δ 11.71 (s, 1H), 9.14 (d, J = 1.7 Hz, 1H), 8.80 – 8.72 (m, 2H), 8.12(s, 1H), 7.97 (dd, J = 8.1, 5.5 Hz, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.16(s, 2H).13C NMR (150 MHz, DMSO-d6) δ 147.5, 141.5, 140.6, 140.2, 135.3, 135.2, 132.9,127.9 (2C), 127.2, 112.5 (2C). HRMS (ESI / Q-TOF) m / z [M+H]+ Calcd for C12H13N4O2S+277.0754; Found 277.0754. (E)-4-(2-(1-(Pyrazin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide (A7) 1-(Pyrazin-2-yl)ethan-1-one (61 mg, 0.5 mmol) was used as a starting material. (E)-4-(2-(1-(Pyrazin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide was obtained in a yield of 114 mg(78%): 1H NMR (600 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.39 (d, J = 1.5 Hz, 1H), 8.59 (dd, J =2.6, 1.5 Hz, 1H), 8.52 (d, J = 2.6 Hz, 1H), 7.76 – 7.68 (m, 2H), 7.51 – 7.44 (m, 2H), 7.15 (s,2H), 2.38 (s, 3H).13C NMR (150 MHz, DMSO-d6) δ 151.7, 148.2, 143.6, 143.0, 142.5, 142.3,135.2, 127.7 (2C), 113.2 (2C), 11.6. HRMS (ESI / Q-TOF) m / z [M+H]+ Calcd for C12H14N5O2S+292.0863; Found 292.0865.(E)-4-(2-(1-(3-Methylpyrazin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide (A8) 1-(3-Methylpyrazin-2-yl)ethan-1-one (68 mg, 0.5 mmol) was used as a starting material. (E)-4- (2-(1-(3-Methylpyrazin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide was obtained in ayield of 115 mg (75%): 1H NMR (600 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.52 (d, J = 2.5 Hz,1H), 8.44 (d, J = 2.5 Hz, 1H), 7.70 (d, J = 8.9 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.12 (s, 2H),2.84 (s, 3H), 2.40 (s, 3H).13C NMR (150 MHz, DMSO-d6) δ 151.9, 150.7, 148.5, 144.4, 141.4,141.3, 135.0, 127.8 (2C), 112.8 (2C), 25.8, 14.3 ppm. HRMS (ESI / Q-TOF) m / z [M+H]+ Calcdfor C13H16N5O2S+306.1019; Found 306.1019. (E)-4-(2-(1-(3,5-Dimethylpyrazin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide (A9) 1-(3,5-Dimethylpyrazin-2-yl)ethan-1-one (75 mg, 0.5 mmol) was used as a starting material. (E)-4-(2-(1-(3,5-Dimethylpyrazin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide wasobtained in a yield of 106 mg (66%): 1H NMR (600 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.42 (s,1H), 7.69 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.11 (s, 2H), 2.81 (s, 3H), 2.49 (s, 3H),2.38 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 150.4, 150.0, 148.6, 147.9, 144.5, 140.7, 134.8,127.8 (2C), 112.7 (2C), 25.4, 20.8, 14.3. HRMS (ESI / Q-TOF) m / z [M+H]+ Calcd forC14H18N5O2S+320.1176; Found 320.1176. (E)-4-(2-(3-(Dimethylamino)-1-(pyrazin-2- yl)propylidene)hydrazineyl)benzenesulfonamide (A10) 3-(Dimethylamino)-1-(pyrazin-2-yl)propan-1-one (90 mg, 0.5 mmol) was used as a starting material. (E)-4-(2-(1-(3,5-Dimethylpyrazin-2-yl)ethylidene)hydrazineyl)benzenesulfonamidewas obtained in a yield of 86 mg (49%): 1H NMR (600 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.41(d, J = 1.5 Hz, 1H), 8.61 (dd, J = 2.4, 1.5 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 8.8 Hz,2H), 7.64 (d, J = 8.8 Hz, 2H), 7.17 (s, 2H), 3.42 – 3.32 (m, 2H), 3.30 – 3.20 (m, 2H), 2.88 (s,6H).13C NMR (150 MHz, MeOD) δ 151.1, 147.7, 143.0, 142.2, 142.2, 138.3, 135.3, 127.5 (2C),113.0 (2C), 53.4, 42.3 (2C), 20.0. HRMS (ESI / Q-TOF) m / z [M+H]+ Calcd for C15H21N6O2S+349.1441; Found 349.1441. Procedure C. Synthesis of 2-phenoxyisoindoline-1,3-dione This synthesis was performed as described in Angew. Chem. Int. Ed. Engl. 54:47, 14017-21(2015). N-hydroxyphthalimide (660 mg, 4.05 mmol) was dissolved in dichloroethane (20 mL). CuCl 400 mg, 4.05 mmol), phenylboronic acid (1000 mg, 8.10 mmol), pyridine (0.35 mL, 4.45 mmol) and 4Å molecular sieves (1000 mg) were subsequently added to the solution. The mixture was warmed to 80 °C and stirred for 48 h. The reaction mass was cooled to room temperature and the molecular sieves were removed by filtration. The crude was adsorbed on SiO2 and purified by column chromatography, eluting with dichloromethane, to obtain 2- phenoxyisoindoline-1,3-dione in a yield of 625 mg (65%). The structure was confirmed using1H and 13C NMR, as well as HRMS.Procedure D. Synthesis of 4-(aminooxy)benzenesulfonamide This protocol was based on the methods described in Bioorg. Med. Chem. 25:6, 1914-1925(2017), and Org. Lett. 16:6, 1830-2 (2014). 2-Phenoxyisoindoline-1,3-dione (400 mg, 1.67mmol) was added portionwise to a stirred and cooled mixture of HSO3Cl (1.11 mL, 16.72 mmol)and SOCl2 (0.12 mL, 1.67 mmol). The solution was heated at 60 °C for 4 h, cooled to roomtemperature and poured over crushed ice. The resulting mixture was extracted with ethyl acetate (10 mL), and the extract was washed with 5% aqueous K2CO3 (3x2 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting brown solid was then dissolved in dichloromethane and slowly added to 7N NH3 in methanol (5 mL) dropwise at 0°C. The solution was stirred overnight at room temperature in a sealed flask. The solvent was then removed under reduced pressure and the crude was purified chromatographically on SiO2 eluting with dichloromethane / methanol (100:1 to 100:10) to provide 4-(aminooxy)benzenesulfonamide intotal yield of 115 mg (36%): 1H NMR (600 MHz, DMSO-d6) δ 7.73 – 7.69 (m, 2H), 7.23 – 7.19(m, 2H), 7.16 (br. s, 2H), 7.12 (s, 2H). 13C NMR (150 MHz, DMSO-d6) δ 164.6, 136.3, 127.9(2C), 113.4 (2C). HRMS (ESI / Q-TOF) m / z [M+H]+ Calcd for C6H9N2O3S+ 189.0328; Found189.0330. Procedure E. Synthesis of 4-(((1-(pyridin-3-yl)ethylidene)amino)oxy)benzenesulfonamide (A11) This protocol was based on the method described in Org. Biomol. Chem. 20(32):6394-6399. Asolution of 4-(aminooxy)benzenesulfonamide (100 mg, 0.53 mmol), 3-acetylpyridine (64 mg, 0.53 mmol), and sodium acetate (13 mg, 0.16 mmol) was prepared in a solvent mixture of ethanol (2 mL) and water (0.5 mL). The reaction mixture was then stirred overnight at 60°C. The solvent was evaporated under reduced pressure. The resulting residue was dissolved in ethyl acetate (3 mL) and successively washed with water (2x1 mL) and brine (1 mL). The organic layer was separated and dried over anhydrous Na2SO4. After evaporating the ethyl acetate under reduced pressure, the crude material was adsorbed onto SiO2. Purification was carried out via column chromatography, eluting with dichloromethane / methanol (100:1 to 100:10) to provide 4-(((1-(pyridin-3-yl)ethylidene)amino)oxy)benzenesulfonamide (A11) in a yield of 58 mg(37%): 1H NMR (600 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.62 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H),7.83 (d, J = 8.9 Hz, 2H), 7.37 (dd, J = 8.0, 4.8 Hz, 1H), 7.30 (d, J = 8.9 Hz, 2H), 6.71 (br. s,2H), 2.45 (s, 3H). 13C NMR (150 MHz, DMSO) δ 161.5, 157.1, 150. 7, 147.4, 137.7, 134.2,131.3, 128.0 (2C), 123.7, 114.4 (2C), 13.4. HRMS (ESI / Q-TOF) m / z [M+H]+ Calcd forC13H14N3O3S+292.0750; Found 292.0752. Procedure F. Synthesis of 4-(2-(3-amino-1H-isoindol-1- ylidene)hydrazineyl)benzenesulfonamide (A12) To a stirred solution of 4-hydrazineylbenzenesulfonamide (349 mg, 1.56 mmol) in ethanol (5mL) phthalonitrile (200 mg, 1.56 mmol) was added and the mixture was heated to reflux, followed by the addition of NaOH (69 mg, 1.72 mmol). The reaction mixture was stirred at reflux overnight and the solvent was then evaporated under reduced pressure. The resulting residue was partitioned between ethyl acetate and a dilute HCl solution. The aqueous phase was separated and adjusted to pH 7 using NaHCO₃ solution. The formed precipitate was collected by filtration. For further purification, chromatography was carried out on SiO2eluting with dichloromethane / methanol (100:1 to 100:10) to isolate 4-(2-(3-amino-1H-isoindol-1-ylidene)hydrazineyl)benzenesulfonamide (A12) in a yield of 108 mg (22%): 1H NMR (600MHz, DMSO-d6) δ 11.82 (s, 1H), 10.84 (br. s, 1H), 10.57 (br. s, 1H), 8.32 (d, J = 7.6 Hz, 1H),8.01 (d, J = 7.6 Hz, 1H), 7.85 (t, J = 7.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.69 (t, J = 7.5 Hz,1H), 7.40 (d, J = 8.4 Hz, 2H), 7.19 (s, 2H). 13C NMR (150 MHz, DMSO-d6) δ 159.8, 147.1,135.9, 135.0, 134.8, 133.5, 130.3, 128.0, 126.8, 124.8, 121.5, 112.5. HRMS (ESI / Q-TOF) m / z [M+H]+Calcd for C14H14N5O2S+316.0863; Found 316.0860. Procedure G. Synthesis of 4-(2-(7-imino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5- ylidene)hydrazineyl)benzenesulfonamide (A13) Pyridine-2,3-dicarbonitrile (200 mg, 1.55 mmol) was dissolved in 7N NH3 in methanol (3.3 mL, NH3, 23.2 mmol). After stirring for 20 minutes at room temperature, the solvent was evaporated under reduced pressure. The residue was taken up in a mixture of dry methanol (2 mL) and dimethylformamide (0.5 mL), and 4-hydrazineylbenzenesulfonamide hydrochloride (347 mg, 1.55 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and the solvent was then removed under reduced pressure. Purification was achieved using preparative HPLC, employing water / acetonitrile + 0.1% trifluoroacetic acid gradient as the mobile phase allowing for 4-(2-(7-amino-5H-pyrrolo[3,4-b]pyridin-5- ylidene)hydrazineyl)benzenesulfonamide (A13) as a mixture with its regioisomer 4-(2-(5- amino-7H-pyrrolo[3,4-b]pyridin-7-ylidene)hydrazineyl)benzenesulfonamide in a ratio of 5:4with a total yield of 74 mg (15%): 1H NMR (600 MHz, DMSO-d6) (two sets of signals, Maj / Minratio 5 / 4) δ 10.32 (br.s, 1Hmin), 10.23 (br.s, 1Hmaj), 8.66 (dd, J = 4.8, 1.3 Hz, 1Hmaj), 8.64 (dd, J= 4.8, 1.3 Hz, 1Hmin), 8.27 (dd, J = 7.7, 1.3 Hz, 1Hmaj), 8.17 (dd, J = 7.7, 1.3 Hz, 1Hmin), 8.14 –7.77 (m, 2Hmaj+2Hmin), 7.71 – 7.65 (m, 2Hmaj+2Hmin), 7.53 (dd, J = 7.7, 4.8 Hz, 1Hmin), 7.43(dd, J = 7.7, 4.8 Hz, 1Hmaj), 7.41 – 7.37 (m, 2Hmaj+2Hmin), 7.08 (br.s, 2Hmaj+2Hmin). 13C NMR(150 MHz, DMSO-d6) (two sets of signals, Maj / Min ratio 5 / 4) δ 164.9, 163.9, 157.3, 152.6,151.4, 149.9, 149.4, 148.2, 147.9, 147.8, 134.2, 134.1, 132.1, 129.5, 128.2, 127.9, 127.7 (2Cmaj),127.7 (2Cmin), 124.9, 122.5, 112.5 (2Cmaj), 112.3 (2Cmin). HRMS (ESI / Q-TOF) m / z [M+H]+Calcd for C13H13N6O2S+317.0815; Found 317.0815. Procedure H. Synthesis of 4-(2-(7-amino-5H-pyrrolo[3,4-b]pyrazin-5- ylidene)hydrazineyl)benzenesulfonamide (A14) Pyrazine-2,3-dicarbonitrile (200 mg, 1.54 mmol) was dissolved in 7N NH3in methanol (3.3 mL, NH3, 23.2 mmol). After stirring for 20 minutes at room temperature, the solvent was evaporated under reduced pressure. The residue was taken up in a mixture of dry methanol (2 mL) and dimethylformamide (0.5 mL), and 4-hydrazineylbenzenesulfonamide hydrochloride (344 mg, 1.54 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and the solvent was then removed under reduced pressure. Purification was achieved using preparative HPLC, employing water / acetonitrile + 0.1% trifluoroacetic acid gradient as the mobile phase allowing for 4-(2-(7-amino-5H-pyrrolo[3,4-b]pyrazin-5-ylidene)hydrazineyl)benzenesulfonamide (A14) in a yield of 138 mg (28%): 1H NMR (600MHz, DMSO-d6) δ 10.65 (br.s, 1H), 8.78 (d, J = 2.6 Hz, 1H), 8.70 (d, J = 2.6 Hz, 1H), 8.45 (br.s, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.11 (br. s, 2H). 13C NMR (150 MHz,DMSO-d6) δ 160.7, 150.0, 147.2, 147.0, 144.1, 135.5, 127.8 (2C), 113.0 (2C). HRMS (ESI / Q-TOF) m / z [M+H]+ Calcd for C12H12N7O2S+ 318.0768; Found 318.0772.In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention.

Claims

Claims 1. A compound of formula (I):formula (I), wherein R1and R2are each independently selected from the group consisting of H, C1-8-alkyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substituted with one or more halogen; each Z is independently selected from the group consisting of C(R), and N;each R is independently selected from the group consisting of H, halogen, preferably F,Cl, or Br; hydroxy, C1-8-alkoxy, C1-8-alkylthio, C1-8-carboxamide group, C1-8-ester group, C1-8-urea group, C1-8-carbamate group, C1-8-alkyl, C6-10-aryl, C5-10-heteroaryl, and derivativesthereof being substituted with one or more halogen; Y is N(R) or O; X is a 5-10 membered aliphatic, aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-5 substituents each independently selected from R’; each R’ is independently selected from the group consisting of halogen, preferably F,Cl, or Br; hydroxy, C1-8-alkoxy, C1-8-alkylthio, C1-8-carboxamide group, C1-8-ester group, C1-8-urea group, C1-8-carbamate group, C1-8-alkyl, C6-10-aryl, C5-10-heteroaryl, and derivativesthereof being substituted with one or more halogen; R3 is H, C(R4)(R5)(R6), or R’’, wherein R’’, together with X and the carbon they areattached to, forms a bi- or tricyclic 8-13 membered heterocyclic ring comprising anunsaturated 5-membered heterocyclic ring comprising 1 nitrogen, wherein the unsaturated 5-membered heterocyclic ring is fused with X and is optionally substituted with N(R7)(R8); andR4, R5, R6, R7, and R8are each independently selected from the group consisting of H,halogen, C1-8-alkyl, C1-8-alkyl-N(R9)(R10), C1-6-alkyl-C1-6-cycloalkyl, C1-6-alkyl-C1-6-heterocyclyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substituted with one ormore halogen, or two of R4, R5, and R6, together with the carbon they are attached to, form a C3-8-cycloalkyl and the rest of R4, R5, and R6is H, wherein R9and R10are each independentlyselected from the group consisting of H, and C1-8-alkyl; provided that if Y is NH, both Z areCH, both R are H, and X is pyridinyl, 2-furanyl, 2-thiophenyl, phenyl or phenyl substitutedwith 1-3 substituents each independently selected from R’, then R3 is not CH3 or CH2CH3; or astereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

2. The compound as claimed in claim 1, wherein the compound has formula (II):formula (II), wherein R1, R2, R4R5, R6, R, X, Y, and Z are as defined in claim 1; or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

3. The compound as claimed in claim 1, wherein the compound has formula (III):formula (III), wherein each dotted line represents an optional bond; R1, R2, R7, R8, R, Y, and Z are as defined in claim 1; andboth X´, together with the carbons they are attached to, together form a 5-6 memberedaliphatic, aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independentlyselected from R’; and R’ is as defined in claim 1; or a stereoisomer, pharmaceuticallyacceptable salt, solvate, or hydrate thereof.

4. The compound as claimed in claim 3, wherein both X´, together with thecarbons they are attached to, together form a 5-6 membered aromatic heterocyclic ring comprising 1-3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aromatic heterocyclic ring being optionally substituted with 1-3 substituents each independently selected from R’; and R’ is as defined in claim 1.

5. The compound as claimed in claim 3, wherein both X´, together with thecarbons they are attached to, together form a 6 membered aromatic ring, wherein the aromatic ring being optionally substituted with 1-3 substituents each independently selected from R’; and R’ is as defined in claim 1.

6. The compound as claimed in claim 2, wherein X is a 5-6 membered aromaticheterocyclic ring comprising 1-3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aromatic heterocyclic ring being optionally substitutedwith 1-3 substituents each independently selected from R’; and R’ is as defined in claim 1.

7. The compound as claimed in claim 2, wherein X is a 6 membered aromaticring, wherein the aromatic ring being optionally substituted with 1-3 substituents each independently selected from R’; wherein each R’ is independently selected from the group consisting of C1-8-alkylthio, C1-8-carboxamide group, C1-8-ester group, C1-8-urea group, C1-8-carbamate group, C6-10-aryl, C5-10-heteroaryl, and derivatives thereof being substituted with one or more halogen.

8. The compound as claimed in any of the preceding claims, whereinR1and R2are H; zero, one, or two Z are N and the rest of Z are C(R); Yis NH; andR is as defined in claim 1.

9. The compound as claimed in any of the preceding claims, whereinR1and R2are H; X is a 5-6 membered aliphatic, aromatic or heterocyclic ring comprising 0-2 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-5 substituents each independently selected from R’, or both X´, together with the carbons they are attached to, together form a 5-6 memberedaliphatic, aromatic or heterocyclic ring comprising 0-2 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’; and R’ is as defined in claim 1; and Y is NH.

10. The compound as claimed in any of the preceding claims, whereinY is NH; both Z are CH; both R are H; and at least one of R4, R5 and R6 is each independently selected from the group consistingof C2-8-alkyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof being substituted with one or more halogen, and the rest of R4, R5and R6is each independently selected from the groupconsisting of H, C1-8-alkyl, C6-10-aryl, C1-10-heteroaryl, and derivatives thereof beingsubstituted with one or more halogen.

11. The compound as claimed in any of the preceding claims, whereinY is NH; and R3is t-Bu.

12. The compound as claimed in any of the preceding claims, whereinR1and R2are H; both Z are CH; Y is NH; and R3is t-Bu.

13. The compound as claimed in any of claims 1 – 7, whereinR1and R2are H; zero, one, or two Z are N and the rest of Z are C(R);Y is O; and R is as defined in claim 1.

14. The compound as claimed in any of claims 1 – 7 and 13, whereinR1and R2are H; X is a 5-6 membered aliphatic, aromatic or heterocyclic ring comprising 0-2 heteroatoms each independently selected from the group consisting of N, O, and S, whereinthe aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-5 substituents each independently selected from R’, or both X´, together with the carbons they are attached to, together form a 5-6 memberedaliphatic, aromatic or heterocyclic ring comprising 0-2 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’; and R’ is as defined in claim 1; and Y is O.

15. The compound as claimed in claim 3, wherein the compound has formula (IV):formula (IV), wherein R1, R2, R7, R8, R, Y, and Z are as defined in claim 3; andeach X´´ is independently selected from the group consisting of C(R’), and N; and R´is as defined in claim 3.

16. The compound as claimed in any preceding claims, wherein the compound isselected from: 4-(2-(2,2-dimethyl-1-(pyridin-3-yl)propylidene)hydrazineyl)benzenesulfonamide;(Z)-4-(2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethylidene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(1-(5-bromopyridin-3-yl)ethylidene)hydrazineyl)benzenesulfonamid;(E)-4-(2-(cyclopropyl(5-fluoropyridin-3-yl)methylene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(1-(quinoxalin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(pyridin-3-ylmethylene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(1-(pyrazin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(1-(3-methylpyrazin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(1-(3,5-dimethylpyrazin-2-yl)ethylidene)hydrazineyl)benzenesulfonamide; (E)-4-(2-(3-(dimethylamino)-1-(pyrazin-2-yl)propylidene)hydrazineyl)benzenesulfonamide; 4-(((1-(pyridin-3-yl)ethylidene)amino)oxy)benzenesulfonamide; 4-(2-(3-amino-1H-isoindol-1-ylidene)hydrazineyl)benzenesulfonamide;4-(2-(7-amino-5H-pyrrolo[3,4-b]pyridin-5-ylidene)hydrazineyl)benzenesulfonamide; and4-(2-(7-amino-5H-pyrrolo[3,4-b]pyrazin-5-ylidene)hydrazineyl)benzenesulfonamide;or a stereoisomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

17. A composition comprising the compound, or a stereoisomer, pharmaceuticallyacceptable salt, solvate, or hydrate thereof, as defined in any of claims 1 – 16.

18. A compound of formula (I), or a stereoisomer, pharmaceutically acceptablesalt, solvate, or hydrate thereof, as defined in any of claims 1 – 16 for use as a medicament.

19. A compound of formula (I), or a stereoisomer, pharmaceutically acceptablesalt, solvate, or hydrate thereof, as defined in any of claims 1 – 16 for use in a method for thetreatment or prevention of an ocular disease or condition, or idiopathic intracranial hypertension (IIH).

20. The compound, or a stereoisomer, pharmaceutically acceptable salt, solvate, orhydrate thereof, as defined in any of claims 1 – 16 for use in the method as claimed in claim19, wherein the ocular disease or condition is selected from glaucoma, macular edema (ME), and a degenerative retinal disease.

21. A method for the preparation of a compound as defined in any of claims 1 – 16;wherein the method comprises:- providing a compound of formula (X) or a salt thereof:formula (X), and a compound of formula (XI´):formula (XI´) or a compound of formula (XI´´):formula (XI´´), wherein both X´, together with the carbons they are attached to, together form a 5-10 memberedaliphatic, aromatic or heterocyclic ring comprising 0-5 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the aliphatic, the aromatic and the heterocyclic ring being optionally substituted with 1-4 substituents each independently selected from R’, each dotted line represents an optional bond, and R1, R2, R3, R, R’, X, Y, and Z are as defined in claim 1; and- reacting the compound of formula (X) or a salt thereof with the compound of formula(XI´) or the compound of formula (XI´´), optionally in the presence of a base, thereby forming a compound as defined in any of claims 1 – 16.

Images