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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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  • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
  • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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  • A61K9/0012—Galenical forms characterised by the site of application
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  • A61K9/0051—Ocular inserts, ocular implants
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  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

• compositions, formulations, and methods for treating ocular diseases inter alia, diabetic macular edema, age-related macular degeneration (wet form), choroidal neovascularization, diabetic retinopathy, retinal vein occlusion (central or branch), ocular trauma, surgery induced edema, surgery induced neovascularization, cystoid macular edema, ocular ischemia, uveitis, and the like.
• diseases or conditions are characterized by changes in the ocular vasculature whether progressive or non-progressive, whether a result of an acute disease or condition, or a chronic disease or condition.
• the eye comprises several structurally and functionally distinct vascular beds, which supply ocular components critical to the maintenance of vision. These include the retinal and choroidal vasculatures, which supply the inner and outer portions of the retina, respectively, and the limbal vasculature located at the periphery of the cornea. Injuries and diseases that impair the normal structure or function of these vascular beds are among the leading causes of visual impairment and blindness. For example, diabetic retinopathy is the most common disease affecting the retinal vasculature, and is the leading cause of vision loss among the working age population in the United States. Vascularization of the cornea secondary to injury or disease is yet another category of ocular vascular disease that can lead to severe impairment of vision.
• Figure 1 depicts the results of two phase three studies to determine the effect of intravitreal injections of ranibizumab in patients with diabetic macular edema.
• Figure 2 depicts the results of a study wherein 4 patients received 5 mg of the 4- ⁇ (S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2- yl)thiazol-4-yl]ethyl ⁇ phenylsulfamic acid subcutaneously twice daily for 28 days and subsequently were treated in one or both eyes (7 eyes total) with either ranibizumab (0.3 or 0.5 mg) or aflibercept (2 mg) by intravitreal injection at the discretion of the study investigator.
• Figure 3 depicts the results of phase three studies to determine the effect of intravitreal injections of ranibizumab in patients with diabetic macular edema.
• Figure 4 depicts the increased visual acuity of a study wherein 4 patients received 5 mg of the 4- ⁇ (S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-
• Figure 5 graphs changes in central foveal thickness over time in an eye treated with a drug/antibody combination.
• Figure 6 graphs changes in central foveal thickness over time in an eye treated with a drug/antibody combination.
• Figure 7 is a graphic representation of in vivo experiments performed in 6 week old C57BL/6 mice.
• Figure 8A illustrates the extent of choroidal neovascularization evident in a control sample stained with FITC-labeled Griffonia simplicifolia (GSA) of the experiment of Figure 7.
• Figure 8B represents the extent of neovascularization in the choroidal tissue of animals treated with aflibercept, stained with FITC-labeled Griffonia simplicifolia (GSA).
• Figure 8C represents the extent of neovascularization in tissue treated with a Tie-
• Figure 8D represents the extent of neovascularization present in tissue receiving a combined therapy of aflibercept and the 4- ⁇ (S)-2-[(S)-2-methoxycarbonylamino)-3- phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl ⁇ phenylsulfamic acid, stained with FITC-labeled Griffonia simplicifolia (GSA).
• GSA Griffonia simplicifolia
• Figure 9 shows the plasma concentration of 4- ⁇ (S)-2-[(S)-2- (methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4- yl] ethyl jphenylsulfamic acid , pre-dose(O), 15 minutes, 1 hour, 2 hours, 3 hours and 4 hours after administration after the first dose on day 14.
• the invention provides a method of treating a condition in a subject in need thereof, the method comprising administering to the subject a
• the invention provides a method of treating a condition in a subject in need thereof, the method comprising administering to the subject a
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising: a) a compound that activates Tie-2, or a pharmaceutically-acceptable salt thereof; and b) an agent that improves the aqueous solubility of the compound that activates Tie-2, or the pharmaceutically-acceptable salt thereof.
• the invention provides a pharmaceutical composition comprising: a) a Tie-2 activator or a pharmaceutically-acceptable salt thereof; and b) an antibody.
• the invention provides a kit comprising: a) a Tie-2 activator or a pharmaceutically-acceptable salt thereof; b) an antibody; and c) written instructions on use of the kit in treatment of a condition.
• the invention provides a method of treating a condition, the method comprising administering to a subject in need thereof: a) a therapeutically- effective amount of a Tie-2 activator or a pharmaceutically-acceptable salt thereof; and b) a therapeutically-effective amount of an antibody.
• the invention provides a complex comprising: a) a Tie-2 activator, or a pharmaceutically-acceptable salt thereof; and b) a molecule comprising a channel, wherein the compound that activates Tie-2, or the pharmaceutically-acceptable salt thereof is held in the channel of the molecule by non-covalent interactions.
• the invention provides a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of complex comprising: a) a Tie-2 activator, or a pharmaceutically-acceptable salt thereof; and b) a molecule comprising a channel, wherein the compound that activates Tie-2, or the pharmaceutically-acceptable salt thereof is held in the channel of the molecule by non-covalent interactions.
• ⁇ - ⁇ is a member of the receptor- like family of the protein tyrosine phosphatases (PTPases).
• PTPases protein tyrosine phosphatases
• ⁇ - ⁇ is a transmembrane protein found primarily in endothelial cells that displays structural and functional similarity to cell adhesion molecules (CAMs).
• CAMs cell adhesion molecules
• ⁇ - ⁇ is unique among receptor-like PTPases in that it contains a single catalytic domain.
• One of the main functions of ⁇ - ⁇ is to regulate Tie-2 negatively.
• Tie-2 is a receptor tyrosine kinase found almost exclusively in endothelial cells.
• the principle regulators of Tie-2 phosphorylation are Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2).
• Ang-1 Angiopoietin-1
• Ang-22 Angiopoietin-2
• the duration of Tie-2 receptor phosphorylation is regulated by ⁇ - ⁇ , which cleaves off the phosphate.
• Tie-2 receptor phosphorylation helps maintain endothelial cell proximity; therefore, the duration of Tie-2 receptor phosphorylation is an important determinant of endothelial cell proximity.
• the present disclosure relates to compositions and methods for treating conditions, such as ocular diseases, for example, those wherein neovasculatization and vascular leakage are present. These diseases are sometimes characterized as diseases wherein there is an elevated angiogenic response in the vessels associated with the eye.
• the present disclosure provides a Human Protein Tyrosine Phosphatase-beta ( ⁇ - ⁇ ) inhibitor that provides vascular stabilization.
• Compounds disclosed herein can be effective as Tie-2 activators.
• the compounds can effect that activity, for example, by binding or inhibiting ⁇ - ⁇ .
• Such compounds can bind, for example, by mimicking the binding mechanism of a native substrate, such as a phosphorylated compound.
• a compound can be a phosphate mimetic or bioisostere, for example, a sulfamic acid.
• the compound could also be derived from an amino acid building block or comprise an amino acid backbone for efficiency and economy of synthesis.
• a compound of the invention is a compound of formula: , wherein:
• Aryl is an aryl group which is substituted or unsubstituted; Aryl is an aryl group which is substituted or unsubstituted; X is alkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, an amide linkage, an ester linkage, a thioether linkage, a carbamate linkage, a carbonate linkage, a urethane linkage, a sulfone linkage, any of which is substituted or unsubstituted, or a chemical bond; and Y is H, aryl, heteroaryl, NH(aryl), NH(heteroa g , or NHCOR g , any of which is substituted or unsubstituted, or
• L is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L is bound forms an amide linkage, a carbamate linkage, a urethane linkage, or a sulfonamide linkage, or a chemical bond, or together with any of R a , R b , R c , and R d forms a ring that is substituted or unsubstituted.
• R a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L , R b , R c , and R d forms a ring that is substituted or unsubstituted.
• R b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L 2 , R a , R c , and R d forms a ring that is substituted or unsubstituted.
• R c is H or alkyl which is substituted or unsubstituted, or together with any of L 2 , R a , R b , and R d forms a ring that is substituted or unsubstituted.
• R d is H or alkyl which is substituted or unsubstituted, or together with any of L 2 , R a , R b , and R c forms a ring that is substituted or unsubstituted
• R g is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or a pharmaceutically- acceptable salt, tautomer, or zwitterion thereof.
• aryl is substituted or unsubstituted phenyl, aryl is substituted or unsubstituted heteroaryl, and X is alkylene.
• aryl 1 is substituted phenyl, aryl is substituted heteroaryl, and X is methylene.
• a compound is of the fomula:
• L is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L is bound forms an amide linkage, a carbamate linkage, a urethane linkage, or a sulfonamide linkage, or a chemical bond.
• R a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.
• R b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.
• R c is H or alkyl which is substituted or unsubstituted
• R d is H or alkyl which is substituted or unsubstituted.
• aryl is para-substituted phenyl, aryl is a substituted
• X is methylene
• L together with the nitrogen atom to which L is bound forms a carbamate linkage
• R a is alkyl, which is substituted or unsubstituted
• R b is arylalkyl, which is substituted or unsubstituted
• R c is H
• R d is H.
• Aryl is:
• R e is H, OH, F, CI, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a urethane group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, and R is H, OH, F, CI, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group,
• R e is H, OH, F, CI, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted
• R is H, OH, F, CI, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.
• R e is H, OH, F, CI, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted and R is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted.
• aryl 1 is 4-phenylsulfamic acid
• R a is alkyl, which is substituted or unsubstituted
• R b is arylalkyl, which is substituted or unsubstituted
• R e is H
• R f is heteroaryl.
• aryl 1 is 4-phenylsulfamic acid
• R a is alkyl, which is substituted or unsubstituted
• R b is arylalkyl, which is substituted or unsubstituted
• R e is H
• R is alkyl
• Aryl is:
• R e is H, OH, F, CI, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a urethane group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, R is H, OH, F, CI, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an
• heterocyclylalkyl heteroaryl, or heteroarylalkyl, any of which is substituted or
• R is H, OH, F, CI, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.
• R e is H, OH, F, CI, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted and R is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted.
• aryl 1 is 4- phenylsulfamic acid
• R a is alkyl, which is substituted or unsubstituted
• R b is arylalkyl, which is substituted or unsubstituted
• R e is H
• R f is heteroaryl
• a substituted phenyl group is:
• each of R phl , R ph2 , R ph3 , R p , and R ph5 is independently H, OH, F, CI, Br, I, CN, sulamic acid, tosylate, mesylate, triflate, besylate, alkyl, alkenyl, alkynyl, an alkoxy group, a sulfhydryl group, a nitro group, a nitroso group, an azido group, a sulfoxide group, a sulfone group, a sulfonamide group, an ether group, a carboxylic acid group, a
• carboxaldehyde group an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a urethane group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or
• Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, acyloxy groups, carbamate groups, amide groups, urethane groups, and ester groups.
• substituted or unsubstituted C 6 or C 10 aryl for example, phenyl, naphthyl (also referred to herein as naphthylen-l-yl (C 10 ) or naphthylen-2-yl (C 10 )); iii) substituted or unsubstituted C 6 or C 10 alkylenearyl; for example, benzyl, 2- phenylethyl, naphthyl en-2-ylmethyl;
• -(CR 102a R 102b ) a OR 101 for example, -OH, -CH 2 OH, -OCH 3 , -CH 2 OCH 3 , -OCH 2 CH 3 , -CH 2 OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , and -CH 2 OCH 2 CH 2 CH 3 ;
• -(CR 102a R 102b ) a C(O)R 101 for example, -COCH 3 , -CH 2 COCH 3 ,
• X is halogen
• the index j is an integer from 0 to 2
• j + k 3; for example, -CH 2 F, -CHF 2 , -CF 3 , -CC1 3 , or -CBr 3 ;
• -(CR 102a R 102b ) a SO 3 R 101 for example, -S0 3 H, -CH 2 S0 3 H, -S0 3 CH 3 , -CH 2 S0 3 CH 3 , -S0 3 C 6 H 5 , and -CH 2 S0 3 C 6 H 5 ;
• each R 101 is independently hydrogen, substituted or unsubstituted Ci-C 6 linear, branched, or cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R 101 units can be taken together to form a ring comprising 3-7 atoms;
• R 102a and R 102b are each independently hydrogen or C1-C4 linear or branched alkyl; the index "a" is from 0 to 4.
• Non-limiting examples of alkyl and alkylene groups include straight, branched, and cyclic alkyl and alkylene groups.
• An alkyl group can be, for example, a Ci, C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C9, Cio, C11, Ci 2 , Ci 3 , C14, C15, Ci 6 , C 17 , C 18 , C19, C 20 , C 21 , C 22 , C 23 ,
• Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
• Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups.
• Non- limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and t-butyl.
• Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro- systems. A cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups.
• Non-limiting examples of alkenyl and alkenylene groups include straight, branched, and cyclic alkenyl groups.
• the olefin or olefins of an alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene.
• An alkenyl or alkenylene group can be, for example, a C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , Cs, C9, Cio, Cn, C 12 , C 13 , C 14 , C 15 , C 16 , Cn, C 18 , Ci , C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted.
• Non-limiting examples of alkynyl or alkynylene groups include straight, branched, and cyclic alkynyl groups.
• the triple bond of an alkylnyl or alkynylene group can be internal or terminal.
• An alkylnyl or alkynylene group can be, for example, a C 2 , C 3 , C 4 , C 5 , C 6 , C7, C 8 , C9, Cio, Cn, C12, Co, Ci4, Cis, Ci6, Cn, Cis, Ci9, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C 5 o group that is substituted or unsubstituted.
• Non-limiting examples of substituted and unsubstituted acyclic hydrocarbyl include:
• linear or branched alkyl non-limiting examples of which include, methyl (Ci), ethyl (C 2 ), n-propyl (C3), z ' so-propyl (C3), n-butyl (C 4 ), sec-butyl (C 4 ), z ' so-butyl (C 4 ), tert-bvXy ⁇ (C 4 ), and the like; substituted linear or branched alkyl, non-limiting examples of which includes, hydroxymethyl (Ci), chloromethyl (Ci),
• linear or branched alkenyl non-limiting examples of which include, ethenyl (C 2 ), 3-propenyl (C3), 1-propenyl ⁇ also 2-methylethenyl) (C3), isopropenyl ⁇ also 2- methylethen-2-yl) (C3), buten-4-yl (C 4 ), and the like; substituted linear or branched alkenyl, non-limiting examples of which include, 2-chloroethenyl ⁇ also
• linear or branched alkynyl non-limiting examples of which include, ethynyl (C 2 ), prop-2-ynyl ⁇ also propargyl) (C 3 ), propyn-l-yl (C 3 ), and 2-methyl-hex-4-yn-l-yl (C7); substituted linear or branched alkynyl, non-limiting examples of which include, 5-hydroxy-5-methylhex-3-ynyl (C 7 ), 6-hydroxy-6-methylhept-3-yn-2-yl (C 8 ), and 5-hydroxy-5-ethylhept-3-ynyl (C9).
• Non-limiting examples of substituted and unsubstituted cyclic hydrocarbyl include:
• rings comprising from 3 to 20 carbon atoms, wherein the atoms which comprise said rings are limited to carbon atoms, and further each ring can be independently substituted with one or more moieties capable of replacing one or more hydrogen atoms.
• the following are non- limiting examples of substituted and unsubstituted carbocyclic rings:
• carbocyclic rings having a single substituted or unsubstituted hydrocarbon ring non-limiting examples of which include, cyclopropyl (C 3 ), 2-methyl-cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), 2,3-dihydroxycyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclopentadienyl (C 5 ), cyclohexyl (C 6 ),
• cyclohexenyl (C 6 ), cycloheptyl (C 7 ), cyclooctanyl (C 8 ), 2,5-dimethylcyclopentyl (C 5 ), 3,5- dichlorocyclohexyl (C 6 ), 4-hydroxycyclohexyl (C 6 ), and 3,3,5-trimethylcyclohex-l-yl
• carbocyclic rings having two or more substituted or unsubstituted fused hydrocarbon rings non-limiting examples of which include, octahydropentalenyl (C 8 ), octahydro-lH-indenyl (C9), 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl (C9),
• Ci-C 6 tethered cyclic hydrocarbyl units (whether carbocyclic units, C 6 or C 10 aryl units, heterocyclic units, or heteroaryl units) can be connected to another moiety, unit, or core of the molecule by way of a Ci-C 6 alkylene unit.
• Non- limiting examples of tethered cyclic hydrocarbyl units include benzyl Ci-(C 6 ) having the formula:
• R a is optionally one or more independently chosen substitutions for hydrogen.
• Further examples include other aryl units, inter alia, (2-hydroxyphenyl)hexyl C 6 -(C 6 ); naphthalen-2-ylmethyl Ci-(Cio), 4-fluorobenzyl Ci-(C 6 ), 2-(3-hydroxyphenyl)ethyl C 2 - (C 6 ), as well as substituted and unsubstituted C 3 -Cio alkylenecarbocyclic units, for example, cyclopropylmethyl Ci-(C 3 ), cyclopentylethyl C 2 -(C 5 ), cyclohexylmethyl Ci- (C 6 );. Included within this category are substituted and unsubstituted C 1 -C 10 alkylene- heteroaryl units, for example a 2-picol l Ci-(C 6 ) unit having the formula:
• Ci-C 12 tethered cyclic hydrocarbyl units include Ci-Cio alkyleneheterocyclic units and alkylene-heteroaryl units, non- limiting examples of which include, aziridinylmethyl Ci-(C 2 ) and oxazol-2-ylmethyl Ci- (C 3 ).
• a halo group can be any halogen atom, for example, fluorine, chlorine, bromine, or iodine.
• a halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms.
• a halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms.
• a halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms.
• An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group.
• An ether or an ether group comprises an alkoxy group.
• alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.
• An aryl group can be heterocyclic or non-heterocyclic.
• An aryl group can be monocyclic or polycyclic.
• An aryl group can be substituted with any number of substituents described herein, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms.
• Non- limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl.
• Non- limiting examples of aryl groups can include: i) C 6 or Cio substituted or unsubstituted aryl rings; phenyl and naphthyl rings whether substituted or unsubstituted, non-limiting examples of which include, phenyl (C 6 ), naphthylen-l-yl (Cio), naphthylen- 2-yl (Cio), 4-fluorophenyl (C 6 ), 2-hydroxyphenyl (C 6 ), 3-methylphenyl (C 6 ), 2-amino-4- fluorophenyl (C 6 ), 2-(N,N-diethylamino)phenyl (C 6 ), 2-cyanophenyl (C 6 ), 2,6-di-tert- butylphenyl (C 6 ), 3-methoxyphenyl (C 6 ), 8-hydroxynaphthylen-2-yl (Cio), 4,5- dimethoxynaphthylen-
• An aryloxy group can be, for example, an oxygen atom substituted with any aryl group, such as phenoxy.
• An aralkyl group can be, for example, any alkyl group substituted with any aryl group, such as benzyl.
• An arylalkoxy group can be, for example, an oxygen atom substituted with any aralkyl group, such as benzyloxy.
• a heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom.
• a heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms.
• a heterocycle can be aromatic (heteroaryl) or non-aromatic.
• Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.
• heterocycles include: heterocyclic units having a single ring containing one or more heteroatoms, non-limiting examples of which include, diazirinyl (Ci), aziridinyl (C 2 ), urazolyl (C 2 ), azetidinyl (C 3 ), pyrazolidinyl (C 3 ), imidazolidinyl (C 3 ), oxazolidinyl (C 3 ), isoxazolinyl (C 3 ), thiazolidinyl (C 3 ), isothiazolinyl (C 3 ), oxathiazolidinonyl (C 3 ), oxazolidinonyl (C 3 ), hydantoinyl (C 3 ), tetrahydrofuranyl (C 4 ), pyrrolidinyl (C 4 ), morpholinyl (C 4 ), piperazinyl (C 4 ), piperidinyl (C 4 ), piperidiny
• heteroaryl examples include: i) heteroaryl rings containing a single ring, non-limiting examples of which include, 1,2,3,4-tetrazolyl (Ci),
• Non- limiting examples of heteroaryl include 1, 2,3 ,4-tetrahydroquino line having the formula:
• An acyl group can be, for example, a carbonyl group substituted with hydrocarbyl, alkyl, hydro carbyloxy, alkoxy, aryl, aryloxy, aralkyl, arylalkoxy, or a heterocycle.
• Non- limiting examples of acyl include acetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxycarbonyl, and ethoxycarbonyl.
• An acyloxy group can be an oxygen atom substituted with an acyl group.
• An ester or an ester group comprises an acyloxy group.
• a non- limiting example of an acyloxy group, or an ester group, is acetate.
• a carbamate group can be an oxygen atom substituted with a carbamoyl group, wherein the nitrogen atom of the carbamoyl group is unsubstituted, monosubstituted, or disubstituted with one or more of hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl.
• the nitrogen atom is disubstituted, the two substituents together with the nitrogen atom can form a heterocycle.
• a compound of the disclosure has Formula (I):
• the units which comprise R and Z can comprise units having any configuration, and, as such, a compound of the disclosure can be a single enantiomer, a diastereomer, or pairs or combinations thereof.
• the compounds can be isolated as salts or hydrates.
• the compounds can comprise more than one cation or anion.
• any number of water molecules, or fractional part thereof for example, less than 1 water molecule present for each molecule of analogue) can be present.
• R is a substituted or unsubstituted thiazolyl unit having the formula:
• R 4" are substituent groups that can be independently chosen from a wide variety of non-carbon atom containing units (for example, hydrogen, hydroxyl, amino, halogen, and nitro) or organic substituent units, such as substituted and unsubstituted acyclic hydrocarbyl and cyclic hydrocarbyl units as described herein.
• the carbon comprising units can comprise, for example, from 1 to 12 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
• An example of compounds of Formula (I) include compounds wherein R units are thiazol-2-yl units having the formula:
• R 2 and R 3 are each independently chosen from:
• R and R can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms; wherein from 1 to 3 atoms can optionally be heteroatoms chosen from oxygen, nitrogen, and sulfur.
• alkynyl methyl (Ci), ethyl (C 2 ), ethenyl (C 2 ), ethynyl (C 2 ), n-propyl (C 3 ), z ' so-propyl (C 3 ), cyclopropyl (C 3 ), 3-propenyl (C 3 ), 1-propenyl ⁇ also 2- methylethenyl) (C 3 ), isopropenyl ⁇ also 2-methylethen-2-yl) (C 3 ), prop-2- ynyl ⁇ also propargyl) (C 3 ), propyn-l-yl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), z ' so-butyl (C 4 ), tert-bvXy ⁇ (C 4 ), cyclobutyl (C 4 ), buten-4-yl (C 4 ), cyclopentyl (C 5 ), cycl
• ii) substituted or unsubstituted C 6 or Cio aryl for example, phenyl, naphthyl (also referred to herein as naphthylen-l-yl (Cio) or naphthylen-2-yl (Cio)); iii) substituted or unsubstituted C 6 or Cio alkylenearyl; for example, benzyl, 2- phenylethyl, naphthyl en-2-ylmethyl;
• X is halogen
• the index j is an integer from 0 to 2
• j + k 3
• the index j ' is an integer from 0 to 2
• j ' + k' 2
• the index h is from 0 to 6; for example, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCF 3 , -CCl 3 , or -CBr 3 ;
• each R 20 is independently hydrogen, substituted or unsubstituted C 1 -C 4 linear, C 3 -C 4 branched, or C 3 -C 4 cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two
• R 20 units can be taken together to form a ring comprising 3-7 atoms;
• R 21 a and R 2 lb are each independently hydrogen or C 1 -C 4 linear or C 3 -C 4 branched alkyl; the index p is from 0 to 4.
• An example of compounds of Formula (I) includes R units having the formula:
• R 3 is hydrogen and R 2 is a unit chosen from methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), iso-propyl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), z ' so-butyl (C 4 ), tert-bvXy ⁇ (C 4 ), n-pentyl (C 5 ), 1-methylbutyl (C 5 ), 2-methylbutyl (C 5 ), 3-methylbutyl (C 5 ), cyclopropyl (C 3 ), n- hexyl (C 6 ), 4-methylpentyl (C 6 ), and cyclohexyl (C 6 ).
• R is a unit chosen from methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), iso-propyl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), z ' so-butyl (C 4 ), and tert-butyl (C 4 ); and R is a unit chosen from methyl (Ci) or ethyl (C 2 ).
• Non-limiting examples of this aspect of R includes 4,5- dimethylthiazol-2-yl, 4-ethyl-5-methylthiazol-2-yl, 4-methyl-5-ethylthiazol-2-yl, and 4,5- diethylthiazol-2-yl.
• An example of compounds of Formula (I) includes R units wherein R is hydrogen and R is a substituted alkyl unit, said substitutions chosen from:
• halogen -F, -CI, -Br, and -I;
• each R 11 is independently hydrogen or C 1 -C 4 linear or C3-C4 branched alkyl.
• Non-limiting examples of units that can be a substitute for a R or R hydrogen atom on R units include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 C1, -CH 2 OH, - CH 2 OCH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , and -CH 2 NH(CH 2 CH 3 ).
• units that can be a substitute for a R or R hydrogen atom on R units include 2,2-difluorocyclopropyl, 2-methoxycyclohexyl, and 4- chlorocyclohexyl.
• R units include units wherein R is
• R is phenyl or substituted phenyl, wherein non- limiting examples of R units include phenyl, 3,4-dimethylphenyl, 4 er -butylphenyl, 4-cyclopropylphenyl, 4- diethylaminophenyl, 4-(trifluoromethyl)phenyl, 4-methoxyphenyl, 4-(difluoromethoxy)- phenyl, 4-(trifluoromethoxy)phenyl, 3-chloropheny, 4-chlorophenyl, and 3,4-dichloro- phenyl, which when incorporated into the definition of R affords the following R units 4- phenylthiazol-2-yl, 3,4-dimethylphenylthiazol-2-yl, 4 er -butylphenylthiazol-2-yl, 4- cyclopropylphenylthiazol-2-yl, 4-diethylaminophenylthiazol-2-yl,
• An example of compounds of Formula (I) includes R units wherein R is chosen from hydrogen, methyl, ethyl, n-propyl, and z ' so-propyl and R is phenyl or substituted phenyl.
• R unit according to the fifth aspect of the first category of R units includes 4-methyl-5-phenylthiazol-2-yl and 4-ethyl-5-phenylthiazol- 2-yl.
• An example of compounds of Formula (I) includes R units wherein R is hydrogen and R is a substituted or unsubstituted heteroaryl unit chosen from 1,2,3,4-tetrazol-l-yl ,l,2,3,4-tetrazol-5-yl, [l,2,3]triazol-4-yl, [l,2,3]triazol-5-yl, [l,2,4]triazol-4-yl,
• compounds of Formula (I) includes R units wherein R is substituted or unsubstituted thiophen-2-yl, for example thiophen-2-yl, 5- chlorothiophen-2-yl, and 5-methylthiophen-2-yl.
• An example of compounds of Formula (I) includes R units wherein R is substituted or unsubstituted thiophen-3-yl, for example thiophen-3-yl, 5-chlorothiophen- 3-yl, and 5-methylthiophen-3-yl.
• An example of compounds of Formula (I) includes R units wherein R and R are taken together to form a saturated or unsaturated ring having from 5 to 7 atoms.
• Non- limiting examples of the sixth aspect of the first category of R units include 5,6-dihydro- 4H-cyclopenta[ ⁇ i]thiazol-2-yl and 4,5,6,7-tetrahydrobenzo[ ⁇ i]thiazol-2-yl.
• compounds of Formula (I) include R units that are thiazol-4- yl or thiazol-5-yl units having the formula:
• R 4 is a unit chosen from:
• alkynyl methyl (Ci), ethyl (C 2 ), ethenyl (C 2 ), ethynyl (C 2 ), n-propyl (C 3 ), z ' so-propyl (C 3 ), cyclopropyl (C 3 ), 3-propenyl (C 3 ), 1-propenyl ⁇ also 2- methylethenyl) (C 3 ), isopropenyl (also 2-methylethen-2-yl) (C 3 ), prop-2- ynyl (also propargyl) (C 3 ), propyn-l-yl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), z ' so-butyl (C 4 ), tert-butyl (C 4 ), cyclobutyl (C 4 ), buten-4-yl (C 4 ), cyclopentyl (C 5 ), cyclohexy
• substituted or unsubstituted C 6 or Cio aryl for example, phenyl, naphthyl (also referred to herein as naphthylen-l-yl (Cio) or naphthylen-2-yl (Cio)); substituted or unsubstituted C 6 or Cio alkylenearyl; for example, benzyl, 2- phenylethyl, naphthyl en-2-ylmethyl;
• -(CR 21a R 21b ) p OR 20 for example, -OH, -CH 2 OH, -OCH 3 , -CH 2 OCH 3 , -OCH 2 CH 3 , -CH 2 OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , and -CH 2 OCH 2 CH 2 CH 3 ;
• -(CR 21a R 21b ) p C(0)R 20 for example, -COCH 3 , -CH 2 COCH 3 , - COCH 2 CH 3 , -CH 2 COCH 2 CH 3 , -COCH 2 CH 2 CH 3 , and - CH 2 COCH 2 CH 2 CH 3 ;
• X is halogen
• the index j is an integer from 0 to 2
• j + k 3
• the index j ' is an integer from 0 to 2
• j ' + k' 2
• the index h is from 0 to 6; for example, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCF 3 , - CCl 3 , or -CBr 3 ;
• -(CR 21a R 21b ) p S0 2 R 20 for example, -S0 2 H, -CH 2 S0 2 H, -S0 2 CH 3 , -CH2SO2CH3, -S0 2 C 6 H 5 , and -CH 2 S0 2 C 6 H 5 ; and
• each R 20 is independently hydrogen, substituted or unsubstituted C 1 -C 4 linear, C3-C 4 branched, or C3-C 4 cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two
• R 20 units can be taken together to form a ring comprising 3-7 atoms;
• R 21 a and R 2 lb are each independently hydrogen or C 1 -C 4 linear or C3-C 4 branched alkyl; the index p is from 0 to 4.
• An example of compounds of Formula (I) includes R units wherein R 4 is hydrogen.
• R 4 is a unit chosen from methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), iso-propyl (C 3 ), n-butyl (C 4 ), sec- butyl (C 4 ), z ' so-butyl (C 4 ), and tert-bvXy ⁇ (C 4 ).
• R 4 is a unit chosen from methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), iso-propyl (C 3 ), n-butyl (C 4 ), sec- butyl (C 4 ), z ' so-butyl (C 4 ), and tert-bvXy ⁇ (C 4 ).
• Non- limiting examples of this aspect of R includes 2-methylthiazol-4-yl, 2-ethylthiazol-4-yl, 2-(n-propyl)thiazol-4-yl, and 2-(iso- propy
• An example of compounds of Formula (I) includes R units wherein R 4 is substituted or unsubstituted phenyl, non-limiting examples of which include phenyl, 2- fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- methylphenyl, and 4-methoxyphenyl.
• An example of compounds of Formula (I) includes R units wherein R 4 is substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophen- 2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4- dimethylthiazol-5-yl, 4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and 3- methyl- l,2,4-oxadiazol-5-yl.
• 5 -member ring R units includes substituted or unsubstituted imidazolyl units having the formula:
• imidazolyl R units includes imidazol-2-yl units having the formula:
• R and R are each independently chosen from:
• R and R can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms; wherein from 1 to 3 atoms can optionally be heteroatoms chosen from oxygen, nitrogen, and sulfur.
• alkynyl methyl (Ci), ethyl (C 2 ), ethenyl (C 2 ), ethynyl (C 2 ), n-propyl (C 3 ), z ' so-propyl (C 3 ), cyclopropyl (C 3 ), 3-propenyl (C 3 ), 1-propenyl (also 2- methylethenyl) (C 3 ), isopropenyl (also 2-methylethen-2-yl) (C 3 ), prop-2- ynyl (also propargyl) (C 3 ), propyn-l-yl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), z ' so-butyl (C 4 ), tert-butyl (C 4 ), cyclobutyl (C 4 ), buten-4-yl (C 4 ), cyclopentyl (C 5 ), cyclohexyl
• X is halogen
• the index j is an integer from 0 to 2
• j + k 3
• the index j ' is an integer from 0 to 2
• j ' + k' 2
• the index h is from 0 to 6; for example, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCF 3 , - CCl 3 , or -CBr 3 ;
• each R is independently hydrogen, substituted or unsubstituted C 1 -C 4 linear, C 3 -C 4 branched, or C 3 -C 4 cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two
• R 20 units can be taken together to form a ring comprising 3-7 atoms;
• R 21 a and R 2 lb are each independently hydrogen or C 1 -C 4 linear or C 3 -C 4 branched alkyl; the index p is from 0 to 4.
• R units includes compounds wherein R units have the formula: wherein R 3 is hydrogen and R 2 is a unit chosen from methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), iso-propyl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), z ' so-butyl (C 4 ), and tert-butyl (C 4 ). 2
• R units includes compounds wherein R is a unit chosen from methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), iso-propyl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), iso- butyl (C 4 ), and tert-butyl (C 4 ); and R is a unit chosen from methyl (Ci) or ethyl (C 2 ).
• Non-limiting examples of this aspect of R includes 4,5-dimethylimidazol-2-yl, 4-ethyl-5- methylimidazol-2-yl, 4-methyl-5-ethylimidazol-2-yl, and 4,5-diethylimidazol-2-yl.
• R units includes compounds wherein R 3 is hydrogen and R 2 is a substituted alkyl unit chosen, said substitutions chosen from:
• halogen -F, -CI, -Br, and -I;
• each R 11 is independently hydrogen or C 1 -C 4 linear or C 3 -C 4 branched alkyl.
• Non- limiting examples of units comprising this embodiment of R includes: - CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH 2 C1, -CH 2 OH, -CH 2 OCH 3 , -CH 2 CH 2 OH, - CH 2 CH 2 OCH 3 , -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , and -CH 2 NH(CH 2 CH 3 ).
• R units includes units wherein R 3 is hydrogen and R 2 is phenyl.
• R units includes units wherein R is hydrogen and R is a heteroaryl unit chosen from 1,2,3,4-tetrazol-l-yl ,l,2,3,4-tetrazol-5-yl, [l,2,3]triazol-4-yl, [l,2,3]triazol-5-yl, [l,2,4]triazol-4-yl, [l,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4- yl, isoxazol-5-yl, [l,2,4]oxadiazol-3-yl, [l,2,4]oxadiazol-5-yl, [l,3,4]oxadiazol-2-yl, furan-2-yl,
• Z is a unit having the formula:
• R 1 is chosen from:
• alkynyl methyl (Ci), ethyl (C 2 ), ethenyl (C 2 ), ethynyl (C 2 ), n-propyl (C 3 ), z ' so-propyl (C 3 ), cyclopropyl (C 3 ), 3-propenyl (C 3 ), 1-propenyl ⁇ also 2- methylethenyl) (C 3 ), isopropenyl ⁇ also 2-methylethen-2-yl) (C 3 ), prop-2- ynyl ⁇ also propargyl) (C 3 ), propyn-l-yl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), z ' so-butyl (C 4 ), tert-bvXy ⁇ (C 4 ), cyclobutyl (C 4 ), buten-4-yl (C 4 ), cyclopentyl (C 5 ), cycl
• ii) substituted or unsubstituted C 6 or Cio aryl for example, phenyl, naphthyl (also referred to herein as naphthylen-l-yl (Cio) or naphthylen-2-yl (Cio)); iii) substituted or unsubstituted C 6 or Cio alkylenearyl; for example, benzyl, 2- phenylethyl, naphthyl en-2-ylmethyl;
• X is halogen
• the index j is an integer from 0 to 2
• j + k 3
• the index j ' is an integer from 0 to 2
• j ' + k' 2
• the index h is from 0 to 6; for example, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCF 3 , -CCl 3 , or -CBr 3 ;
• each R is independently hydrogen, substituted or unsubstituted Ci-C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two
• R 30 units can be taken together to form a ring comprising 3-7 atoms;
• R 31 a and R 3 lb are each independently hydrogen or C1-C4 linear or C 3 -C 4 branched alkyl; the index q is from 0 to 4.
• R 1 units includes substituted or unsubstituted phenyl (C 6 aryl) units, wherein each substitution is independently chosen from: halogen, C1-C4 linear, branched alkyl, or cyclic alkyl, -OR 11 , -CN, -N(R n ) 2 , -C0 2 R n , -C(0)N(R u ) 2 , - NR n C(0)R u , -NO2, and -S0 2 R u ; each R 11 is independently hydrogen; substituted or unsubstituted Ci-C 4 linear, C 3 -C 4 branched, C 3 -C 4 cyclic alkyl, alkenyl, or alkynyl; substituted or unsubstituted phenyl or benzyl; or two R 11 units can be taken together to form a ring comprising from 3-7 atoms.
• R 1 units includes substituted C 6 aryl units chosen from phenyl, 2- fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4- hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3- dimethoxyphenyl, 3,4-dimethoxyphenyl, and 3,5-dimethoxyphenyl.
• R 1 units includes substituted or unsubstituted C 6 aryl units chosen from 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2.4- dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3,4- trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 3,4,5- trichlorophenyl, and 2,4,6-trichlorophenyl.
• R 1 units includes substituted C 6 aryl units chosen from 2- methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl,
• R 1 units includes substituted C 6 aryl units chosen from 2- aminophenyl, 2-(N-methylamino)phenyl, 2-(N,N-dimethylamino)phenyl, 2-(N- ethylamino)phenyl, 2-(N,N-diethylamino)phenyl, 3-aminophenyl, 3-(N- methylamino)phenyl, 3-(N,N-dimethylamino)phenyl, 3-(N-ethylamino)phenyl, 3-(N,N- diethylamino)phenyl, 4-aminophenyl, 4-(N-methylamino)phenyl, 4-(N,N- dimethylamino)phenyl, 4-(N-ethylamino)phenyl, and 4-(N,N-diethylamino)phenyl.
• R 1 can comprise heteroaryl units.
• C 1 -C 9 heteroaryl units include:
• R heteroaryl units can be substituted or unsubstituted.
• units that can substitute for hydrogen include units chosen from:
• R 9 is Ci-C 6 linear and branched alkyl; Ci-C 6 linear and C 3 -C6 branched alkoxy; or -NHCH 2 C(0)R 10 ; R 10 is chosen from hydrogen, methyl, ethyl, and tert-butyl.
• R 1 relates to units substituted by an alkyl unit chosen from methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, z ' so-butyl, sec-butyl, and tert-butyl.
• R 1 includes units that are substituted by substituted or
• R 11 and R 16 are each independently hydrogen, methyl, or ethyl.
• R 1 relates to phenyl and benzyl units substituted by a carboxy unit having the formula -C(0)R 9 ;
• R 9 is chosen from methyl, methoxy, ethyl, and ethoxy.
• R 1 includes phenyl and benzyl units substituted by an amide unit having the formula -NHC(0)R 9 ;
• R 9 is chosen from methyl, methoxy, ethyl, ethoxy, tert- butyl, and tert-butoxy.
• R 1 includes phenyl and benzyl units substituted by one or more fluoro or chloro units.
• L is a linking unit which is present when the index n is equal to 1 , but is absent when the index n is equal to 0.
• L units have the formula:
• R 5a and R 5b are each independently:
• Ci-C 6 linear or C 3 -C 6 branched alkyl substituted or unsubstituted Ci-C 6 linear or C 3 -C 6 branched alkyl; or v) a unit having the formula:
• R 7a and R 7b are each independently:
• Ci-C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl substituted or unsubstituted Ci-C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl.
• R 8 is:
• R 6a and R 6b are each independently:
• indices t, w and x are each independently from 0 to 4.
• R 5a , R 5b , R 7a , R 7b , and R 8 units are each independently chosen:
• ii) substituted or unsubstituted C 6 or Cio aryl for example, phenyl, naphthyl (also referred to herein as naphthylen-l-yl (Cio) or naphthylen-2-yl (Cio)); iii) substituted or unsubstituted C 6 or Cio alkylenearyl; for example, benzyl, 2- phenylethyl, naphthyl en-2-ylmethyl;
• -(CR 41a R 41b ) r OR 40 for example, -OH, -CH 2 OH, -OCH 3 , -CH 2 OCH 3 , -OCH 2 CH 3 , -CH 2 OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , and -CH 2 OCH 2 CH 2 CH 3 ;
• -(CR 41a R 41b ) r C(0)R 40 for example, -COCH 3 , -CH 2 COCH 3 , -COCH 2 CH 3 , -CH 2 COCH 2 CH 3 , -COCH 2 CH 2 CH 3 , and -CH 2 COCH 2 CH 2 CH 3 ;
• each R 40 is independently hydrogen, substituted or unsubstituted Ci-C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R 40 units can be taken together to form a ring comprising 3-7 atoms;
• R 41a and R 41b are each independently hydrogen or C 1 -C 4 linear or C 3 -C 4 branched alkyl; the index r is from 0 to 4.
• L units relates to units having the formula:
• linking units having the formula:
• R 5a is:
• this embodiment provides the following non-limiting examples of L units:
• this embodiment provides the following non- limiting examples of L units:
• L units includes units wherein Q is -C(O)-, the indices x and z are equal to 0, w is equal to 1 or 2, a first R 6a unit chosen from phenyl, 2- fluorophenyl, 3 -fluorophenyl, 4-f uorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4- hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3- dimethoxyphenyl, 3,4-dimethoxyphenyl, and 3,5-dimethoxyphenyl; a second R 6a unit chosen
• An example of this embodiment of L includes a first R a unit as depicted herein above that is a substituted or unsubstituted heteroaryl unit as described herein above.
• An example of this embodiment of L includes units having the formula:
• R 6a and R 6b are hydrogen and the index w is equal to 1 or 2; said units chosen from:
• R 5a and R 5b are hydrogen and the index x is equal to 1 or 2; said units chosen from:
• R 5a and R 5b are hydrogen and the index w is equal to 0, 1 or 2; said units chosen from:
• L units having the formula:
• R 8a and R 8b are hydrogen or methyl and the index w is equal to 0, 1 or 2; said units chosen from:
• An aspect of Category I of the present disclosure relates to compounds wherein R a substituted or unsubstituted thiazol-2-yl unit having the formula:
• R units are thiazol-2-yl units, that when substituted, are substituted with R and R 3 units.
• R and R 5a units are further described in Table I.
• Reagents and conditions (e) (i) H 2 :Pd/C, MeOH; (ii) S0 3 -pyridine, NH 4 OH; rt, 2 hr.
• reaction mixture is concentrated and the residue dissolved in EtOAc, washed successively with 5% citric acid, water, 5% NaHC0 3 , water and brine, dried (Na 2 S0 4 ), filtered and concentrated in vacuo to a residue that is triturated with a mixture of
• a catalytic amount of Pd/C (10%> w/w) is added and the mixture is stirred under a hydrogen atmosphere 2 hours.
• the reaction mixture is filtered through a bed of CELITETM and the solvent is removed under reduced pressure.
• the crude product is dissolved in pyridine (12 mL) and treated with S0 3 -pyridine (0.314 g).
• the reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH 4 OH (50 mL) is added.
• the mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.222 g of the desired product as the ammonium salt.
• the disclosed inhibitors can also be isolated as the free acid.
• a non-limiting example of this procedure is described herein below in Example 4.
• the compounds of this embodiment can be prepared according to the procedure outlined above in Scheme I and described in Example 1 by substituting the appropriate Boc- -amino acid for (5)-(2-tert-butoxycarbonylamino)-3-phenylpropionic acid in step (d).
• the second aspect of Category I of the present disclosure relates to compounds wherein R is a substituted or unsubstituted thiazol-4-yl having the formula:
• Reagents and conditions (d) (i) H 2 :Pd/C, MeOH; (ii) S0 3 -pyridine, NH 4 OH; rt, 12hr.
• the reaction mixture is cooled to room temperature and diethyl ether is added to precipitate the intermediate 2-(nitrophenyl)-(5)-l-(4-phenylthiazol-2-yl)ethyl amine which is isolated by filtration as the hydrobromide salt.
• the hydrobromide salt is dissolved in DMF (3 mL) together with diisoproylethylamine (0.42 mL, 2.31 mmol), 1-hydroxybenzotriazole (0.118 g, 0.79 mmol) and (5)-(2-tert-butoxycarbonyl-amino)-3-phenylpropionic acid (0.212 g, 0.80 mmol). The mixture is stirred at 0 °C for 30 minutes then at room temperature overnight.
• the reaction mixture is filtered through a bed of CELITETM and the solvent is removed under reduced pressure.
• the crude product is dissolved in pyridine (12 mL) and treated with S0 3 -pyridine (0.296 g).
• the reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH 4 OH (10 mL) is added.
• the mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.050 g of the desired product as the ammonium salt.
• An aspect of Category II of the present disclosure relates to compounds wherein R is a substituted or unsubstituted thiazol-4-yl unit having the formula:
• R units are thiazol-4-yl units, that when substituted, are substituted with R 4 units.
• R and R 5a units are further described in Table IV.
• Reagents and conditions (b) (i) H 2 :Pd/C, MeOH; (ii) S0 3 -pyridine, NH 4 OH; rt, 18 hr.
• the reaction mixture is cooled to room temperature and diethyl ether is added to precipitate the intermediate 2-(nitrophenyl)-(5)-l-(4-ethylthiazol-2-yl)ethylamine which is isolated by filtration as the hydrobromide salt.
• the hydrobromide salt is dissolved in DMF (8 mL) together with diisoproylethylamine (0.38 mL, 2.13 mmol), 1-hydroxybenzotriazole (107 mg, 0.71 mmol) and (5)-(2-methoxycarbonyl-amino)-3-phenylpropionic acid (175 mg, 0.78 mmol). The mixture is stirred at 0 °C for 30 minutes then at room temperature overnight.
• a catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 18 hours.
• the reaction mixture is filtered through a bed of CELITETM and the solvent is removed under reduced pressure.
• the crude product is dissolved in pyridine (12 mL) and treated with S0 3 -pyridine (223 mg, 1.40 mmol).
• the reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH 4 OH (12 mL) is added.
• the mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 25 mg of the desired product as the ammonium salt.
• compound 13 in another iteration of the process of the present disclosure, can be isolated as the free acid by adapting the procedure described herein below.
• MeOH (270 mL, 15 mL/g) is added to provide a suspension.
• the vessel is put on a Parr hydrogenation apparatus.
• the vessel is submitted to a fill/vacuum evacuate process with N 2 (3 x 20 psi) to inert, followed by the same procedure with H 2 (3 x 40 psi).
• the vessel is filled with H 2 and the vessel is shaken under 40 psi H 2 for -40 hr.
• the vessel is evacuated and the atmosphere is purged with N 2 (5 x 20 psi). An aliquot is filtered and analyzed by HPLC to insure complete conversion.
• the suspension is filtered through a pad of celite to remove the catalyst, and the homogeneous yellow filtrate is concentrated by rotary evaporation to afford 16.06 g (95% yield) of the desired product as a tan solid, which is used without further purification.
• Acetonitrile 50 mL, 5 mL/g is added and the yellow suspension is stirred at room temperature.
• a second 3-necked 500 mL RBF is charged with S0 3 - pyr (5.13 g, 32.2 mmol, 1.4 eq.) and acetonitrile (50 mL 5 mL/g) and the white suspension is stirred at room temperature.
• H 2 0 (200 mL, 20 mL/g) is added to the orange suspension to provide a yellow-orange homogeneous solution having a pH of approximately 2.4.
• Concentrated H 3 P0 4 is added slowly over 12 minutes to lower the pH to approximately 1.4. During this pH adjustment, an off-white precipitate is formed and the solution is stirred at room temperature for 1 hr. The suspension is filtered and the filter cake is washed with the filtrate. The filter cake is air- dried on the filter overnight to afford 10.89 g (89 % yield) of the desired product as a tan solid.
• Category III of the present disclosure relates to compounds wherein R is a substituted or unsubstituted thiazol-2-yl unit having the formula:
• R units are thiazol-2-yl units, that when substituted, are substituted with R and R 3 units.
• R and R 5a units are further described in Table V.
• Reagents and conditions (a) Ac-Phe, EDCI, HOBt, DIPEA, DMF; rt, 18 hr.
• Reagents and conditions (b) (i) H 2 :Pd/C, MeOH; (ii) S0 3 -pyridine, NH 4 OH.
• the reaction mixture is filtered through a bed of CELITETM and the solvent is removed under reduced pressure.
• the crude product is dissolved in pyridine (12 mL) and treated with S03-pyridine (0.320 g).
• the reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH 4 OH (30 mL) is added.
• the mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.215 g of the desired product as the ammonium salt.
• the first aspect of Category IV of the present disclosure relates to compounds wherein R is a substituted or unsubstituted thiazol-2-yl unit having the formula:
• Reagents and conditions (a) Boc-Val; EDCI, HOBt, DIPEA, DMF; rt, 18 hr.
• a catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 2 hours.
• the reaction mixture is filtered through a bed of CELITETM and the solvent is removed under reduced pressure.
• the crude product is dissolved in pyridine (5 mL) and treated with S0 3 -pyridine (0.146 g).
• the reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH 4 OH (30 mL) is added.
• the mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.148 g of the desired product as the ammonium salt.
• Category IV of the present disclosure relates to compounds having the formula:
• R is a substituted or unsubstituted thiophen-2-yl or thiophen-4-yl unit and non- limiting examples of R° are further described in Table VIII.
• the crude product is dissolved in pyridine (12 mL) and treated with S03-pyridine (0.195 g, 1.23 mmol). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH 4 OH (10 mL) is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.080 g of the desired product as the ammonium salt.
• the first aspect of Category V of the present disclosure relates to 2-(thiazol-2-yl) compounds having the formula:
• R 1 , R2 , R 3 , and L are further defined herein in Table IX below.
• the compounds encompassed within the first aspect of Category V of the present disclosure can be prepared by the procedure outlined in Scheme VII and described in Example 8 herein below.
• Reagents and conditions (a) C 6 H 5 CH 2 C0 2 H, EDCI, HOBt, DIPEA, DMF; rt, 18 hr.
• Reagents and conditions (b) (i) H 2 :Pd/C, MeOH; (ii) S0 3 -pyridine, NH 4 OH, rt, 18 hr.
• the crude product is dissolved in pyridine (12 mL) and treated with S0 3 -pyridine (0.177 g, 1.23). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH 4 OH (10 mL) is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.136 g of the desired product as the ammonium salt.
• the second aspect of Category V of the present disclosure relates to 2-(thiazol-4- yl) compounds having the formula:
• R 1 , R 4 , and L are further defined herein in Table X below.
• Reagents and conditions (b) (3-Cl)C 6 H 4 CH 2 C0 2 H, EDCI, HOBt, DIPEA, DMF; rt, 18 hr.
• linking unit L comprises a phenyl unit, said linking group having the formula:
• R 1 is hydrogen
• R 6a is phenyl
• R 5a is phenyl or substituted phenyl and non-limiting examples of the units R 2 , R 3 , and R 5a are further exemplified below in Table XI.
• Reagents and conditions (b) NaOH, THF/MeOH; rt, 18 hr.
• the fourth aspect of Category V of the present disclosure relates to compounds having the formula:
• linking unit L comprises a phenyl unit, said linking group having the formula:
• Reagents and conditions (c) (i) tin (II) chloride, EtOH; (ii) S0 3 -pyridine, NH 4 OH; rt, 18 hr.
• the mixture is stirred at 0 °C for 30 minutes then at room temperature overnight.
• the reaction mixture is diluted with water and extracted with EtOAc.
• the combined organic phase is washed with 1 N aqueous HC1, 5 % aqueous NaHC0 3 , water and brine, and dried over Na 2 S0 4 .
• the solvent is removed in vacuo to afford 0.169 g (31 % yield) of the desired product which is used without further purification.
• Category VI of the present disclosure relates to 2-(thiazol-2-yl) compounds having the formula:
• R , R , and R are further defined herein in Table XIII herein.
• N-methyl imidazole CH 2 C1 2 ; rt, 18 hr.
• Reagents and conditions (b) (i) H 2 :Pd/C, MeOH; (ii) S0 3 -pyridine, NH 4 OH.
• intermediate nitro compounds of the following can be prepared by coupling the appropriate 4-oxo-carboxcylic acid with intermediate 3 under the conditions described herein above for the formation of intermediate 4 of scheme
• the first aspect of Category VII of the present disclosure relates to 2-(thiazol-2-yl) compounds having the formula:
• Reagents and conditions (a) benzyl isocyanate, TEA, CH 2 CI 2 ; rt, 18 hr.
• Reagents and conditions (b) (i) H 2 :Pd/C, MeOH; (ii) S0 3 -pyridine, NH 4 OH.
• the crude product is dissolved in pyridine (12 mL) and treated with S0 3 -pyridine (0.220 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH 4 OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.143 g of the desired product as the ammonium salt.
• the second aspect of Category VII of the present disclosure relates to 2-(thiazol-4- yl) compounds having the formula:
• Reagents and conditions (a) benzyl isocyanate, TEA, CH 2 C1 2 ; rt, 18 hr.
• the reaction mixture is filtered through a bed of CELITETM and the solvent is removed under reduced pressure.
• the crude product is dissolved in pyridine (12 mL) and treated with S0 3 -pyridine (0.110 g).
• the reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH 4 OH is added.
• the mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.080 g of the desired product as the ammonium salt.
• Category VIII of the present disclosure relates to 2-(thiazol-4-yl) compounds having the formula:
• R 1 , R 4 , and L are further defined herein in Table XVI herein below.
• Reagents and conditions (b) (i) H 2 :Pd/C, MeOH; (ii) S0 3 -pyridine, NH 4 OH.
• 1-phenylmethanesulfonamide (38) To a suspension of 2-(4-nitrophenyl)-l-(2-thiophene2- ylthiazol-4-yl)ethylamine, 8, (330 mg, 0.80 mmol) in CH 2 C1 2 (6 mL) at 0 °C is added diisopropylethylamine (0.30 mL, 1.6 mmol) followed by phenylmethanesulfonyl chloride (167 mg, 0.88 mmol). The reaction mixture is stirred at room temperature for 14 hours. The mixture is diluted with CH 2 C1 2 and washed with sat. NaHC0 3 followed by brine, dried (Na 2 S0 4 ), filtered and concentrated in vacuo. The resulting residue is purified over silica to afford 210 mg of the desired product as a white solid.
• the reaction mixture is filtered through a bed of CELITETM and the solvent is removed under reduced pressure.
• the crude product is dissolved in pyridine (12 mL) and treated with S0 3 -pyridine (197 mg, 1.23 mmol).
• the reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH 4 OH is added.
• the mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.060 g of the desired product as the ammonium salt.
• Reagents and conditions (a) Na 2 S03, H 2 0; microwave @ 200°C, 20 min.

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