WO2008002570A2 - Human protein tyrosine phosphatase inhibitors and methods of use - Google Patents

Human protein tyrosine phosphatase inhibitors and methods of use Download PDF

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Publication number
WO2008002570A2
WO2008002570A2 PCT/US2007/014823 US2007014823W WO2008002570A2 WO 2008002570 A2 WO2008002570 A2 WO 2008002570A2 US 2007014823 W US2007014823 W US 2007014823W WO 2008002570 A2 WO2008002570 A2 WO 2008002570A2
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Prior art keywords
ethyl
substituted
unsubstituted
phenyl
chosen
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PCT/US2007/014823
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French (fr)
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WO2008002570A3 (en
WO2008002570B1 (en
Inventor
Jeffrey Lyle Gray
Kande Amarasighe
Cynthia Monesa Clark
Mathew Brian Maier
Ryan Nichols
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The Procter & Gamble Company
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Priority to ES07809908.2T priority Critical patent/ES2534392T3/en
Priority to KR1020097001694A priority patent/KR101179087B1/en
Application filed by The Procter & Gamble Company filed Critical The Procter & Gamble Company
Priority to NZ574406A priority patent/NZ574406A/en
Priority to PL07809908T priority patent/PL2038265T3/en
Priority to JP2009518227A priority patent/JP5261383B2/en
Priority to CN2007800309846A priority patent/CN101506180B/en
Priority to EP07809908.2A priority patent/EP2038265B1/en
Priority to BRPI0713357-0A priority patent/BRPI0713357A2/en
Priority to AU2007265454A priority patent/AU2007265454B2/en
Priority to DK07809908.2T priority patent/DK2038265T3/en
Priority to MX2009000289A priority patent/MX2009000289A/en
Priority to CA2657107A priority patent/CA2657107C/en
Priority to SI200731650T priority patent/SI2038265T1/en
Publication of WO2008002570A2 publication Critical patent/WO2008002570A2/en
Publication of WO2008002570A3 publication Critical patent/WO2008002570A3/en
Publication of WO2008002570B1 publication Critical patent/WO2008002570B1/en
Priority to IL196129A priority patent/IL196129A/en
Priority to HK09108320.5A priority patent/HK1129387A1/en

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Definitions

  • the present disclosure relates to compounds effective as human protein tyrosine phosphatase beta (HPTP- ⁇ ) inhibitors thereby regulating angiogenesis.
  • the present disclosure further relates to compositions comprising one or more human protein tyrosine phosphatase beta (HPTP- ⁇ ) inhibitors, and to methods for regulating angiogenesis.
  • Angiogenesis the sprouting of new blood vessels from the pre-existing vasculature, plays a crucial role in a wide range of physiological and pathological processes (Nguyen, L.L. et ai, Int. Rev. Cytol., 204, 1-48, (2001)).
  • Angiogenesis is a complex process, mediated by communication between the endothelial cells that line blood vessels and their surrounding environment, hi the early stages of angiogenesis, tissue or tumor cells produce and secrete pro- angiogenic growth factors in response to environmental stimuli such as hypoxia. These factors diffuse to nearby endothelial cells and stimulate receptors that lead to the production and secretion of proteases that degrade the surrounding extracellular matrix.
  • Endothelial cells begin to migrate and proliferate into the surrounding tissue toward the source of these growth factors (Bussolino, F., Trends Biochem. ScL, 22, 251-256, (1997)). Endothelial cells then stop proliferating and differentiate into tubular structures, which is the first step in the formation of stable, mature blood vessels. Subsequently, periendothelial cells, such as pericytes and smooth muscle cells, are recruited to the newly formed vessel in a further step toward vessel maturation.
  • periendothelial cells such as pericytes and smooth muscle cells
  • Angiogenesis is regulated by a balance of naturally occurring pro- and anti -angiogenic factors.
  • Vascular endothelial growth factor, fibroblast growth factor, and angiopoeitin represent a few of the many potential pro-angiogenic growth factors.
  • These ligands bind to their respective receptor tyrosine kinases on the endothelial cell surface and transduce signals that promote cell migration and proliferation.
  • regulatory factors have been identified, the molecular mechanisms of this process are still not fully understood.
  • ocular neovascularization has been implicated as the most common cause of blindness and underlies the pathology of approximately 20 eye diseases.
  • newly formed capillary blood vessels invade the joints and destroy cartilage.
  • new capillaries formed in the retina invade the vitreous humor, causing bleeding and blindness.
  • Both the growth and metastasis of solid tumors are also angiogenesis-dependent (Folkman et al., "Tumor Angiogenesis,” Chapter 10, 206-32, in The Molecular Basis ofCancer, Mendelsohn et al., eds., W. B. Saunders, (1995)).
  • tumors which enlarge to greater than 2 mm in diameter must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels. After these new blood vessels become embedded in the tumor, they provide nutrients and growth factors essential for tumor growth as well as a means for tumor cells to enter the circulation and metastasize to distant sites, such as liver, lung or bone (Weidner, New Eng. J. Med., 324, 1, 1-8 (1991)).
  • natural inhibitors of angiogenesis may prevent the growth of small tumors (O'Reilly et al., Cell, 79, 315-28 (1994)).
  • Tissue growth and repair are biologic events wherein cellular proliferation and angiogenesis occur.
  • an important aspect of wound repair is the revascularization of damaged tissue by angiogenesis.
  • Atherosclerotic lesions in large vessels may cause tissue ischemia that could be ameliorated by modulating blood vessel growth to the affected tissue.
  • atherosclerotic lesions in the coronary arteries may cause angina and myocardial infarction that could be prevented if one could restore blood flow by stimulating the growth of collateral arteries.
  • atherosclerotic lesions in the large arteries that supply the legs may cause ischemia in the skeletal muscle that limits mobility and in some cases necessitates amputation, which may also be prevented by improving blood flow with angiogenic therapy.
  • diabetes and hypertension are characterized by a decrease in the number and density of small blood vessels such as arterioles and capillaries. These small blood vessels are important for the delivery of oxygen and nutrients. A decrease in the number and density of these vessels contributes to the adverse consequences of hypertension and diabetes including claudication, ischemic ulcers, accelerated hypertension, and renal failure. These common disorders and many other less common ailments, such as Burgers disease, could be ameliorated by increasing the number and density of small blood vessels using angiogenic therapy.
  • the compounds of Formula (I), and/or their pharmaceutically acceptable salts have been found to be inhibitors of human protein tyrosine phosphatase beta (HPTP- ⁇ ), and hence are capable of regulating angiogenesis in humans, so as to treat various diseases that include but are not limited to diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales' disease, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis,
  • the present disclosure further relates to pharmaceutical compositions comprising one or more of the compounds of Formula (I), and pharmaceutically acceptable salts thereof.
  • the present disclosure also relates to methods for controlling angiogenesis, and thereby providing a treatment for diseases affected by angiogenesis, said methods comprising administering to a human an effective amount of one or more compounds having Formula (I), and pharmaceutically acceptable salts thereof, as disclosed herein.
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the relevant active compound without causing clinically unacceptable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • a composition includes mixtures of two or more such compositions
  • a phenylsulfamic acid includes mixtures of two or more such phenylsulfamic acids
  • the compound includes mixtures of two or more such compounds, and the like.
  • Ranges can be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10" is also disclosed.
  • An organic unit can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, or 1-4 carbon atoms.
  • Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical.
  • an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical.
  • an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.
  • organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamido, substituted alkylcarboxamido, dialkylcarboxamido, substituted dialkylcarboxamido, alkylsulfonyl, alkylsulf ⁇ nyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein.
  • organic radicals that include heteroatoms include alkoxy radicals, trifiuoromethoxy radicals, acetoxy radicals, dimethyla
  • Substituted and unsubstituted linear, branched, or cyclic alkyl units include the following non-limiting examples: methyl (Ci), ethyl (C 2 ), n-propyl (C3), iso-propyl (C 3 ), cyclopropyl (C3), n-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), tert-butyl (C 4 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), cyclohexyl (Ce), and the like; whereas substituted linear, branched, or cyclic alkyl, non-limiting examples of which includes, hydroxymethyl (Ci), chloromethyl (Ci), trifluoromethyl (Ci), aminomethyl (C 1 ), 1-chloroethyl (C 2 ), 2-hydroxyethyl (C 2 ), 1,2-difluoroethyl (
  • Substituted and unsubstituted linear, branched, or cyclic alkenyl include, ethenyl (C 2 ), 3- propenyl (C 3 ), 1-propenyl ⁇ also 2-methylethenyl) (C 3 ), 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 2-chloro vinyl) (C 2 ), 4-hydroxybuten-l-yl (C 4 ), 7- hydroxy-7-methyloct-4-en-2-yl (C 9 ), 7-hydroxy-7-methyloct-3,5-dien-2-yl (C 9 ), and the like.
  • Substituted and unsubstituted linear or branched alkynyl include, ethynyl (C 2 ), prop-2- ynyl ⁇ also propargyl) (C 3 ), propyn-1-yl (C 3 ), and 2-methyl-hex-4-yn-l-yl (C 7 ); 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 ), 5-hydroxy-5-ethylhept-3-ynyl (C 9 ), and the like.
  • aryl denotes organic rings that consist only of a conjugated planar carbon ring system with delocalized pi electrons, non-limiting examples of which include phenyl (Ce) 5 naphthylen-1-yl (Cio), naphthylen-2-yl (C 1 0).
  • Aryl rings can have one or more hydrogen atoms substituted by another organic or inorganic radical.
  • Non-limiting examples of substituted aryl rings include: 4-fluorophenyl (Ce), 2-hydroxyphenyl ⁇ C ⁇ ), 3- methylphenyl (C 6 ), 2-amino-4-fluorophenyl (C ⁇ ), 2-( ⁇ yV-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-l-yl (Cio), and 6-cyanonaphthylen-l-yl (Cio).
  • heteroaryl denotes an aromatic ring system having from 5 to 10 atoms.
  • the rings can be a single ring, for example, a ring having 5 or 6 atoms wherein at least one ring atom is a heteroatom not limited to nitrogen, oxygen, or sulfur.
  • heteroaryl can denote a fused ring system having 8 to 10 atoms wherein at least one of the rings is an aromatic ring and at least one atom of the aromatic ring is a heteroatom not limited nitrogen, oxygen, or sulfur.
  • heterocyclic denotes a ring system having from 3 to 10 atoms wherein at least one of the ring atoms is a heteroatom not limited to nitrogen, oxygen, or sulfur.
  • the rings can be single rings, fused rings, or bicyclic rings.
  • Non-limiting examples of heterocyclic rings include:
  • heteroaryl or heterocyclic rings can be optionally substituted with one or more substitutes for hydrogen as described herein further.
  • thiophene-2-yl and thiophene-3-yl are used to describe the heteroaryl units having the respective formulae: whereas in naming the compounds of the present disclosure, the chemical nomenclature for these moieties are typically spelled “thiophen-2-yl and thiophen-3-yl” respectively.
  • thiophene-2-yl and thiophene-3-yl are used when describing these rings as units or moieties which make up the compounds of the present disclosure solely to make it unambiguous to the artisan of ordinary skill which rings are referred to herein.
  • substituted is used throughout the specification.
  • substituted is defined herein as "a hydrocarbyl moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several substituents as defined herein below.”
  • the units, when substituting for hydrogen atoms are capable of replacing one hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety at a time.
  • these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety, or unit.
  • a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like.
  • a two hydrogen atom replacement includes carbonyl, oximino, and the like.
  • a two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like.
  • a three hydrogen replacement includes cyano, and the like.
  • substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain; can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as "substituted" any number of the hydrogen atoms may be replaced.
  • 4-hydroxyphenyl is a "substituted aromatic carbocyclic ring"
  • (N,N-dimethyl-5-amino)octanyl is a " substituted C 8 alkyl unit
  • 3- guanidinopropyl is a "substituted C 3 alkyl unit
  • 2-carboxypyridinyl is a "substituted heteroaryl unit.”
  • the following are non-limiting examples of units that can substitute for hydrogen atomsit: i) C 1 -C 12 linear, branched, or cyclic alkyl, alkenyl, and alkynyl; for example, methyl
  • CONHCH 3 CONHCH 3 , -CH 2 CONHCH 3 , -CON(CH 3 ) 2 , and -CH 2 CON(CH 3 ) 2 ; ix) -(CR 14a R 14b ) z N(R 13 ) 2 ; ; for example, -NH 2 , -CH 2 NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -
  • each R 13 is independently hydrogen, substituted or unsubstituted C 1 -C 4 linear, branched, or cyclic alkyl, phenyl, benzyl; or two R 13 units can be taken together to form a ring comprising 3-7 atoms;
  • R l4a and R I4b are each independently hydrogen or Ci -C 4 linear or branched alkyl; the index p is from O to 4.
  • the present disclosure addresses several unmet medical needs, inter alia;
  • compositions effective as human protein tyrosine phosphatase beta (HPTP- ⁇ ) inhibitors and thereby providing a method for regulating angiogenesis in a disorder, disease, malady, or condition wherein angiogenesis is elevated;
  • compositions effective as human protein tyrosine phosphatase beta (HPTP- ⁇ ) inhibitors Providing compositions effective as human protein tyrosine phosphatase beta (HPTP- ⁇ ) inhibitors; and thereby providing a method for regulating angiogenesis in a disorder, disease, malady, or condition; and
  • compositions effective as human protein tyrosine phosphatase beta (HPTP- ⁇ ) inhibitors and thereby providing a method for regulating angiogenesis in a disorder, disease, malady, or condition wherein angiogenesis is decreased.
  • HPTP- ⁇ human protein tyrosine phosphatase beta inhibitors of the present disclosure, that are capable of regulating angiogenesis and thereby serving as a method for treating elevated or diminished angiogenesis in humans or in treating diseases that are caused by insufficient regulation of human protein tyrosine phosphatase beta (HPTP- ⁇ ).
  • the compounds disclosed herein include all pharmaceutically acceptable salt forms, for example, salts of both basic groups, inter alia, amines, as well as salts of acidic groups, inter alia, sulfamic acids, and carboxylic acids.
  • anions that can form salts with basic groups, such as amines: chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate, and the like.
  • cations that can form salts of acidic groups, such as carboxylic acid / carboxylate units: sodium, lithium, potassium, calcium, magnesium, bismuth, and the like.
  • the compounds of the present disclosure are ethyl-amino substituted phenylsulfamic acids, or their pharmaceutically acceptable salts, having the core structure of Compound (I) shown in the drawing below:
  • the units R and Z can be any of the alternatives further defined and exemplified herein below.
  • the carbon atom bearing the amino unit has the absolute stereochemistry(S) stereochemistry as indicated in the drawing above, which typically corresponds to an (S) configuration at the same amine-bearing carbon atom, but which could vary depending on the nature of the R substituent group and the resulting priority changes.
  • the R units of the compounds of Formula (I) can be substituted or unsubstituted heterocyclic or heteroaryl rings having from 3 to 15 ring atoms.
  • the substituted or unsubstituted heterocyclic or heteroaryl rings of the R group of the compounds of Formula (I) can be represented below by the generic ring, A, in the drawing shown below:
  • R 15 units can be optionally substituted by one, two, or three independently chosen substituents represented in the generic formula by R 15 units.
  • R 15 substituent units include: i) linear, branched, or cyclic alkyl, alkenyl, and alkynyl; for example, methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), /s ⁇ -propyl (C 3 ), cyclopropyl (C 3 ), propylen-2-yl (C 3 ), propargyl (C 3 ), n-butyl (C 4 ), iso-butyl (C 4 ), sec-butyl (C 4 ), tert-b ⁇ ty ⁇ (C 4 ), cyclobutyl (C 4 ), n-pentyl (C 5 ), cyclopentyl (C 5 ), n-hexyl (C O ), and cyclo
  • each R 16 is independently hydrogen, substituted or unsubstituted C 1 -C 4 linear, branched, or cyclic alkyl; or two R 16 units can be taken together to form a ring comprising 3-7 ring atoms; R l7a and R l 7b are each independently hydrogen or C 1 -C4 linear or branched alkyl; the index q is from 0 to 4.
  • R 15 units comprise C1-C 1 2 linear, branched, or cyclic alkyl, alkenyl; substituted or unsubstituted Ce or Cio aryl; substituted or unsubstituted C 1 -C 9 heterocyclic; or substituted or unsubstituted C 1 -Cg heteroaryl; R 15 units can further have one or more hydrogen atoms substituted by R 18 units.
  • R 18 units include: i) linear, branched, or cyclic alkyl, alkenyl, and alkynyl; for example, methyl (Cj), ethyl (C 2 ), n-propyl (C 3 ), zs ⁇ -propyl (C 3 ), cyclopropyl (C 3 ), propylen-2-yl (C 3 ), propargyl (C 3 ), n-butyl (C 4 ), wo-butyl (C 4 ), .sec-butyl (C 4 ), tert-buty ⁇ (C 4 ), cyclobutyl (C 4 ), n-pentyl (C 5 ), cyclopentyl (C 5 ), n-hexyl (C 6 ), and cyclohexyl (C 6 ); ii) -(CR 20a R 20b ) q OR 19 ; for example, -OH, -CH 2 OH,
  • each R 19 is independently hydrogen, substituted or unsubstituted C 1 -C 4 linear, branched, or cyclic alkyl; or two R 19 units can be taken together to form a ring comprising 3-7 atoms;
  • R 20a and R 20b are each independently hydrogen or CpC 4 linear or branched alkyl; the index p is from O to 4.
  • R 15 and R 18 units may be represented by specific ring substitutions, for example, a ring encompassed within the definition of R can be depicted as either having the formula:
  • R units comprise a ring having from 3 to 15 ring atoms.
  • R units can comprise 5-member heteroaryl rings.
  • the 5-member heteroaryl rings can be substituted with one or more substitutes for hydrogen, for example, with a methyl group:
  • 5-member ring R units includes thiazolyl units having the formula:
  • thiazolyl R unit includes thiazol-2-yl units having the formula: wherein R ⁇ and R/ are each independentl chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-C 6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv) substituted or unsubstituted C 1 -C9 heteroaryl; or R 2 and R 3 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms.
  • R unit relates to units having the formula: wherein R 3 is hydrogen and R 2 is a unit chosen from methyl (Cj), 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 ).
  • 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 (C4). iso-butyl (C 4 ), and tert-butyl (C 4 ); and R 3 is a unit chosen from methyl (C]) or ethyl (C2).
  • 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.
  • R unit relates to units wherein R 3 is hydrogen and R 2 is a substituted alkyl unit, the substitutions chosen from: i) halogen: -F, -Cl, -Br, and -I; ii) -N(R n ) 2 ; and iii) -OR 11 ; wherein each R 1 ' is independently hydrogen or Ci-C 4 linear or branched alkyl.
  • R 1 ' is independently hydrogen or Ci-C 4 linear or branched alkyl.
  • R units include units wherein R 3 is hydrogen and R 2 is phenyl.
  • R units include units wherein R 3 is hydrogen and R 2 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-yI, [l,3,4]oxadiazol-2-yl,
  • R includes units wherein R 2 is thiophene-2-yl or thiophene-3-yl.
  • R units includes thiazol-4-yl units having the formula: wherein R 4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted C 1 -C 9 heteroaryl.
  • R units includes compounds wherein R 4 is hydrogen.
  • R units includes compounds wherein R 4 is a unit chosen from methyl (Ci), ethyl (C 2 ), n-propyl (C3), iso-propyl (C3), n-butyl (C 4 ), .sec-butyl (C 4 ), iso-butyl (C4), and tert-butyl (C4).
  • R 4 is a unit chosen from methyl (Ci), ethyl (C 2 ), n-propyl (C3), iso-propyl (C3), n-butyl (C 4 ), .sec-butyl (C 4 ), iso-butyl (C4), and tert-butyl (C4).
  • R is a unit chosen from methyl (Ci), ethyl (C 2 ), n-propyl (C3), iso-propyl (C3), n-butyl (C 4 ), .sec-butyl (C 4 ),
  • R units includes compounds 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 .
  • R units includes compounds wherein R 4 is substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-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 2 and R 3 are each independently chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-C 6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv) substituted or unsubstituted Ci -Cg heteroaryl; or R 2 and R 3 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms.
  • R units include compounds wherein R units have 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 ), .see-butyl (C 4 ), /so-butyl (C 4 ), and tert-butyl (C 4 ).
  • R units includes compounds wherein R 2 is a unit chosen from methyl (Ci), ethyl (C 2 ), n-propyl (Cs) 5 iso-propyl (C 3 ), n-butyl (C 4 ), _?ec-butyl (C 4 ), iso-buty ⁇ (C 4 ), and tert-buty ⁇ (C 4 ); and R 3 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-methylrrnidazol-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: i) halogen: -F, -Cl, -Br, and -I; ii) -N(R") 2 ; and iii) -OR 1 1 ; wherein each R 11 is independently hydrogen or Ci -C 4 linear or 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 Cl, -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 include units wherein R 3 is hydrogen and R 2 is phenyl.
  • R units include units wherein R 3 is hydrogen and R 2 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-yi, [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, fur
  • R includes units wherein R 2 is thiophene-2-yl or thiophene-3-yl.
  • R units includes imidazol-4-yl units having the formula: wherein R 4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-C 6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted C1-C9 heteroaryl.
  • R units relates to compounds wherein R 4 is hydrogen.
  • R units includes compounds wherein R 4 is hydrogen.
  • R units includes compounds wherein 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 ), /s ⁇ -butyl (C4), and rert-butyl (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 ), /s ⁇ -butyl (C4), and rert-butyl (C 4 ).
  • Non-limiting examples of this aspect of R includes 2-methylimidazol- 4-yl, 2-ethylimidazol-4-yl, 2-(n-propyl)imidazol-4-yl, and 2-(/-?
  • R units includes compounds 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.
  • 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.
  • R units includes compounds wherein R 4 is substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, A- 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 are substituted or unsubstituted oxazolyl units having the formula:
  • oxazolyl R units includes oxazol-2-yl units having the formula:
  • R 2 and R 3 are each independently chosen from: i) hydrogen; ii) substituted or unsubstituted C J -C 6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv) substituted or unsubstituted C1-C9 heteroaryl; or R 2 and R 3 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms.
  • R units include compounds wherein R units have the formula:
  • R 3 is hydrogen and R 2 is a unit chosen from methyl (C]), 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-buty ⁇ (C 4 ).
  • R units includes units wherein R 2 is a unit chosen from methyl (Cj), ethyl (C 2 ), n-propyl (C 3 ), iso-propyl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), zso-butyl (C 4 ), and tert- butyl (C 4 ); and R 3 is a unit chosen from methyl (Ci) or ethyl (C 2 ).
  • Non-limiting examples of this aspect of R includes 4,5-dimethyloxazol-2-yl, 4-ethyl-5-methyloxazol-2-yl, 4-methyl-5- ethyloxazol-2-yl, and 4,5-diethyloxazol-2-yl.
  • R units includes units wherein R 3 is hydrogen and R 2 is a substituted alkyl unit chosen, said substitutions chosen from: i) halogen: -F 5 -Cl, -Br, and -I; ii) -N(R ⁇ ) 2 ; and iii) -OR 1 1 ; wherein each R 11 is independently hydrogen or C 1 -C 4 linear or 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 Cl, -CH 2 OH, -CH 2 OCH 3 , -CH 2 CH 2 OH 9 -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 include units wherein R 3 is hydrogen and R 2 is phenyl.
  • R units include units wherein R 3 is hydrogen and R 2 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, [1, 2,4]triazol-5-yl J 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, fur
  • R includes units wherein R is thiophene-2-yl or thiophene-3-yl.
  • R units includes oxazol-4-yl units having the formula: wherein R 4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted C 1 -CO linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted Ci -C 9 heteroaryl.
  • R 4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted Ci -Ce linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted Cj -C 9 heteroaryl.
  • R units relates to compounds wherein R 4 is hydrogen.
  • R units includes compounds wherein R 4 is hydrogen.
  • R units includes compounds wherein R 4 is a unit chosen from methyl (Cj), ethyl (C 2 ), n-propyl (C 3 ), iso-propyl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), /s ⁇ -butyl (C 4 ), and tert-bx ⁇ y ⁇ (C 4 ).
  • R 4 is a unit chosen from methyl (Cj), ethyl (C 2 ), n-propyl (C 3 ), iso-propyl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), /s ⁇ -butyl (C 4 ), and tert-bx ⁇ y ⁇ (C 4 ).
  • Non-limiting examples of this aspect of R includes 2-methyloxazol-4- yl, 2-ethyloxazol-4-yl, 2-(n-propyl)oxazol-4-yl, and 2-(
  • R units includes compounds 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 .
  • R units includes compounds wherein R 4 is substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-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.
  • R units relate to oxazol-5-yl units having the formula: wherein R is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted CrC 6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted C1-C9 heteroaryl.
  • R units includes compounds wherein R 4 is hydrogen.
  • R units includes compounds wherein R 4 is a unit chosen from methyl (Ci), ethyl (C2), 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 ).
  • R 4 is a unit chosen from methyl (Ci), ethyl (C2), 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 ).
  • Non-limiting examples of this aspect of R includes 2-methyloxazol-4- yl, 2-ethyloxazol-4-yl, 2-(n-propyl)oxazol-4-yl, and 2-(wo-propyl)oxa
  • R units includes compounds 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 .
  • R units includes compounds wherein R 4 is substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-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.
  • a yet further example of 5-member ring R units includes substituted or unsubstituted [l,2,4]oxadiazolyl units having the formula:
  • [l,2,4]oxadiazolyl R units includes [l,2,4]oxadiazol-3-yl units having the formula: wherein R 2 is chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-C 6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted Ci -C9 heteroaryl;
  • R units includes units wherein R 2 is hydrogen.
  • R units wherein R 2 is a unit chosen from methyl (Ci), ethyl (C2), n-propyl (C 3 ), iso-propyl (C 3 ), n-butyl (C4), sec-butyl (C4), /s ⁇ -butyl (C 4 ), and /erf-butyl (C4); and R 3 is a unit chosen from methyl (Ci) or ethyl (C 2 ).
  • Non-limiting examples of this aspect of R includes 5-methyl[l,2,4]oxadiazol-2-yl, 5-ethyl[l,2,4]-oxadiazol-2-yl, 5- propyl[l,2,4]oxadiazol-2-yl, and 5-cyclopropyl[l,2,4]oxadiazol-2-yl.
  • R units includes units wherein R 2 is a substituted alkyl unit chosen, said substitutions chosen from: i) halogen: -F, -Cl, -Br, and -I; ii) -N(R 1 ') 2 ; and iii) -OR 11 ; wherein each R 11 is independently hydrogen or C 1 -C 4 linear or branched alkyl.
  • R 2 is a substituted alkyl unit chosen, said substitutions chosen from: i) halogen: -F, -Cl, -Br, and -I; ii) -N(R 1 ') 2 ; and iii) -OR 11 ; wherein each R 11 is independently hydrogen or C 1 -C 4 linear or branched alkyl.
  • Non-limiting examples of units comprising this embodiment of R includes: -CH 2 F, -
  • R units includes units wherein R 2 is phenyl.
  • R units includes units wherein R 2 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,
  • R units include units wherein R 2 is thiophene-2-yl or thiophene-3- yi.
  • R units includes [l,2,4]oxadiazol-5-yl units having the formula: wherein R 4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-C ⁇ linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted Cj -C 9 heteroaryl.
  • R units includes compounds wherein R 4 is hydrogen.
  • R units include compounds wherein 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 ), iso-butyl (C 4 ), and tert-bntyl (C 4 ).
  • Non-limiting examples of this aspect of R includes 3-methyl[l,2,4]oxadiazol-5- yl, 3-ethyl[l,2,4]oxadiazol-5-yl, 3-(n-propyl)[l,2,4]oxadiazol-5-yl, and 3-(iso- propyl)[ 1 ,2,4]oxadiazol-5-yl.
  • R units includes compounds 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 .
  • R units includes compounds wherein R 4 is substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-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 heteroaryl rings include: i)
  • R units can comprise 5-member heterocyclic rings.
  • 5-member heterocyclic rings include: i)
  • R units can comprise 6-member heterocyclic rings.
  • 6-member heterocyclic rings include: i)
  • R units can comprise 6-member heteraryl rings.
  • 6-member heteroaryl rings include: i)
  • 6-member heteroaryl rings includes pyrimidin-2-yl units having the formula:
  • R 2 , R 3 and R 4 are each independently chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-C ⁇ linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv) substituted or unsubstituted C 1 -C 9 heteroaryl; or
  • R 2 and R 3 or R 3 and R 4 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms.
  • R units having the formula:
  • R 3 and R 4 are both 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 ), js ⁇ -butyl (C 4 ), and tert-b ⁇ tyl (C 4 ).
  • R units include units wherein R 2 and R 3 are chosen from methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), iso-propyl (C 3 ), n-butyl (C 4 ), sec-butyl (C 4 ), is ⁇ -butyl (C 4 ), and tert-butyl (C 4 ); and R 4 is hydrogen.
  • R 4 is hydrogen.
  • Non-limiting examples of this aspect of R includes 4,5- dimethylpyrimidin-2-yl, 4,5-diethylpyrimidin-2-yl, 4-methyl-5-ethyl-pyrimidin-2-yl, and 4-ethyl- 5-methyl-pyrimidin-2-yl.
  • R units include units wherein R 4 is hydrogen and R 2 and R 3 are chosen from: i) halogen: — F, -Cl 5 -Br, and —I; ii) -N(R 1 ') 2 ; and iii) -OR 1 1 ; wherein each R 1 ' is independently hydrogen or Cj-C 4 linear or 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 Cl, -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 2 or R 3 is substituted phenyl and R 4 is hydrogen.
  • R units includes units wherein R 4 is hydrogen and R 2 or R 3 is a heteroaryl unit chosen from 1,2,3,4-tetrazol-l-yl ,l,2,3,4-tetrazol-5-yl, [l,2,3]triazoI-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, pyrr ⁇ l-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
  • R units wherein R 2 is thiophene-2-yl and wherein R 2 is thiophene-3-yl thereby providing R units that are 4-(thiophene-2-yl)pyrimidin-2- yl, 5-(thiophene-2-yl)pyrimidin-2-yl, 4-(thiophene-3-yl)pyrimidin-2-yl, and 5-(thiophene-2- yl)pyrimidin-3-yl.
  • Non-limiting examples of 6-member heteroaryl rings include: i)
  • R units can also comprise fuse ring heteroaryl units.
  • Non-limiting examples of R units include: i)
  • R units that are fused heteroaryl rings can be optionally substituted by one or more independently chosen substitutes for hydrogen as described herein above.
  • Z is a unit having the formula:
  • R 1 is chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-Ce linear, branched or cyclic alkyl; iii) substituted or unsubstituted Ce or Cio aryl; iv) substituted or unsubstituted C 1 -C 9 heterocyclic rings; or v) substituted or unsubstituted C 1 -C 9 heteroaryl rings.
  • R 1 units includes substituted or unsubstituted phenyl (C 6 aryl) units, wherein each substitution is independently chosen from: halogen, C 1 -C 4 linear, branched alkyl, or cyclic alkyl, -OR 1 ', -CN, -N(R 1 ') 2 , -CO 2 R 1 ', -C(O)N(R 1 ') 2 , -NR 11 C(O)R 11 , -NO 2 , and - SO2R 1 '; each R 1 ' is independently hydrogen; substituted or unsubstituted C 1 -C 4 linear, branched, 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 Ce aryl units chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4- difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 2,3,4- trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6- trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4- dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3,4- t
  • R 1 units includes substituted C 6 aryl units chosen from 2- methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5- dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5- trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2- ethylphenyl, 3-ethyl-phenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5- diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethyl
  • R 1 units includes substituted C 6 aryl units chosen from 2-aminophenyl, 2-(7V-methylamino)phenyl, 2-(NJV-dimethylamino)phenyl, 2-(N- ethylamino)phenyl, 2-(Ay ⁇ -diethylamino)phenyl, 3-aminophenyl, 3-(N-methylamino)phenyl, 3- ( ⁇ yV-dimethylamino)phenyl, 3-(iV-ethylamino)phenyl, 3-(iV ⁇ V-diethylamino)phenyl, 4- aminophenyl, 4-(N-methylamino)phenyl, 4-(JVJV-dimethylamino)phenyl, 4-(N- ethylamino)phenyl, and 4-(i ⁇ yV-diethylamino)phenyl.
  • R 1 can comprise heteroaryl units.
  • heteroaryl units include: i) ⁇ )
  • R 1 heteroaryl units can be substituted or unsubstituted.
  • units that can substitute for hydrogen include units chosen from: i) C]-C 6 linear, branched, and cyclic alkyl; ii) substituted or unsubstituted phenyl and benzyl; iii) substituted of unsubstituted C 1 -C 9 heteroaryl; iv) -C(O)R 9 ; and v) -NHC(O)R 9 ; wherein R 9 is Ci-C 6 linear and branched alkyl; Cj-C 6 linear and branched alkoxy; or —
  • 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, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.
  • R 1 includes units that are substituted by substituted or unsubstituted phenyl and benzyl, wherein the phenyl and benzyl substitutions are chosen from one or more: i) halogen; ii) C 1 -C 3 alkyl; iii) C1-C 3 alkoxy; iv) -CO 2 R 11 ; and v) -NHCOR 16 ; wherein R 1 ' 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(O)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(O)R 9 ;
  • R 9 is chosen from methyl, methoxy, ethyl, ethoxy, t ⁇ rr-butyl, and tert-butoxy.
  • R 1 includes phenyl and benzyl units substituted by one or more fiuoro or chloro units.
  • L is a linking unit chosen from: i) -C(O)NH[C(R 5a R 5b )J w -; ii) -C(O)[C(R 6a R 6b )] x -; iii) -C(O)[C(R 7a R 7b )] y C(O)-; iv) -SO 2 [C(R 83 R 815 )] ⁇ -; wherein R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently: i) hydrogen; ii) C1-C4 substituted or unsubstituted linear or branched alkyl; iii) substituted or unsubstituted aryl; iv) substituted or unsubstituted heterocyclic rings; v) substituted or unsubstituted C1-C 9 heteroaryl rings; and the
  • L units includes linking units having the formula:
  • R 6a is hydrogen, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl
  • substitutions for phenyl and heteroaryl are chosen from: i) C 1 -C 6 linear, branched, and cyclic alkyl; ii) substituted or unsubstituted phenyl and benzyl; iii) substituted of unsubstituted C 1 -C 9 heteroaryl; iv) -C(O)R 16 ; and v) -NHC(O)R 16 ; wherein R 16 is Ci-C 6 linear and branched alkyl; Ci-C ⁇ linear and branched alkoxy; or -
  • R 17 is chosen from hydrogen, methyl, ethyl, and tert-butyl; the index x is 1 or 2.
  • L units includes units wherein a first R 6a unit 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; a second R 6a unit is hydrogen and R b units are hydrogen.
  • a linking unit having the formula:
  • a further example of L includes a first R unit as depicted herein above that is a substituted or unsubstituted heteroaryl unit as described herein above.
  • a yet further example of L includes units having the formula:
  • L units having the formula:
  • L units having the formula:
  • L units having the formula:
  • a described herein above the compounds of the present invention includes all pharmaceutically acceptable salt forms.
  • salts for example, a salt of the sulfonic acid:
  • the compounds can also exist in a zwitterionic form, for example: as a salt of a strong acid, for example:
  • analogs (compounds) of the present disclosure are arranged into several Categories to assist the formulator in applying a rational synthetic strategy for the preparation of analogs which are not expressly exampled herein.
  • the arrangement into categories does not imply increased or decreased efficacy for any of the compositions of matter described herein.
  • the first aspect of Category I of the present disclosure relates to 2-(thiazol-2-yl) compounds having the formula:
  • R 1 , R 2 , R 3 , and L are further defined herein in Table I herein below.
  • Reagents and conditions (d) C 6 H 4 CO 2 H, EDCI, HOBt, DIPEA, DMF; rt, 18 hr.
  • Reagents and conditions (e) (i) H 2 :Pd/C, MeOH; (ii) SO 3 -pyridine, NH 4 OH 5 rt, 18 hr.
  • reaction mixture is concentrated and the residue dissolved in EtOAc, washed successively with 5% citric acid, water, 5% NaHCO 3 , water and brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo to a residue that is triturated with a mixture of EtOAc/petroleum ether to provide 2.2 g (74% yield) of the desired product as a white solid.
  • the crude product is dissolved in pyridine (12 mL) and treated with S ⁇ 3 -pyridine (0.177 g, 1.23). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH 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 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 CELITETM to remove the catalyst, and the homogeneous yellow filtrate is concentrated by rotary evaporation to afford the desired product which is used without further purification.
  • the resulting opaque mixture is stirred vigorously while allowed to slowly cool to room temperature. After stirring for 45 min, or once the reaction is determined to be complete by HPLC, water (20 mL/g) is added to the colored suspension to provide a homogeneous solution having a pH of approximately 2.4. Concentrated H 3 PO 4 is added slowly to lower the pH to approximately 1.4. During this pH adjustment, an off-white precipitate typically forms and the solution is stirred at rooni temperature for an additional hour. The suspension is filtered and the filter cake is washed with the filtrate. The filter cake is air-dried overnight to afford the desired product as the free acid.
  • the following are non-limiting examples of the first aspect of Category I of the present disclosure.
  • the second aspect of Category I of the present disclosure relates to 2-(thiazol-4-yl) compounds having the formula:
  • R , R , and L are further defined herein in Table II herein below.
  • Reagents and conditions (a)(i) (wo-butyl)OCOCl, Et 3 N, THF; 0 0 C, 20 min. (ii) CH 2 N 2 ; room temp for 3 hours.
  • Reagents and conditions (b) 48% HBr, THF; 0 0 C, 1.5 hr.
  • Reagents and conditions (d) (3-Cl)C 6 H 4 CO 2 H, EDCI, HOBt, DIPEA, DMF; rt, 18 hr.
  • Reagents and conditions (e) (i) H 2 :Pd/C, MeOH; (ii) SO 3 -py ⁇ idine, NH 4 OH 3 rt, 18 hr.
  • the reaction mixture is stirred at 0 0 C for 20 minutes and filtered.
  • the filtrate is treated with an ether solution of diazomethane ( ⁇ 16 mmol) at 0 0 C.
  • the reaction mixture is stirred at room temperature for 3 hours then concentrated in vacuo.
  • the resulting residue is dissolved in EtOAc and washed successively with water and brine, dried (Na 2 SO 4 ), filtered and concentrated.
  • the residue is purified over silica (hexane/EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product as a slightly yellow 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 S ⁇ 3 -pyridine (0.157 g).
  • the reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH 4 OH is added.
  • the mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.078 g of the desired product as the ammonium salt.
  • the third aspect of Category I of the present disclosure relates to compounds having the formula:
  • linking unit L comprises a phenyl unit, said linking group having the formula:
  • R is phenyl or substituted phenyl and non-limiting examples of the units R , R 5 and R 6a are further exemplified herein below in Table III.
  • Reagents and conditions (b) (i) H 2 :Pd/C, MeOH; (ii) SO 3 -pyridine, NH 4 OH; it, 18 hr.
  • the crude product is dissolved in pyridine (30 mL) and treated with SO 3 - pyridine (0.621 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH 4 OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.415 g of the desired product as the ammonium salt.
  • the fourth aspect of Category I of the present disclosure relates to compounds having the formula:
  • linking unit L comprises a phenyl unit, said linking group having the formula:
  • R 5a is substituted or unsubstituted heteroaryl and the units R 2 , R 3 , and R 5a are further exemplified herein below in Table IV.
  • Reagents and conditions (c) (i) H 2 :Pd/C, MeOH; (ii) SO 3 -pyridine, NH 4 OH; rt, 18 hr.
  • Category II of the present disclosure relates to 2-(thiazol-2-yl) compounds having the formula:
  • R 1 , R 2 , R 3 , and L are further defined herein in Table V herein below.
  • Reagents and conditions (a) 3-benzoylpropionic acid, TsCl, TV-methyl imidazole, CH 2 Cl 2 ; rt, 18 hr.
  • Reagents and conditions (b) (i) H 2 :Pd/C, MeOH; (ii) SO 3 -pyridine, NH 4 OH.
  • the crude product is dissolved in pyridine (5 mL) and treated with SO 3 - pyridine (0.153 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH 4 OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.090 g of the desired product as the ammonium salt.
  • the 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 I.
  • the first aspect of Category III of the present disclosure relates to 2-(thiazol-2-yl) compounds having the formula:
  • Reagents and conditions (a) benzyl isocyanate, TEA, CH2CI2; it, 18 hr.
  • Reagents and conditions (b) (i) H 2 :Pd/C, MeOH; (ii) SO 3 -pyridine, NH 4 OH.
  • the crude product is dissolved in pyridine (12 mL) and treated with SO 3 -pyridine (0.220 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH 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 III of the present disclosure relates to 2-(thiazol-4-yl) compounds having the formula:
  • Reagents and conditions (b) (i) H 2 :Pd/C, MeOH; (ii) SO 3 -pyridine, NH 4 OH.
  • the reaction mixture is filtered through a bed of CELITE and the solvent is removed under reduced pressure.
  • the crude product is dissolved in pyridine (12 mL) and treated with S ⁇ 3 -pyridine (0.110 g).
  • the reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH 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.
  • Reagents and conditions (a) C 6 H 4 CH 2 SO 2 Cl, DIPEA, CH 2 Cl 2 ; 0 0 C to rt, 14 hr.
  • Reagents and conditions (b) (i) H 2 :Pd/C, MeOH; (ii) SO 3 -pyridine, NH 4 OH.
  • the reaction mixture is stirred at room temperature for 14 hours.
  • the mixture is diluted with CH 2 Cl 2 and washed with sat. NaHCO 3 followed by brine, dried (Na 2 SO 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 S ⁇ 3 -pyridine (197 mg, 1.23 mmol).
  • the reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH 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.
  • R 1 is a substituted or unsubstituted heteroaryl and R 4 is Ci-C 6 linear, branched, or cyclic alkyl as further described herein below in Table IX.
  • Reagents and conditions (b) thiophosgene, CaCO 3 , CCU, H 2 O; rt, 18 hr.
  • Reagents and conditions (c) (i) H 2 :Pd/C, MeOH; (ii) SO 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 5 mL pyridine and treated with S O 3 -pyridine (114 mg).
  • the reaction is stirred at room temperature for 5 minutes after which 10 mL of a 7% solution OfNH 4 OH is added.
  • the mixture is then concentrated and the resulting residue is purified by reverse-phase chromatography to afford 0.033 g of the desired product as the ammonium salt.
  • the second aspect of Category V of the present disclosure relates to compounds having the formula:
  • R 1 is a substituted or unsubstituted heteroaryl and R 4 is substituted or unsubstituted phenyl and substituted or unsubstituted heteroaryl as further described herein below in Table X.
  • Reagents and conditions (a)(i) (w ⁇ -butyl)OCOCl, Et 3 N, THF; 0 0 C, 20 min. (ii) CH 2 N 2 ; 0 0 C to room temp for 3 hours.
  • Reagents and conditions (b) 48% HBr, THF; 0 0 C, 1.5 hr.
  • Reagents and conditions (d) thiophosgene, CaCO 3 , CCI 4 , H 2 O; it, 18 hr.
  • Reagents and conditions (e)(i) CH 3 C(O)NHNH 2 , EtOH; reflux, 2 hr. (ii) POCl 3 , rt 18 hr; 50 0 C 2 hr.
  • the filtrate is treated with an ether solution of diazomethane ( ⁇ 16 mmol) at 0 0 C.
  • the reaction mixture is stirred at room temperature for 3 hours and concentrated.
  • the residue is dissolved in EtOAc and washed successively with water and brine, dried (Na 2 SO * *), filtered and concentrated in vacuo.
  • the resulting residue is purified over silica (hexane/EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product as a slightly yellow solid.
  • the reaction mixture is filtered through a bed of CELITETM and the solvent removed under reduced pressure.
  • the crude product is dissolved in pyridine (4 mL) and treated with S ⁇ 3 - ⁇ yridine (0.304 g, 1.91 mmol).
  • the reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH 4 OH (5.0 mL) is added.
  • the mixture is then concentrated and the resulting residue is purified by reverse phase preparative HPLC to afford 0.052 g (11% yield) of the desired product as the ammonium salt.
  • Reagents and conditions (a) thiophosgene ,CaC ⁇ 3 , CCWH 2 O; rt, 18 hr.
  • Reagents and conditions (c) (i) H 2 :Pd/C, MeOH; (ii) SO 3 -pyridine, NH 4 OH; 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 6 mL pyridine and treated with SC> 3 -pyridine (140 mg).
  • the reaction is stirred at room temperature for 5 minutes after which 10 mL of a 7% solution OfNH 4 OH is added.
  • the mixture is then concentrated and the resulting residue is purified by reverse-phase chromatography to afford 0.033g of the desired product as the ammonium salt.
  • Reagents and conditions (a) l-azido-l-(3-methoxyphenyl)ethanone, PPI1 3 , dioxane, 90 °C 20 minutes.
  • Reagents and conditions (b) (i) H 2 :Pd/C, MeOH; (ii) SO 3 -pyridine, NH 4 OH; 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 (10 mL) and treated with SO ⁇ -pyridine (190 mg, 1.2 mmol).
  • the reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH 4 OH is added.
  • the mixture is then concentrated and the resulting residue is purified by reverse-phase chromatography to afford 0.042 g of the desired product as the ammonium salt.
  • compounds of the present disclosure comprising R 1 units having non-exemplified units can be prepared by modifying the procedures described herein above.
  • compounds of Category V comprising substituted or unsubstituted [1 ,2,4]triazole-3-yl units can be prepared by s
  • the first aspect of Category VI of the present disclosure relates to compounds having the formula:
  • R 1 is heteroaryl and R 4 is further described herein below in Table XI.
  • Reagents and conditions (c) (i) H 2 :Pd/C, MeOH; (ii) SO 3 -pyridine, NH 4 OH, it, 18 hr.
  • the mixture is stirred at 0 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 HCl, 5 % aqueous NaHCO 3 , water and brine, and dried over Na 2 SO 4 .
  • the solvent is removed in vacuo to afford the desired product which is used without further purification.
  • 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 SO3- pyridine (0.157 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH 4 OH is added. The mixture is then concentrated and the resulting residue can be purified- by reverse phase chromatography to afford the desired product as the ammonium salt.
  • the second aspect of Category VI of the present disclosure relates to compounds having the formula:
  • R 1 is aryl and R 2 and R 3 are further described herein below in Table XII.
  • Reagents and conditions (b) C 6 H 4 CO 2 H, EDCI, HOBt 5 DIPEA, DMF; rt, 18 hr.
  • Reagents and conditions (c) (i) H 2 :Pd/C, MeOH; (ii) SO 3 -pyridine, NH 4 OH, rt, 18 hr.
  • the mixture is stirred at 0 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 HCl, 5 % aqueous NaHCO 3 , water and brine, and dried over Na 2 S ⁇ 4.
  • the solvent is removed in vacuo to afford the desired product which is used without further purification.
  • the crude product is dissolved in pyridine (12 mL) and treated with S ⁇ 3 -pyridine (0.177 g, 1.23). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH 4 OH (10 mL) is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford the desired product as the ammonium salt.
  • Regulation of HPTP- ⁇ provides a method for modulating the activity of angiopoietin receptor-type tyrosine kinase Tie-2, and thereby mediate, affect, or otherwise control disease states related to angiogenesis wherein angiogenesis is improperly regulated by the human body.
  • the compounds of the present disclosure serve as a method for providing regulation of angiogenesis. As such the present disclosure addresses several unmet medical needs, inter alia;
  • compositions effective as human protein tyrosine phosphatase beta (HPTP- ⁇ ) inhibitors Providing compositions effective as human protein tyrosine phosphatase beta (HPTP- ⁇ ) inhibitors; and thereby providing a method for regulating angiogenesis in a disorder wherein angiogenesis is elevated;
  • compositions effective as human protein tyrosine phosphatase beta (HPTP- ⁇ ) inhibitors Providing compositions effective as human protein tyrosine phosphatase beta (HPTP- ⁇ ) inhibitors; and thereby providing a method for regulating angiogenesis in a disorder; and
  • compositions effective human protein tyrosine phosphatase beta (HPTP- ⁇ ) inhibitors and thereby providing a method for regulating angiogenesis in a disorder wherein angiogenesis is decreased.
  • the term "regulate” is defined as including, but is not limited to, up-regulate or down-regulate, to fix, to bring order or uniformity, to govern, or to direct by various means.
  • an antibody may be used in a method for the treatment of an "angiogenesis elevated disorder” or "angiogenesis reduced disorder”.
  • an "angiogenesis elevated disorder” is one that involves unwanted or elevated angiogenesis in the biological manifestation of the disease, disorder, and/or condition; in the biological cascade leading to the disorder; or as a symptom of the disorder.
  • the “angiogenesis reduced disorder” is one that involves wanted or reduced angiogenesis in the biological manifestations.
  • This "involvement" of angiogenesis in an angiogenesis elevated/reduced disorder includes, but is not limited to, the following:
  • angiogenesis as a "cause" of the disorder or biological manifestation, whether the level of angiogenesis is elevated or reduced genetically, by infection, by autoimmunity, trauma, biomechanical causes, lifestyle, or by some other causes.
  • angiogenesis as part of the observable manifestation of the disease or disorder. That is, the disease or disorder is measurable in terms of the increased or reduced angiogenesis. From a clinical standpoint, angiogenesis indicates the disease; however, angiogenesis need not be the "hallmark" of the disease or disorder.
  • the angiogenesis is part of the biochemical or cellular cascade that results in the disease or disorder.
  • regulation of angiogenesis may interrupt the cascade, and may control the disease.
  • Non-limiting examples of angiogenesis regulated disorders that may be treated by the present disclosure are herein described below.
  • compositions or formulations that comprise one or more human protein tyrosine phosphatase beta (HPTP- ⁇ ) inhibitors as disclosed herein.
  • the disclosed compositions comprise: a) an effective amount of one or more phenylsufamic acids or salts thereof according to the present disclosure that are effective as human protein tyrosine phosphatase beta (HPTP-p) inhibitors; and b) one or more excipients.
  • excipient and “carrier” are used interchangeably throughout the description of the present disclosure and said terms are defined herein as, "ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”
  • excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient.
  • An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach.
  • the formulator can also take advantage of the fact the compounds of the present disclosure have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.
  • Non-limiting examples of disclosed compositions include: a) from about 0.001 mg to about 1000 mg of one or more phenylsulfamic acids or salts thereof according to the present disclosure; and b) one or more excipients.
  • compositions includes: a) from about 0.01 mg to about 100 mg of one or more phenylsulfamic acids or salts thereof according to the present disclosure; and b) one or more excipients.
  • compositions includes: a) from about 0.1 mg to about 10 mg of one or more phenylsulfamic acids or salts thereof according to the present disclosure; and b) one or more excipients.
  • an effective amount means "an amount of one or more phenylsulfamic acids, effective at dosages and for periods of time necessary to achieve the desired or therapeutic result.”
  • An effective amount may vary according to factors known in the art, such as the disease state, age, sex, and weight of the human or animal being treated.
  • dosage regimes may be described in examples herein, a person skilled in the art would appreciated that the dosage regime may be altered to provide optimum therapeutic response. Thus, it is not possible to specify an exact “effective amount.” For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • the compositions of the present disclosure can be administered as frequently as necessary to achieve a therapeutic amount.
  • the present disclosure relates to methods for regulating angiogenesis in a human comprising administering to a human one or more of the disclosed compounds.
  • One example of the disclosed methods includes a method for treating an angiogenesis regulated disorder in a subject, wherein the angiogenesis regulated disorder is an angiogenesis elevated disorder, and said disorder is chosen from diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein ⁇ occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, EaI es 1 disease, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxo
  • angiogenesis regulated disorder in a subject, wherein the angiogenesis regulated disorder is an angiogenesis elevated disorder, and said disorder is chosen from inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Osler-Weber-Rendu disease, or hereditary hemorrhagic telangiectasia, solid or blood borne tumors and acquired immune deficiency syndrome.
  • inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Osler-Weber-Rendu disease, or hereditary hemorrhagic telangiectasia, solid or blood borne tumors and acquired immune deficiency syndrome.
  • a further example of the disclosed methods includes a method for treating an angiogenesis regulated disorder in a subject wherein the angiogenesis regulated disorder is an angiogenesis reduced disorder and chosen from skeletal muscle and myocardial ischemia, stroke, coronary artery disease, peripheral vascular disease, coronary artery disease.
  • a yet further example of the disclosed methods includes a method of vascularizing ischemic tissue.
  • ischemic tissue means tissue that is deprived of adequate blood flow.
  • ischemic tissue include, but are not limited to, tissue that lack adequate blood supply resulting from myocardial and cerebral infarctions, mesenteric or limb ischemia, or the result of a vascular occlusion or stenosis.
  • the interruption of the supply of oxygenated blood may be caused by a vascular occlusion.
  • Such vascular occlusion may be caused by arteriosclerosis, trauma, surgical procedures, disease, and/or other etiologies.
  • the treatment of skeletal muscle and myocardial ischemia stroke, coronary artery disease, peripheral vascular disease, coronary artery disease.
  • a still further example of the disclosed methods includes a method of repairing tissue.
  • repairing tissue means promoting tissue repair, regeneration, growth, and/or maintenance including, but not limited to, wound repair or tissue engineering.
  • tissue may be damaged by, including, but not limited to, traumatic injuries or conditions including arthritis, osteoporosis and other skeletal disorders, and burns.
  • Tissue may also be damaged by injuries due to surgical procedures, irradiation, laceration, toxic chemicals, viral infection or bacterial infections, or burns.
  • Tissue in need of repair also includes non-healing wounds. Examples of non-healing wounds include non-healing skin ulcers resulting from diabetic pathology; or fractures that do not heal readily.
  • the disclosed compounds are also suitable for use in effecting tissue repair in the context of guided tissue regeneration (GTR) procedures.
  • GTR guided tissue regeneration
  • tissue engineering is defined as the creation, design, and fabrication of biological prosthetic devices, in combination with synthetic or natural materials, for the augmentation or replacement of body tissues and organs.
  • tissue engineering is defined as the creation, design, and fabrication of biological prosthetic devices, in combination with synthetic or natural materials, for the augmentation or replacement of body tissues and organs.
  • the present methods may be used to augment the design and growth of human tissues outside the body for later implantation in the repair or replacement of diseased tissues.
  • antibodies may be useful in promoting the growth of skin graft replacements that are used as a therapy in the treatment of burns.
  • Other examples of the tissue engineering example of the disclosed methods includes in cell-containing or cell-free devices that induce the regeneration of functional human tissues when implanted at a site that requires regeneration.
  • biomaterial-guided tissue regeneration may be used to promote bone re-growth in, for example, periodontal disease.
  • antibodies may be used to promote the growth of reconstituted tissues assembled into three-dimensional configurations at the site of a wound or other tissue in need of such repair.
  • the compounds disclosed herein can be included in external or internal devices containing human tissues designed to replace the function of diseased internal tissues. This approach involves isolating cells from the body, placing them with structural matrices, and implanting the new system inside the body or using the system outside the body.
  • antibodies may be included in a cell-lined vascular graft to promote the growth of the cells contained in the graft. It is envisioned that the methods of the disclosure may be used to augment tissue repair, regeneration and engineering in products such as cartilage and bone, central nervous system tissues, muscle, liver, and pancreatic islet (insulin-producing) cells.
  • the present disclosure also relates to the use of the disclosed phenylsulfamic acids in the manufacture of a medicament for promoting the growth of skin graft replacements.
  • the present disclosure also relates to the use of the disclosed phenylsulfamic acids according to the present disclosure in the manufacture of a medicament for use in effecting tissue repair in the context of guided tissue regeneration (GTR) procedures.
  • GTR guided tissue regeneration
  • the disclosed compounds can be used in the manufacture of one or more medicaments, non-limiting examples of these medicaments are: l
  • Medicaments for the treatment an angiogenesis regulated disorder in a subject, wherein the angiogenesis regulated disorder is an angiogenesis elevated disorder.
  • angiogenesis regulated disorder in a subject, wherein the angiogenesis regulated disorder is an angiogenesis elevated disorder chosen from Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Osler- Weber-Rendu disease, or hereditary hemorrhagic telangiectasia, solid or blood borne tumors and acquired immune deficiency syndrome.
  • angiogenesis elevated disorder chosen from Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Osler- Weber-Rendu disease, or hereditary hemorrhagic telangiectasia, solid or blood borne tumors and acquired immune deficiency syndrome.
  • Medicaments useful for the purposes of tissue engineering thereby inducing enhanced tissue growth.
  • Medicaments for the treatment an angiogenesis regulated disorder in a subject, wherein the angiogenesis regulated disorder is an angiogenesis reduced disorder.
  • Antibodies of the disclosed compounds maybe screened in angiogenesis assays that are known in the art.
  • Such assays include in vitro assays that measure surrogates of blood vessel growth in cultured cells or formation of vascular structures from tissue explants and in vivo assays that measure blood vessel growth directly or indirectly (Auerbach,R., et al. (2003). Clin Chem 49, 32-40, Vailhe,B., et al. (2001). Lab Invest 81, 439-452).
  • in vitro models which are suitable for use in the present disclosure employ cultured endothelial cells or tissue explants and measure the effect of agents on "angiogenic" cell responses or on the formation of blood capillary-like structures.
  • in vitro angiogenesis assays include but are not limited to endothelial cell migration and proliferation, capillary tube formation, endothelial sprouting, the aortic ring explant assay and the chick aortic arch assay.
  • in vivo agents or antibodies which are suitable for use in the present disclosure are administered locally or systemically in the presence or absence of growth factors (i.e. VEGF or angiopoietin 1) and new blood vessel growth is measured by direct observation or by measuring a surrogate marker such as hemoglobin content or a fluorescent indicator.
  • growth factors i.e. VEGF or angiopoietin 1
  • new blood vessel growth is measured by direct observation or by measuring a surrogate marker such as hemoglobin content or a fluorescent indicator.
  • Standard routine techniques are available to determine if a tissue is at risk of suffering ischemic damage from undesirable vascular occlusion.
  • these methods include a variety of imaging techniques (e.g., radiotracer methodologies, x-ray, and MRI) and physiological tests. Therefore, induction of angiogenesis as an effective means of preventing or attenuating ischemia in tissues affected by or at risk of being affected by a vascular occlusion can be readily determined.
  • a person skilled in the art of using standard techniques can measure the vascularization of tissue.
  • Non-limiting examples of measuring vascularization in a subject include SPECT (single photon emission computed tomography); PET (positron emission tomography); MRI (magnetic resonance imaging); and combination thereof, by measuring blood flow to tissue before and after treatment.
  • Angiography maybe used as.an assessment of macroscopic vascularity. Histologic evaluation may be used to quantify vascularity at the small vessel level.
  • HPTP ⁇ IC 5 O ⁇ M
  • PTPlB IC 50 ⁇ M

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Abstract

The present disclosure relates to compounds effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors thereby regulating angiogenesis. The present disclosure further relates to compositions comprising said human protein tyrosine phosphatase beta (HPTP-β) inhibitors, and to methods for regulating angiogenesis.

Description

HUMAN PROTEIN TYROSINE PHOSPHATASE INHIBITORS AND
METHODS OF USE
FIELD
The present disclosure relates to compounds effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors thereby regulating angiogenesis. The present disclosure further relates to compositions comprising one or more human protein tyrosine phosphatase beta (HPTP-β) inhibitors, and to methods for regulating angiogenesis.
BACKGROUND
Angiogenesis, the sprouting of new blood vessels from the pre-existing vasculature, plays a crucial role in a wide range of physiological and pathological processes (Nguyen, L.L. et ai, Int. Rev. Cytol., 204, 1-48, (2001)). Angiogenesis is a complex process, mediated by communication between the endothelial cells that line blood vessels and their surrounding environment, hi the early stages of angiogenesis, tissue or tumor cells produce and secrete pro- angiogenic growth factors in response to environmental stimuli such as hypoxia. These factors diffuse to nearby endothelial cells and stimulate receptors that lead to the production and secretion of proteases that degrade the surrounding extracellular matrix. The activated endothelial cells begin to migrate and proliferate into the surrounding tissue toward the source of these growth factors (Bussolino, F., Trends Biochem. ScL, 22, 251-256, (1997)). Endothelial cells then stop proliferating and differentiate into tubular structures, which is the first step in the formation of stable, mature blood vessels. Subsequently, periendothelial cells, such as pericytes and smooth muscle cells, are recruited to the newly formed vessel in a further step toward vessel maturation.
Angiogenesis is regulated by a balance of naturally occurring pro- and anti -angiogenic factors. Vascular endothelial growth factor, fibroblast growth factor, and angiopoeitin represent a few of the many potential pro-angiogenic growth factors. These ligands bind to their respective receptor tyrosine kinases on the endothelial cell surface and transduce signals that promote cell migration and proliferation. Whereas many regulatory factors have been identified, the molecular mechanisms of this process are still not fully understood. There are many disease states driven by persistent unregulated or improperly regulated angiogenesis. In such disease states, unregulated or improperly regulated angiogenesis may either cause a particular disease or exacerbate an existing pathological condition. For example, ocular neovascularization has been implicated as the most common cause of blindness and underlies the pathology of approximately 20 eye diseases. In certain previously existing conditions such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous humor, causing bleeding and blindness. Both the growth and metastasis of solid tumors are also angiogenesis- dependent (Folkman et al., "Tumor Angiogenesis," Chapter 10, 206-32, in The Molecular Basis ofCancer, Mendelsohn et al., eds., W. B. Saunders, (1995)). It has been shown that tumors which enlarge to greater than 2 mm in diameter must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels. After these new blood vessels become embedded in the tumor, they provide nutrients and growth factors essential for tumor growth as well as a means for tumor cells to enter the circulation and metastasize to distant sites, such as liver, lung or bone (Weidner, New Eng. J. Med., 324, 1, 1-8 (1991)). When used as drugs in tumor-bearing animals, natural inhibitors of angiogenesis may prevent the growth of small tumors (O'Reilly et al., Cell, 79, 315-28 (1994)). In some protocols, the application of such inhibitors leads to tumor regression and dormancy even after cessation of treatment (O'Reilly et al., Cell, 88, 277-85 (1997)). Moreover, supplying inhibitors of angiogenesis to certain tumors may potentiate their response to other therapeutic regimens (Teischer et al., Int. J. Cancer, 57, 920-25 (1994)).
Although many disease states are driven by persistent unregulated or improperly regulated angiogenesis, some disease states could be treated by increased angiogenesis. Tissue growth and repair are biologic events wherein cellular proliferation and angiogenesis occur. Thus an important aspect of wound repair is the revascularization of damaged tissue by angiogenesis.
Chronic, non-healing wounds are a major cause of prolonged morbidity in the aged human population. This is especially the case in bedridden or diabetic patients who develop severe, non-healing skin ulcers. In many of these cases, the delay in healing is a result of inadequate blood supply either as a result of continuous pressure or of vascular blockage. Poor capillary circulation due to small artery atherosclerosis or venous stasis contributes to the failure to repair damaged tissue. Such tissues are often infected with microorganisms that proliferate unchallenged by the innate defense systems of the body which require well vascularized tissue to effectively eliminate pathogenic organisms. As a result, most therapeutic intervention centers on restoring blood flow to ischemic tissues thereby allowing nutrients and immunological factors access to the site of the wound.
Atherosclerotic lesions in large vessels may cause tissue ischemia that could be ameliorated by modulating blood vessel growth to the affected tissue. For example, atherosclerotic lesions in the coronary arteries may cause angina and myocardial infarction that could be prevented if one could restore blood flow by stimulating the growth of collateral arteries. Similarly, atherosclerotic lesions in the large arteries that supply the legs may cause ischemia in the skeletal muscle that limits mobility and in some cases necessitates amputation, which may also be prevented by improving blood flow with angiogenic therapy.
Other diseases such as diabetes and hypertension are characterized by a decrease in the number and density of small blood vessels such as arterioles and capillaries. These small blood vessels are important for the delivery of oxygen and nutrients. A decrease in the number and density of these vessels contributes to the adverse consequences of hypertension and diabetes including claudication, ischemic ulcers, accelerated hypertension, and renal failure. These common disorders and many other less common ailments, such as Burgers disease, could be ameliorated by increasing the number and density of small blood vessels using angiogenic therapy.
It has been suggested that one means for regulating angiogenesis is to treat patients with a human protein tyrosine phosphatase beta (HPTP-β) inhibitor (Kruegar et al., EMBOJ., 9, (1990)) and, therefore, to satisfy this need the compounds of the present disclosure have been prepared.
SUMMARY
The present disclosure relates to compounds having Formula (I) as shown below:
Figure imgf000004_0001
or pharmaceutically acceptable salts thereof, wherein the R and Z groups can be defined by any of the various alternative descriptions offered below. The compounds of Formula (I), and/or their pharmaceutically acceptable salts have been found to be inhibitors of human protein tyrosine phosphatase beta (HPTP-β), and hence are capable of regulating angiogenesis in humans, so as to treat various diseases that include but are not limited to diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales' disease, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, trauma and post-laser complications, diseases associated with rubeosis, and proliferative vitreoretinopathy, Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Osler-Weber-Rendu disease, hereditary hemorrhagic telangiectasia, solid or blood borne tumors and acquired immune deficiency syndrome, skeletal muscle and myocardial ischemia, stroke, coronary artery disease, peripheral vascular disease, and coronary artery disease.
The present disclosure further relates to pharmaceutical compositions comprising one or more of the compounds of Formula (I), and pharmaceutically acceptable salts thereof.
The present disclosure also relates to methods for controlling angiogenesis, and thereby providing a treatment for diseases affected by angiogenesis, said methods comprising administering to a human an effective amount of one or more compounds having Formula (I), and pharmaceutically acceptable salts thereof, as disclosed herein.
These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present disclosure. DETAILED DESCRIPTION
In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings:
All percentages, ratios and proportions herein are by weight, unless otherwise specified.
All temperatures are in degrees Celsius (° C) unless otherwise specified.
By "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the relevant active compound without causing clinically unacceptable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
Throughout the description and claims of this specification the word "comprise" and other forms of the word, such as "comprising" and "comprises," means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps.
As used in the description and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions, reference to "a phenylsulfamic acid" includes mixtures of two or more such phenylsulfamic acids, reference to "the compound" includes mixtures of two or more such compounds, and the like.
"Optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
Ranges can be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as "about" that particular value in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It is also understood that when a value is disclosed, then "less than or equal to" the value, "greater than or equal to the value," and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value "10" is disclosed, then "less than or equal to 10" as well as "greater than or equal to 10" is also disclosed. It is also understood that throughout the application data are provided in a number of different formats and that this data represent endpoints and starting points and ranges for any combination of the data points. For example, if a particular data point "10" and a particular data point "15" are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
An organic unit can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, or 1-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamido, substituted alkylcarboxamido, dialkylcarboxamido, substituted dialkylcarboxamido, alkylsulfonyl, alkylsulfϊnyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifiuoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.
Substituted and unsubstituted linear, branched, or cyclic alkyl units include the following non-limiting examples: methyl (Ci), ethyl (C2), n-propyl (C3), iso-propyl (C3), cyclopropyl (C3), n-butyl (C4), sec-butyl (C4), iso-butyl (C4), tert-butyl (C4), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (Ce), and the like; whereas substituted linear, branched, or cyclic alkyl, non-limiting examples of which includes, hydroxymethyl (Ci), chloromethyl (Ci), trifluoromethyl (Ci), aminomethyl (C1), 1-chloroethyl (C2), 2-hydroxyethyl (C2), 1,2-difluoroethyl (C2), 2,2,2- trifluoroethyl (C3X 3-carboxypropyl (C3), 2,3-dihydroxycyclobutyl (C4), and the like. Substituted and unsubstituted linear, branched, or cyclic alkenyl include, ethenyl (C2), 3- propenyl (C3), 1-propenyl {also 2-methylethenyl) (C3), isopropenyl {also 2-methylethen-2-yl) (C3), buten-4-yl (C4), and the like; substituted linear or branched alkenyl, non-limiting examples of which include, 2-chloroethenyl {also 2-chloro vinyl) (C2), 4-hydroxybuten-l-yl (C4), 7- hydroxy-7-methyloct-4-en-2-yl (C9), 7-hydroxy-7-methyloct-3,5-dien-2-yl (C9), and the like.
Substituted and unsubstituted linear or branched alkynyl include, ethynyl (C2), prop-2- ynyl {also propargyl) (C3), propyn-1-yl (C3), 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 (C7), 6-hydroxy-6-methylhept-3-yn-2-yl (C8), 5-hydroxy-5-ethylhept-3-ynyl (C9), and the like.
The term "aryl" as used herein denotes organic rings that consist only of a conjugated planar carbon ring system with delocalized pi electrons, non-limiting examples of which include phenyl (Ce)5 naphthylen-1-yl (Cio), naphthylen-2-yl (C10). Aryl rings can have one or more hydrogen atoms substituted by another organic or inorganic radical. Non-limiting examples of substituted aryl rings include: 4-fluorophenyl (Ce), 2-hydroxyphenyl {Cβ), 3- methylphenyl (C6), 2-amino-4-fluorophenyl (Cβ), 2-(ΛyV-diethylamino)phenyl (C6), 2- cyanophenyl (C6), 2,6-di-tert-butylphenyl (C6), 3-methoxyphenyl (C6), 8-hydroxynaphthylen-2- yl (Cio), 4,5-dimethoxynaphthylen-l-yl (Cio), and 6-cyanonaphthylen-l-yl (Cio).
The term "heteroaryl" denotes an aromatic ring system having from 5 to 10 atoms. The rings can be a single ring, for example, a ring having 5 or 6 atoms wherein at least one ring atom is a heteroatom not limited to nitrogen, oxygen, or sulfur. Or "heteroaryl" can denote a fused ring system having 8 to 10 atoms wherein at least one of the rings is an aromatic ring and at least one atom of the aromatic ring is a heteroatom not limited nitrogen, oxygen, or sulfur.
The following are non-limiting examples of heteroaryl rings according to the present disclosure:
Figure imgf000008_0001
The term "heterocyclic" denotes a ring system having from 3 to 10 atoms wherein at least one of the ring atoms is a heteroatom not limited to nitrogen, oxygen, or sulfur. The rings can be single rings, fused rings, or bicyclic rings. Non-limiting examples of heterocyclic rings include:
Figure imgf000009_0001
All of the aforementioned heteroaryl or heterocyclic rings can be optionally substituted with one or more substitutes for hydrogen as described herein further.
Throughout the description of the present disclosure the terms having the spelling "thiophene-2-yl and thiophene-3-yl" are used to describe the heteroaryl units having the respective formulae:
Figure imgf000009_0002
whereas in naming the compounds of the present disclosure, the chemical nomenclature for these moieties are typically spelled "thiophen-2-yl and thiophen-3-yl" respectively. Herein the terms "thiophene-2-yl and thiophene-3-yl" are used when describing these rings as units or moieties which make up the compounds of the present disclosure solely to make it unambiguous to the artisan of ordinary skill which rings are referred to herein.
The term "substituted" is used throughout the specification. The term "substituted" is defined herein as "a hydrocarbyl moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several substituents as defined herein below." The units, when substituting for hydrogen atoms are capable of replacing one hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety, or unit. For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. A three hydrogen replacement includes cyano, and the like. The term substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain; can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as "substituted" any number of the hydrogen atoms may be replaced. For example, 4-hydroxyphenyl is a "substituted aromatic carbocyclic ring", (N,N-dimethyl-5-amino)octanyl is a " substituted C8 alkyl unit, 3- guanidinopropyl is a "substituted C3 alkyl unit," and 2-carboxypyridinyl is a "substituted heteroaryl unit." The following are non-limiting examples of units that can substitute for hydrogen atomsit: i) C1-C12 linear, branched, or cyclic alkyl, alkenyl, and alkynyl; for example, methyl
(Ci), ethyl (C2), ethenyl (C2), ethynyl (C2), π-propyl (C3), wo-propyl (C3), cyclopropyl (C3), 3-propenyl (C3), 1-propenyl (also 2-methylethenyl) (C3), isopropenyl (also 2-methylethen-2-yl) (C3), prop-2-ynyl (also propargyl) (C3), propyn-1-yl (C3), n-butyl (Gj), sec-butyl (C4), wo-butyl (C4), tert-butyl (C4), cyclobutyl (C4), buten-4-yl (C4), cyclopentyl (C5), cyclohexyl (CO); ii) substituted or unsubstituted C6 or Cjo aryl; for example, phenyl, naphthyl (also referred to herein as naphthylen-1-yl (C10) or naphthylen-2-yl (Cio)); iii) substituted or unsubstituted C1-C9 heterocyclic rings; as described herein below; iv) substituted or unsubstituted C1-C9 heteroaryl rings; as described herein below; v) -(CR143R14^2OR13; for example, -OH, -CH2OH, -OCH3, -CH2OCH3, -
OCH2CH3, -CH2OCH2CH3, -OCH2CH2CH3, and -CH2OCH2CH2CH3; vi) -(CR14aRI4b)2C(O)R13; for example, -COCH3, -CH2COCH3, -OCH2CH3, -
CH2COCH2CH3, -COCH2CH2CH3, and -CH2COCH2CH2CH3; vii) -(CR14aR14b)2C(O)OR13; for example, -CO2CH3, -CH2CO2CH3,
CO2CH2CH3, -CH2CO2CH2CH3, -CO2CH2CH2CH3, and
CH2CO2CH2CH2CH3; viii) -<CR14aR14b)zC(O)N(RI3)2; for example, -CONH2, -CH2CONH2,
CONHCH3, -CH2CONHCH3, -CON(CH3)2, and -CH2CON(CH3)2; ix) -(CR14aR14b)zN(R13)2; ; for example, -NH2, -CH2NH2, -NHCH3, -N(CH3)2, -
NH(CH2CH3), -CH2NHCH3, -CH2N(CH3)2, and -CH2NH(CH2CH3); x) halogen; -F, -Cl, -Br, and -I; xi) -(CRl4aRI4b)zCN; xii) -(CRMaR14b)zNO2; xiii) -CHjXkJ wherein X is halogen, j is from O to 2, j + k = 3; for example, —
CH2F, -CHF2, -CF3, -CCl3, Or-CBr3; xiv) -(CR14aR14b)zSR13; -SH, -CH2SH, -SCH3, -CH2SCH3, -SC6H5, and
CH2SC6H5; xv) -(CRI4aRI4b)zSO2R13; -SO2H, -CH2SO2H, -SO2CH3, -CH2SO2CH3,
SO2C6H5, and -CH2SO2C6H5; and xiii) -(CRl4aR14b)zSO3R13; for example, -SO3H, -CH2SO3H, -SO3CH3,
CH2SO3CH3, -SO3C6H5, and -CH2SO3C6H5; wherein each R13 is independently hydrogen, substituted or unsubstituted C1-C4 linear, branched, or cyclic alkyl, phenyl, benzyl; or two R13 units can be taken together to form a ring comprising 3-7 atoms; Rl4a and RI4b are each independently hydrogen or Ci -C4 linear or branched alkyl; the index p is from O to 4.
The present disclosure addresses several unmet medical needs, inter alia;
1) Providing compositions effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors; and thereby providing a method for regulating angiogenesis in a disorder, disease, malady, or condition wherein angiogenesis is elevated;
2) Providing compositions effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors; and thereby providing a method for regulating angiogenesis in a disorder, disease, malady, or condition; and
3) Providing compositions effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors; and thereby providing a method for regulating angiogenesis in a disorder, disease, malady, or condition wherein angiogenesis is decreased.
These and other unmet medical needs are resolved by the human protein tyrosine phosphatase beta (HPTP-β) inhibitors of the present disclosure, that are capable of regulating angiogenesis and thereby serving as a method for treating elevated or diminished angiogenesis in humans or in treating diseases that are caused by insufficient regulation of human protein tyrosine phosphatase beta (HPTP-β).
The compounds disclosed herein include all pharmaceutically acceptable salt forms, for example, salts of both basic groups, inter alia, amines, as well as salts of acidic groups, inter alia, sulfamic acids, and carboxylic acids. The following are non-limiting examples of anions that can form salts with basic groups, such as amines: chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate, and the like. The following are non-limiting examples of cations that can form salts of acidic groups, such as carboxylic acid / carboxylate units: sodium, lithium, potassium, calcium, magnesium, bismuth, and the like.
The compounds of the present disclosure are ethyl-amino substituted phenylsulfamic acids, or their pharmaceutically acceptable salts, having the core structure of Compound (I) shown in the drawing below:
Figure imgf000012_0001
wherein the units R and Z can be any of the alternatives further defined and exemplified herein below. In such compounds of Formula (I), the carbon atom bearing the amino unit has the absolute stereochemistry(S) stereochemistry as indicated in the drawing above, which typically corresponds to an (S) configuration at the same amine-bearing carbon atom, but which could vary depending on the nature of the R substituent group and the resulting priority changes.
R Units
In some embodiments, the R units of the compounds of Formula (I) can be substituted or unsubstituted heterocyclic or heteroaryl rings having from 3 to 15 ring atoms. The substituted or unsubstituted heterocyclic or heteroaryl rings of the R group of the compounds of Formula (I) can be represented below by the generic ring, A, in the drawing shown below:
Figure imgf000012_0002
These heterocyclic or heteroaryl "A" rings can be optionally substituted by one, two, or three independently chosen substituents represented in the generic formula by R15 units. Non- limiting examples of the R15 substituent units include: i) linear, branched, or cyclic alkyl, alkenyl, and alkynyl; for example, methyl (Ci), ethyl (C2), n-propyl (C3), /sσ-propyl (C3), cyclopropyl (C3), propylen-2-yl (C3), propargyl (C3), n-butyl (C4), iso-butyl (C4), sec-butyl (C4), tert-bυtyϊ (C4), cyclobutyl (C4), n-pentyl (C5), cyclopentyl (C5), n-hexyl (CO), and cyclohexyl
(C6); ii) substituted or unsubstituted aryl; for example, phenyl, 2-fluorophenyl, 3- chlorophenyl, 4-methylphenyl, 2-aminoρhenyl, 3-hydroxyphenyl, 4- trifluoromethylphenyl, and biphenyl-4-yl; iii) substituted or unsubstituted heterocyclic; examples of which are provided herein below; iv) substituted or unsubstituted heteroaryl; examples of which are provided herein below; v) -(CRI7aRI7b)qOR16; for example, -OH, -CH2OH, -OCH3, -CH2OCH3, -
OCH2CH3, -CH2OCH2CH3, -OCH2CH2CH3, and -CH2OCH2CH2CH3; vi) -(CR17aR17b)qC(O)R16; for example, -COCH3, -CH2COCH3, -OCH2CH3,
-CH2COCH2CH3, -COCH2CH2CH3, and -CH2COCH2CH2CH3; vii) -(CR17aRI7b)qC(O)OR16; for example, -CO2CH3, -CH2CO2CH3,
CO2CH2CH3, -CH2CO2CH2CH3, -CO2CH2CH2CH3, and
CH2CO2CH2CH2CH3; viii) -(CRI7aR17b)qC(O)N(R16)2; for example, -CONH2, -CH2CONH2,
CONHCH3, -CH2CONHCH3, -CON(CH3)2, and -CH2CON(CH3)2; ix) -(CR17aR17b)qOC(O)N(R16)2; for example, -OC(O)NH2, -CH2OC(O)NH2,
-OC(O)NHCH3, -CH2OC(O)NHCH3, -OC(O)N(CH3)2, and
CH2OC(O)N(CHs)2; x) -(CR17aR17b)qN(R16)2; for example, -NH2, -CH2NH2, -NHCH3, -N(CH3)2, -
NH(CH2CH3), -CH2NHCH3, -CH2N(CH3)2, and -CH2NH(CH2CH3); xi) halogen: -F, -Cl, -Br, and -I; xii) — CHmXn; wherein X is halogen, ni is from O to 2, m+n =3; for example, —
CH2F, -CHF2, -CF3, -CCl3, or -CBr3; xiii) -(CRI7aR17b)qCN; for example; -CN, -CH2CN, and -CH2CH2CN; xiv) -(CR17aR17b)qNO2; for example; -NO2, -CH2NO2, and -CH2CH2NO2; XV) -(CR17aR17b)qSO2R16; for example, -SO2H, -CH2SO2H, -SO2CH3,
CH2SO2CH3, -SO2C6H5, and -CH2SO2C6H5; and xvi) -CCR17aR17b)qSO3R16; for example, -SO3H, -CH2SO3H, -SO3CH3,
CH2SO3CH3, -SO3C6H5, 8Hd-CH2SO3C6H5; wherein each R16 is independently hydrogen, substituted or unsubstituted C1-C4 linear, branched, or cyclic alkyl; or two R16 units can be taken together to form a ring comprising 3-7 ring atoms; Rl7a and Rl 7b are each independently hydrogen or C1-C4 linear or branched alkyl; the index q is from 0 to 4.
When R15 units comprise C1-C12 linear, branched, or cyclic alkyl, alkenyl; substituted or unsubstituted Ce or Cio aryl; substituted or unsubstituted C1-C9 heterocyclic; or substituted or unsubstituted C1-Cg heteroaryl; R15 units can further have one or more hydrogen atoms substituted by R18 units. Non-limiting examples of R18 units include: i) linear, branched, or cyclic alkyl, alkenyl, and alkynyl; for example, methyl (Cj), ethyl (C2), n-propyl (C3), zsø-propyl (C3), cyclopropyl (C3), propylen-2-yl (C3), propargyl (C3), n-butyl (C4), wo-butyl (C4), .sec-butyl (C4), tert-buty\ (C4), cyclobutyl (C4), n-pentyl (C5), cyclopentyl (C5), n-hexyl (C6), and cyclohexyl (C6); ii) -(CR20aR20b)qOR19; for example, -OH, -CH2OH, -OCH3, -CH2OCH3, -
OCH2CH3, -CH2OCH2CH3, -OCH2CH2CH3, and -CH2OCH2CH2CH3; iii) -(CR20aR20b)qC(O)R19; for example, -COCH3, -CH2COCH3, -OCH2CH3,
-CH2COCH2CH3. -COCH2CH2CH3, and -CH2COCH2CH2CH3; iv) -(CR20aR20b)qC(O)OR19; for example, -CO2CH3, -CH2CO2CH3, CO2CH2CH3, -CH2CO2CH2CH3, -CO2CH2CH2CH3, and CH2CO2CH2CH2CH3; v) -(CR20aR20b)qC(O)N(R19)2; for example, -CONH2, -CH2CONH2,
CONHCH3, -CH2CONHCH3, -CON(CH3)2, and -CH2CON(CH3)2; vi) -(CR203R20OqOC(O)N(R19)2; for example, -OC(O)NH2, -CH2OC(O)NH2, -OC(O)NHCH3, -CH2OC(O)NHCH3, -OC(O)N(CH3)2, and CH2OC(O)N(CH3)2; vii) -(CR20aR20b)qN(R19)2; for example, -NH2, -CH2NH2, -NHCH3, -N(CH3)2, -
NH(CH2CH3), -CH2NHCH3, -CH2N(CH3)2, and -CH2NH(CH2CH3); viii) halogen: — F, -Cl, -Br, and —I; ix) -CHmXn; wherein X is halogen, m is from O to 2, m+n =3; for example, —
CH2F, -CHF2, -CF3, -CCl3, or -CBr3; x) -(CR20aR20b)qCN; for example; -CN, -CH2CN, and -CH2CH2CN; xi) -(CR20aR20b)qNO2; for example; -NO2, -CH2NO2, and -CH2CH2NO2; xii) -(CR20aR20b)qSO2R19; for example, -SO2H, -CH2SO2H, -SO2CH3,
CH2SO2CH3, -SO2C6H5, and -CH2SO2C6H5; and xiii) -(CR20aR20b)qSO3R19; for example, -SO3H, -CH2SO3H, -SO3CH3,
CH2SO3CH3, -SO3C6H5, and -CH2SO3C6H5; wherein each R19 is independently hydrogen, substituted or unsubstituted C1-C4 linear, branched, or cyclic alkyl; or two R19 units can be taken together to form a ring comprising 3-7 atoms; R20a and R20b are each independently hydrogen or CpC4 linear or branched alkyl; the index p is from O to 4.
In the description that follows, R15 and R18 units may be represented by specific ring substitutions, for example, a ring encompassed within the definition of R can be depicted as either having the formula:
or as having the formula:
Figure imgf000015_0001
Both of the above formulae stand equally well for an optionally substituted thiazolyl ring.
R Units
R units comprise a ring having from 3 to 15 ring atoms.
R units can comprise 5-member heteroaryl rings. The following are non-limiting examples of 5-member heteroaryl rings: i)
Figure imgf000015_0002
Figure imgf000016_0001
xii)
xiii)
xiv)
xv)
xvi)
Figure imgf000017_0001
As described herein, the 5-member heteroaryl rings can be substituted with one or more substitutes for hydrogen, for example, with a methyl group:
Figure imgf000017_0002
or with a substitute for hydrogen that itself is further substituted, for example:
Figure imgf000017_0003
Examples of 5-member ring R units includes thiazolyl units having the formula:
Figure imgf000018_0001
One example of a thiazolyl R unit includes thiazol-2-yl units having the formula:
Figure imgf000018_0002
wherein R^ and R/ are each independentl chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-C6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv) substituted or unsubstituted C1-C9 heteroaryl; or R2 and R3 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms.
One example of this R unit relates to units having the formula:
Figure imgf000018_0003
wherein R3 is hydrogen and R2 is a unit chosen from methyl (Cj), ethyl (C2), n-propyl (C3), iso- propyl (C3), n-butyl (C4), sec-butyl (C4), iso-butyl (C4), and tert-butyl (C4).
Another example of this R unit relates to units wherein
R2 is a unit chosen from methyl (Ci), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), sec- butyl (C4). iso-butyl (C4), and tert-butyl (C4); and R3 is a unit chosen from methyl (C]) or ethyl (C2). 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.
A further example of this R unit relates to units wherein R3 is hydrogen and R2 is a substituted alkyl unit, the substitutions chosen from: i) halogen: -F, -Cl, -Br, and -I; ii) -N(Rn)2; and iii) -OR11; wherein each R1 ' is independently hydrogen or Ci-C4 linear or branched alkyl. Non-limiting examples of units comprising this embodiment of R includes: -CH2F, —
CHF2, -CF3, -CH2CF3, -CH2Cl, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2CH2OCH3, - CH2NH2, -CH2NHCH3, -CH2N(CH3);,, and -CH2NH(CH2CH3). A yet further example of R units include units wherein R3 is hydrogen and R2 is phenyl.
A still further example of R units include units wherein R3 is hydrogen and R2 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-yI, [l,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [l,2,4]thiadiazol-3-yl, [l,2,4]thiadiazol-5-yl, and [l,3,4]thiadiazol-2- yi.
One example of R includes units wherein R2 is thiophene-2-yl or thiophene-3-yl. Another example of R units includes thiazol-4-yl units having the formula:
Figure imgf000019_0001
wherein R4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted C1-C6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted C1-C9 heteroaryl.
An example of R units includes compounds wherein R4 is hydrogen.
Another example of R units includes compounds wherein R4 is a unit chosen from methyl (Ci), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), .sec-butyl (C4), iso-butyl (C4), and tert-butyl (C4). 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-(«ø-propyl)thiazol-4-yl.
A further example of R units includes compounds wherein R4 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 .
A yet further example of R units includes compounds wherein R4 is substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-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.
Another example of 5-member ring R units includes substituted or unsubstituted imidazolyl units having the formula:
Figure imgf000020_0001
One example of imidazolyl R units includes imidazol-2-yl units having the formula:
Figure imgf000020_0002
wherein R2 and R3 are each independently chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-C6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv) substituted or unsubstituted Ci -Cg heteroaryl; or R2 and R3 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms.
One example of R units includes compounds wherein R units have the formula:
Figure imgf000020_0003
wherein R3 is hydrogen and R2 is a unit chosen from methyl (Ci), ethyl (C2), n-propyl (C3), iso- propyl (C3), n-butyl (C4), .see-butyl (C4), /so-butyl (C4), and tert-butyl (C4).
Another example of R units includes compounds wherein R2 is a unit chosen from methyl (Ci), ethyl (C2), n-propyl (Cs)5 iso-propyl (C3), n-butyl (C4), _?ec-butyl (C4), iso-buty\ (C4), and tert-buty\ (C4); and R3 is a unit chosen from methyl (Ci) or ethyl (C2). Non-limiting examples of this aspect of R includes 4,5-dimethylimidazol-2-yl, 4-ethyl-5-methylrrnidazol-2-yl, 4-methyl-5-ethylimidazol-2-yl, and 4,5-diethylimidazol-2-yl.
An example of R units includes compounds wherein R3 is hydrogen and R2 is a substituted alkyl unit chosen, said substitutions chosen from: i) halogen: -F, -Cl, -Br, and -I; ii) -N(R")2; and iii) -OR1 1; wherein each R11 is independently hydrogen or Ci -C4 linear or branched alkyl. Non-limiting examples of units comprising this embodiment of R includes: -CH2F, — CHF2, -CF3, -CH2CF3, -CH2Cl, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2CH2OCH3, - CH2NH2, -CH2NHCH3, -CH2N(CH3)2, and -CH2NH(CH2CH3).
A yet further example of R units include units wherein R3 is hydrogen and R2 is phenyl.
A still further example of R units include units wherein R3 is hydrogen and R2 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-yi, [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, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [l,2,4]thiadiazol-3-yl, [l,2,4]thiadiazol-5-yl, and [l,3,4]thiadiazol-2- yi.
One example of R includes units wherein R2 is thiophene-2-yl or thiophene-3-yl. Another example of R units includes imidazol-4-yl units having the formula:
Figure imgf000021_0001
wherein R4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-C6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted C1-C9 heteroaryl.
One example of this embodiment of R units relates to compounds wherein R4 is hydrogen.
An example of R units includes compounds wherein R4 is hydrogen.
Another example of R units includes compounds wherein R4 is a unit chosen from methyl (Ci), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), sec-butyl (C4), /sø-butyl (C4), and rert-butyl (C4). Non-limiting examples of this aspect of R includes 2-methylimidazol- 4-yl, 2-ethylimidazol-4-yl, 2-(n-propyl)imidazol-4-yl, and 2-(/-?σ-propyI)imidazol-4-yl. A further example of R units includes compounds wherein R4 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.
A yet further example of R units includes compounds wherein R4 is substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, A- ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and 3-methyl-l,2,4-oxadiazol-5-yl.
Further examples of 5-member ring R units are substituted or unsubstituted oxazolyl units having the formula:
Figure imgf000022_0001
One example of oxazolyl R units includes oxazol-2-yl units having the formula:
Figure imgf000022_0002
wherein R2 and R3 are each independently chosen from: i) hydrogen; ii) substituted or unsubstituted C J-C6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv) substituted or unsubstituted C1-C9 heteroaryl; or R2 and R3 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms.
One example of R units includes compounds wherein R units have the formula:
Figure imgf000022_0003
wherein R3 is hydrogen and R2 is a unit chosen from methyl (C]), ethyl (C2), n-propyl (C3), iso- propyl (C3), n-butyl (C4), sec-butyl (C4), iso-butyl (C4), and tert-buty\ (C4).
Another example of R units includes units wherein R2 is a unit chosen from methyl (Cj), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), sec-butyl (C4), zso-butyl (C4), and tert- butyl (C4); and R3 is a unit chosen from methyl (Ci) or ethyl (C2). Non-limiting examples of this aspect of R includes 4,5-dimethyloxazol-2-yl, 4-ethyl-5-methyloxazol-2-yl, 4-methyl-5- ethyloxazol-2-yl, and 4,5-diethyloxazol-2-yl.
A further example of R units includes units wherein R3 is hydrogen and R2 is a substituted alkyl unit chosen, said substitutions chosen from: i) halogen: -F5 -Cl, -Br, and -I; ii) -N(Rπ)2; and iii) -OR1 1; wherein each R11 is independently hydrogen or C1-C4 linear or branched alkyl. Non-limiting examples of units comprising this embodiment of R includes: -CH2F, - CHF2, -CF3, -CH2CF3, -CH2Cl, -CH2OH, -CH2OCH3, -CH2CH2OH9 -CH2CH2OCH3, - CH2NH2, -CH2NHCH3, -CH2N(CH3)2, and -CH2NH(CH2CH3).
A yet further example of R units include units wherein R3 is hydrogen and R2 is phenyl.
A still further example of R units include units wherein R3 is hydrogen and R2 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, [1, 2,4]triazol-5-ylJ 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, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [l,2,4]thiadiazol-3-yl, [l,2,4]thiadiazol-5-yl, and [l,3,4]thiadiazol-2- yi.
One example of R includes units wherein R is thiophene-2-yl or thiophene-3-yl. Another example of R units includes oxazol-4-yl units having the formula:
Figure imgf000023_0001
wherein R4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted C1-CO linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted Ci -C9 heteroaryl. wherein R4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted Ci -Ce linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted Cj -C9 heteroaryl.
One example of this embodiment of R units relates to compounds wherein R4 is hydrogen.
An example of R units includes compounds wherein R4 is hydrogen.
Another example of R units includes compounds wherein R4 is a unit chosen from methyl (Cj), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), sec-butyl (C4), /sø-butyl (C4), and tert-bxύy\ (C4). Non-limiting examples of this aspect of R includes 2-methyloxazol-4- yl, 2-ethyloxazol-4-yl, 2-(n-propyl)oxazol-4-yl, and 2-(wo-propyl)oxazol-4-yl.
A further example of R units includes compounds wherein R4 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 .
A yet further example of R units includes compounds wherein R4 is substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-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.
A further example of R units relates to oxazol-5-yl units having the formula:
Figure imgf000024_0001
wherein R is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted CrC6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted C1-C9 heteroaryl. An example of R units includes compounds wherein R4 is hydrogen. Another example of R units includes compounds wherein R4 is a unit chosen from methyl (Ci), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), sec-butyl (C4), iso-butyl (C4), and tert-butyl (C4). Non-limiting examples of this aspect of R includes 2-methyloxazol-4- yl, 2-ethyloxazol-4-yl, 2-(n-propyl)oxazol-4-yl, and 2-(wo-propyl)oxazol-4-yl.
A further example of R units includes compounds wherein R4 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 .
A yet further example of R units includes compounds wherein R4 is substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-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.
A yet further example of 5-member ring R units includes substituted or unsubstituted [l,2,4]oxadiazolyl units having the formula:
Figure imgf000025_0001
One example of [l,2,4]oxadiazolyl R units includes [l,2,4]oxadiazol-3-yl units having the formula:
Figure imgf000025_0002
wherein R2 is chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-C6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted Ci -C9 heteroaryl;
One example of R units includes units wherein R2 is hydrogen.
Another example includes R units wherein R2 is a unit chosen from methyl (Ci), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), sec-butyl (C4), /sø-butyl (C4), and /erf-butyl (C4); and R3 is a unit chosen from methyl (Ci) or ethyl (C2). Non-limiting examples of this aspect of R includes 5-methyl[l,2,4]oxadiazol-2-yl, 5-ethyl[l,2,4]-oxadiazol-2-yl, 5- propyl[l,2,4]oxadiazol-2-yl, and 5-cyclopropyl[l,2,4]oxadiazol-2-yl. A further example of R units includes units wherein R2 is a substituted alkyl unit chosen, said substitutions chosen from: i) halogen: -F, -Cl, -Br, and -I; ii) -N(R1 ')2; and iii) -OR11; wherein each R11 is independently hydrogen or C1-C4 linear or branched alkyl. Non-limiting examples of units comprising this embodiment of R includes: -CH2F, -
CHF2, -CF3, -CH2CF3, -CH2Cl, -CH2OH3 -CH2OCH3, -CH2CH2OH, -CH2CH2OCH3, - CH2NH2, -CH2NHCH3, -CH2N(CH3)2, and -CH2NH(CH2CH3).
A yet further example of R units includes units wherein R2 is phenyl.
A still further example of R units includes units wherein R2 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, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [l,2,4]thiadiazol-3-yl, [l,2,4]thiadiazol-5-yl5 and [l,3,4]thiadiazol-2- yi.
Specific examples of R units include units wherein R2 is thiophene-2-yl or thiophene-3- yi.
Another example of R units includes [l,2,4]oxadiazol-5-yl units having the formula:
Figure imgf000026_0001
wherein R4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-Cδ linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted Cj -C9 heteroaryl.
One example of R units includes compounds wherein R4 is hydrogen.
Another example of R units include compounds wherein R4 is a unit chosen from methyl (Ci), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), .sec-butyl (C4), iso-butyl (C4), and tert-bntyl (C4). Non-limiting examples of this aspect of R includes 3-methyl[l,2,4]oxadiazol-5- yl, 3-ethyl[l,2,4]oxadiazol-5-yl, 3-(n-propyl)[l,2,4]oxadiazol-5-yl, and 3-(iso- propyl)[ 1 ,2,4]oxadiazol-5-yl.
A further example of R units includes compounds wherein R4 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 .
A yet further example of R units includes compounds wherein R4 is substituted or unsubstituted heteroaryl, non-limiting examples of which include thiophene-2-yl, thiophene-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.
Further non-limiting examples of 5-member heteroaryl rings include: i)
Figure imgf000027_0001
ϋ)
Figure imgf000027_0002
iii)
Figure imgf000027_0003
iv)
Figure imgf000027_0004
V)
Figure imgf000028_0001
Vi)
vii)
Figure imgf000028_0002
viii)
Figure imgf000028_0003
R units can comprise 5-member heterocyclic rings. Non-limiting examples of 5-member heterocyclic rings include: i)
Figure imgf000028_0004
ϋ)
iϋ)
Figure imgf000028_0005
iv)
« -N XTHXI v)
Figure imgf000029_0001
Vi)
vii)
Figure imgf000029_0002
R units can comprise 6-member heterocyclic rings. Non-limiting examples of 6-member heterocyclic rings include: i)
Figure imgf000029_0003
ϋ)
iϋ) iv)
Figure imgf000029_0004
R units can comprise 6-member heteraryl rings. Non-limiting examples of 6-member heteroaryl rings include: i)
ϋ)
iii)
iv)
Figure imgf000030_0001
A example of 6-member heteroaryl rings includes pyrimidin-2-yl units having the formula:
Figure imgf000030_0002
wherein R2, R3 and R4 are each independently chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-Cβ linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv) substituted or unsubstituted C1-C9 heteroaryl; or
R2 and R3 or R3 and R4 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms.
Another example of R units includes units having the formula:
Figure imgf000030_0003
wherein R3 and R4 are both hydrogen and R2 is a unit chosen from methyl (Ci), ethyl (C2), n- propyl (C3), iso-propyl (C3), n-butyl (C4), sec-butyl (C4), jsø-butyl (C4), and tert-bυtyl (C4).
Further examples of R units include units wherein R2 and R3 are chosen from methyl (Ci), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), sec-butyl (C4), isø-butyl (C4), and tert-butyl (C4); and R4 is hydrogen. Non-limiting examples of this aspect of R includes 4,5- dimethylpyrimidin-2-yl, 4,5-diethylpyrimidin-2-yl, 4-methyl-5-ethyl-pyrimidin-2-yl, and 4-ethyl- 5-methyl-pyrimidin-2-yl.
A yet further example of R units include units wherein R4 is hydrogen and R2 and R3 are chosen from: i) halogen: — F, -Cl5 -Br, and —I; ii) -N(R1 ')2; and iii) -OR1 1; wherein each R1 ' is independently hydrogen or Cj-C4 linear or branched alkyl. Non-limiting examples of units comprising this embodiment of R includes: -CH2F, — CHF2, -CF3, -CH2CF3, -CH2Cl, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2CH2OCH3, - CH2NH2, -CH2NHCH3, -CH2N(CH3)2, and -CH2NH(CH2CH3).
A yet further example of R units includes units wherein R2 or R3 is substituted phenyl and R4 is hydrogen.
A still further example of R units includes units wherein R4 is hydrogen and R2 or R3 is a heteroaryl unit chosen from 1,2,3,4-tetrazol-l-yl ,l,2,3,4-tetrazol-5-yl, [l,2,3]triazoI-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, pyrrόl-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, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [l,2,4]thiadiazol-3-yl, [l,2,4]thiadiazol-5-yl, and [l,3,4]thiadiazol-2- yi.
The following are non-limiting examples of R units wherein R2 is thiophene-2-yl and wherein R2 is thiophene-3-yl thereby providing R units that are 4-(thiophene-2-yl)pyrimidin-2- yl, 5-(thiophene-2-yl)pyrimidin-2-yl, 4-(thiophene-3-yl)pyrimidin-2-yl, and 5-(thiophene-2- yl)pyrimidin-3-yl.
Non-limiting examples of 6-member heteroaryl rings include: i)
ϋ)
Figure imgf000032_0001
R units can also comprise fuse ring heteroaryl units. Non-limiting examples of R units include: i)
Figure imgf000032_0002
ϋ)
Figure imgf000032_0003
iii)
Figure imgf000032_0004
iv)
Figure imgf000032_0005
V) Vi)
vii)
Figure imgf000033_0001
R units that are fused heteroaryl rings can be optionally substituted by one or more independently chosen substitutes for hydrogen as described herein above.
Z Units
Z is a unit having the formula:
-(L)n-R' wherein R1 is chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-Ce linear, branched or cyclic alkyl; iii) substituted or unsubstituted Ce or Cio aryl; iv) substituted or unsubstituted C1-C9 heterocyclic rings; or v) substituted or unsubstituted C1-C9 heteroaryl rings.
One example of R1 units includes substituted or unsubstituted phenyl (C6 aryl) units, wherein each substitution is independently chosen from: halogen, C1-C4 linear, branched alkyl, or cyclic alkyl, -OR1 ', -CN, -N(R1 ')2, -CO2R1 ', -C(O)N(R1 ')2, -NR11C(O)R11, -NO2, and - SO2R1 '; each R1 ' is independently hydrogen; substituted or unsubstituted C1-C4 linear, branched, cyclic alkyl, alkenyl, or alkynyl; substituted or unsubstituted phenyl or benzyl; or two R11 units can be taken together to form a ring comprising from 3-7 atoms. Another example of R1 units includes substituted C6 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.
A further example of R1 units includes substituted or unsubstituted Ce aryl units chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4- difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 2,3,4- trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6- trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4- dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3,4- trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichloroρhenyl, 2,4,5 -trichlorophenyl, 3,4,5- trichlorophenyl, and 2,4,6-trichlorophenyl.
A yet further example of R1 units includes substituted C6 aryl units chosen from 2- methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5- dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5- trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2- ethylphenyl, 3-ethyl-phenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5- diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6-triethylphenyl, 2-isopropylphenyl, 3- isopropylphenyl, and 4-isopropylphenyl.
Another still further example of R1 units includes substituted C6 aryl units chosen from 2-aminophenyl, 2-(7V-methylamino)phenyl, 2-(NJV-dimethylamino)phenyl, 2-(N- ethylamino)phenyl, 2-(Ay^-diethylamino)phenyl, 3-aminophenyl, 3-(N-methylamino)phenyl, 3- (ΛyV-dimethylamino)phenyl, 3-(iV-ethylamino)phenyl, 3-(iV^V-diethylamino)phenyl, 4- aminophenyl, 4-(N-methylamino)phenyl, 4-(JVJV-dimethylamino)phenyl, 4-(N- ethylamino)phenyl, and 4-(i\yV-diethylamino)phenyl.
R1 can comprise heteroaryl units. Non-limiting examples of heteroaryl units include: i) ϋ)
iii)
iv)
V)
Vi)
vii)
Figure imgf000035_0001
viii)
P-
-i-O N- ix)
X)
Figure imgf000035_0002
xi) xii)
xiii)
xiv)
Figure imgf000036_0001
R1 heteroaryl units can be substituted or unsubstituted. Non-limiting examples of units that can substitute for hydrogen include units chosen from: i) C]-C6 linear, branched, and cyclic alkyl; ii) substituted or unsubstituted phenyl and benzyl; iii) substituted of unsubstituted C1-C9 heteroaryl; iv) -C(O)R9; and v) -NHC(O)R9; wherein R9 is Ci-C6 linear and branched alkyl; Cj-C6 linear and branched alkoxy; or —
NHCH2C(O)R10; R10 is chosen from hydrogen, methyl, ethyl, and tert-butyl
An example of R1 relates to units substituted by an alkyl unit chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.
Another example of R1 includes units that are substituted by substituted or unsubstituted phenyl and benzyl, wherein the phenyl and benzyl substitutions are chosen from one or more: i) halogen; ii) C1-C3 alkyl; iii) C1-C3 alkoxy; iv) -CO2R11; and v) -NHCOR16; wherein R1 ' and R16 are each independently hydrogen, methyl, or ethyl. Another example of R1 relates to phenyl and benzyl units substituted by a carboxy unit having the formula -C(O)R9; R9 is chosen from methyl, methoxy, ethyl, and ethoxy.
A further example of R1 includes phenyl and benzyl units substituted by an amide unit having the formula -NHC(O)R9; R9 is chosen from methyl, methoxy, ethyl, ethoxy, tørr-butyl, and tert-butoxy.
A yet further example of R1 includes phenyl and benzyl units substituted by one or more fiuoro or chloro units.
L is a linking unit chosen from: i) -C(O)NH[C(R5aR5b)Jw-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R83R815)]^-; wherein R5a, R5b, R6a, R6b, R7a, R7b, R8a, and R8b are each independently: i) hydrogen; ii) C1-C4 substituted or unsubstituted linear or branched alkyl; iii) substituted or unsubstituted aryl; iv) substituted or unsubstituted heterocyclic rings; v) substituted or unsubstituted C1-C9 heteroaryl rings; and the indices w, x, y, and z are each independently from 1 to 4. The linking group may be present, i.e. when the index n is equal to 1, or absent when the index n is equal to 0, for example, the linking unit is absent in Category V compounds further described herein below.
One example of L units includes linking units having the formula:
-C(O)[C(R6aR6b)]x- wherein R6a is hydrogen, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl, said substitutions for phenyl and heteroaryl are chosen from: i) C1-C6 linear, branched, and cyclic alkyl; ii) substituted or unsubstituted phenyl and benzyl; iii) substituted of unsubstituted C1-C9 heteroaryl; iv) -C(O)R16; and v) -NHC(O)R16; wherein R16 is Ci-C6 linear and branched alkyl; Ci-Cδ linear and branched alkoxy; or -
NHCHaC(O)R17; R17 is chosen from hydrogen, methyl, ethyl, and tert-butyl; the index x is 1 or 2.
Another example of L units includes units wherein a first R6a unit 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; a second R6a unit is hydrogen and R b units are hydrogen. For example a linking unit having the formula:
Figure imgf000038_0001
A further example of L includes a first R unit as depicted herein above that is a substituted or unsubstituted heteroaryl unit as described herein above.
A yet further example of L includes units having the formula:
-C(O)[C(R6aR6b)]x-; wherein R6a and R6b are hydrogen and the index x is equal to 1 or 2; said units chosen from: i) -C(O)CH2-; and ii) -C(O)CH2CH2-.
Another example of L units includes units having the formula:
-C(O)[C(R7aR7b)]yC(O)-; wherein R7a and R7b are hydrogen and the index x is equal to 1 or 2; said units chosen from: i) -C(O)CH2C(O)-; and ii) -C(O)CH2CH2C(O)-.
A still further example of L units includes units having the formula:
-C(O)NH[C(R5aR5b)]w-; wherein R5a and R5b are hydrogen and the index w is equal to 0, 1 or 2; said units chosen from: ii) -C(O)NH-; ii) -C(O)NHCH2-; and iii) -C(O)NHCH2CH2-.
A yet still farther example of L units includes units having the formula:
-SO2[C(R8aR8b)]z-; wherein R8a and R8b are hydrogen and the index z is equal to 0, 1 or 2; said units chosen from: ϋ) -SO2-; ii) -SO2CH2-; and iii) -SO2CH2CH2-.
A described herein above the compounds of the present invention includes all pharmaceutically acceptable salt forms. A compound having the formula:
Figure imgf000039_0001
can form salts, for example, a salt of the sulfonic acid:
Figure imgf000039_0002
The compounds can also exist in a zwitterionic form, for example:
Figure imgf000040_0001
as a salt of a strong acid, for example:
Figure imgf000040_0002
The analogs (compounds) of the present disclosure are arranged into several Categories to assist the formulator in applying a rational synthetic strategy for the preparation of analogs which are not expressly exampled herein. The arrangement into categories does not imply increased or decreased efficacy for any of the compositions of matter described herein.
The first aspect of Category I of the present disclosure relates to 2-(thiazol-2-yl) compounds having the formula:
Figure imgf000040_0003
wherein R1, R2, R3, and L are further defined herein in Table I herein below.
TABLE I
Figure imgf000040_0004
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
The compounds encompassed within the first aspect of Category I of the present disclosure can be prepared by the procedure outlined in Scheme I and described in Example 1 herein below.
Scheme I
Figure imgf000044_0001
Reagents and conditions: (a)(i) (wo-butyl)OCOCl, NMM, DMF; 00C, 20 min.
(ii) NH3; 0 0C for 30 min.
Figure imgf000044_0002
1 2
Reagents and conditions: (b) Lawesson's reagent, THF; rt, 3 hr..
Figure imgf000044_0003
3 Reagents and conditions: (c) CH3CN; reflux, 2hr.
Figure imgf000044_0004
Reagents and conditions: (d) C6H4CO2H, EDCI, HOBt, DIPEA, DMF; rt, 18 hr.
Figure imgf000045_0001
4 5
Reagents and conditions: (e) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH5 rt, 18 hr.
EXAMPLE 1 {4-[2-(-S)-(4-Ethylthiazol-2-yl)-2-(2-phenylacetylamido)ethyl]phenyl}sulfamic acid (5)
(S) -tert-butyl 1 -am ino-3 - (4-nitropheny 1 )- 1 -oxopropan-2- ylcarbamate
Preparation of [l-(S)-carbamoyl-2-(4-nitrophenyl)ethyl]carbamic acid tert-butyl ester (1): To a O °C solution of 2-(»S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid and N- methylmorpholine (1.1 mL, 9.65 mmol) in DMF (10 πiL) is added dropwise iso-butyl chloroformate (1.25 mL, 9.65 mmol). The mixture is stirred at 0 0C for 20 minutes, after which NH3 (g) is passed through the reaction mixture for 30 minutes at 0 0C. The reaction mixture is concentrated and the residue dissolved in EtOAc, washed successively with 5% citric acid, water, 5% NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated in vacuo to a residue that is triturated with a mixture of EtOAc/petroleum ether to provide 2.2 g (74% yield) of the desired product as a white solid.
Preparation of [2-(4-nitrophenyl)-l-(tS)-thiocarbamoylethyl]carbamic acid tert-butyl ester (2): To a solution of [l-(iS)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-butyl ester, 1, (0.400 g, 1.29 mmol) in THF (10 mL) is added Lawesson's reagent (0.262 g. 0.65 mmol). The reaction mixture is stirred for 3 hours and concentrated to a residue that is purified over silica to provide 0.350 g (83% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.29 (s, IH)5 8.10 (d. J= 8.4 Hz, 2H)5 8.01 (s, IH), 7.42 (d, J= 8.4 Hz5 2H), 5.70 (d, J= 7.2 Hz5 IH), 4.85 (d, J= 7.2 Hz, IH), 3.11-3.30 (m, IH), 1.21 (s, 9H). Preparation of l-(S)-(4-ethylthiazol-2-yl)-2-(4-nitropheπyl)ethyl amine hydrobromide (3): A mixture of [2-(4-nitrophenyl)-l-(iS)-thiocarbamoylethyl]-carbamic acid tert-buty\ ester, 2, (1Og, 30.7mmol) and l-bromo-2-butanone (90%, 3.8mL, 33.8mmol) in CH3CN (500 mL) is refluxed for 18 hours. The reaction mixture is cooled to room temperature and diethyl ether is added to the solution and the precipitate which forms is removed by filtration to afford 7.47g of the desired product. ESI+ MS 278 (M+l).
Preparation of TV-[I -(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide (4): To a solution of l-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.393 g, 1.1 mmol), phenylacetic acid (0.190 g, 1.4 mmol) and 1-hydroxybenzotriazole (HOBt) (0.094 g, 0.70 mmol) in DMF ( 10 mL) at 0°, is added l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDCI) (0.268g, 1.4 mmol) followed by triethylamine (0.60 mL, 4.2mmol). The mixture is stirred at 00C 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 HCl3 5 % aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.260 g (60 % yield) of the desired product which is used without further purification. ESI+ MS 396 (M+l).
Preparation of {4-[2-(^-(4-ethylthiazol-2-yl)-2-(2-phenylacetylamido)ethyl]- phenyl} sulfamic acid (5): iV-[l-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl- acetamide, 4, (0.260 g) is dissolved in MeOH (4 mL). 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 CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with Sθ3-pyridine (0.177 g, 1.23). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH4OH (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. 1H NMR (CD3OD) δ 8.60 (d, IH, J = 8.1Hz), 7.33-7.23 (m, 3H), 7.16-7.00 (m, 6H), 5.44-5.41 (m, IH), 3.28 (IH, A of ABX, obscured by solvent), 3.03 (IH, B of ABX, J = 14.1, 9.6Hz), 2.80 (q, 2H, J = 10.5, 7.8Hz) 1.31 (t, 3H5 J = 4.6Hz). The following is a general procedure for isolating the final compound as a free acid.
Reduction of the aryl nitro group to free a amine:
To a Parr hydrogenation vessel is charged the nitro compound [for example, intermediate 4] (1.0 eq) and Pd/C (10 % Pd on C3 50 % wet, Degussa-type ElOl NE/W, 2.68 g, 15 wt %) as solids. MeOH (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 N2 (3 x 20 psi) to inert, followed by the same procedure with H2 (3 x 40 psi). The vessel is filled with H2 and the vessel is shaken under 40 psi H2 for ~40 hr. The vessel is evacuated and the atmosphere is purged with N2 (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 the desired product which is used without further purification.
Preparation of free sulfamic acid: A 100 mL RBF is charged with the free amine (1.0 eq) prepared in the step described herein above. Acetonitrile (5 mL/g) is added and the yellow suspension which is typically yellow to orange in color is stirred at room temperature. A second 3-necked 500 mL RBF is charged with SCb- pyr (1.4 eq) and acetonitrile (5 mL/g) and the suspension is stirred at room temperature. Both suspensions are gently heated until the reaction solution containing the amine becomes orange to red-orange in color (typically at about 40-45 0C). This substrate containing solution is poured in one portion into the stirring suspension of SCV pyr at 35 0C. The resulting opaque mixture is stirred vigorously while allowed to slowly cool to room temperature. After stirring for 45 min, or once the reaction is determined to be complete by HPLC, water (20 mL/g) is added to the colored suspension to provide a homogeneous solution having a pH of approximately 2.4. Concentrated H3PO4 is added slowly to lower the pH to approximately 1.4. During this pH adjustment, an off-white precipitate typically forms and the solution is stirred at rooni temperature for an additional hour. The suspension is filtered and the filter cake is washed with the filtrate. The filter cake is air-dried overnight to afford the desired product as the free acid. The following are non-limiting examples of the first aspect of Category I of the present disclosure.
Figure imgf000048_0001
(5)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-fluorophenyl)acetamido)ethyl)phenyl-sulfamic acid: 1H NMR (CD3OD) δ 8.65(d, IH5 J = 8.4Hz), 7.29-7.15 (m, IH), 7.13-7.03 (m, 7H)5 5.46- 5.42 (m, IH)5 3.64-3.51 (m, 2H), 3.29 (IH)5 3.04 (IH, B of ABX, J = 13.8, 9.6Hz), 2.81 (q, 2H, J = 15.6, 3.9Hz), 1.31 (t, 3H3 J = 7.8Hz). 19F NMR (CD3OD) δ 43.64. (S)-4-(2-(4-Ethylthiazol- 2-yl)-2-(2-(2-fluorophenyl)acetamido)ethyl)phenyl-sulfamic acid
Figure imgf000048_0002
(5)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-fluorophenyl)acetamido)ethyl)phenyl-sulfamic acid: 1H NMR (CD3OD) δ 8.74 (d, IH, J = 8.4Hz)5 7.32 (q, IH, J = 6.6, 14.2Hz), 7.10-6.91 (m, 8H), 5.47-5.40 (m, IH), 3.53 (s, 2H), 3.30 (IH), 3.11 (IH, B of ABX5 J = 9.6, 14.1Hz), 2.80 (q, 2H5 J = 6.6, 15.1Hz), 1.31 (t, 3H, J = 7.8Hz). 19F NMR δ 47.42.
Figure imgf000048_0003
(^)-4-(2-(2-(2,3-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid: 1H NMR (CD3OD) δ 7.16-7.05 (m, 5H)5 6.85-6.80 (m, IH), 5.48-5.43 (m, IH), 3.63 (s, 2H), 3.38 (IH, A of ABX, obscured by solvent), 3.03 (IH), 2.80 (q, H, J = 15.1, 7.8Hz), 1.31 (t, 3H, J = 7.5Hz).
Figure imgf000049_0001
(-S)-4-(2-(2-(3,4-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid: 1H NMR (CD3OD) δ 8.75 (d, IH, J = 7.8Hz), 7.23-7.04 (m, 6H), 6.88-6.84 (m, IH), 5.44- 5.40 (m, IH), 3.49 (s, 2H), 3.34 (IH), 3.02 (IH, B of ABX, J = 14.1, 9.9Hz), 2.80 (q, 2H, J = 15.1 , 7.8Hz), 1.31 (t, IH, J = 7.5Hz). 19F NMR (CD3OD) δ 22.18, 19.45.
Figure imgf000049_0002
(5)-4-(2-(2-(2-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid: 1H NMR (CD30D) δ 7.39-7.36 (m, IH), 7.27-7.21 (m, 2H), 7.15-6.98 (m, 5H), 5.49-5.44 (m, IH)5 3.69 (d, 2H, J = 11.7Hz), 3.32 (IH), 3.04 (IH, B of ABX, J = 9.3, 13.9Hz), 2.80 (q, 2H, J = 7.8, 15.3Hz), 1.31 (t, 3H, J = 7.5Hz).
Figure imgf000049_0003
(5)-4-(2-(2-(3-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid: 1H NMR (CD3OD) δ 7.33-7.23 (m, 3H), 7.13-7.03 (m, 5H), 5.43 (q, IH, J = 5.1, 9.6Hz), 3.51 (s, 2H), 3.29 (IH), 3.03 (IH, B of ABX, J = 9.9, 14.1Hz), 2.80 (q, 2H, J = 7.5, 15Hz), 1.31 (t, 3H, J = 7.8Hz).
Figure imgf000050_0001
(5)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)phenyl-sulfamic acid: 1H NMR (CD3OD) δ 7.16-7.08 (m, 3H), 7.03-7.00 (m, 3H), 6.70-6.63 (m, 2H), 5.42-5.40 (m, IH), 3.44 (s, 2H), 3.28 (IH, A of ABX, obscured by solvent), 3.04 (B of ABX, J = 14.1, 9.6Hz), 2.89 (q, 2H, J = 15, 7.5Hz), 1.31 (t, 3H, J = 7.5Hz).
Figure imgf000050_0002
(5)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-methoxyphenyl)acetamido)ethyl)phenyl-sulfamic acid: 1H NMR (CD3OD) δ 8.00 (d, IH, J = 7.8Hz)5 7.26 (t, IH, J = 13.2Hz), 7.09-7.05 (m, 4H), 7.01 (s, IH), 6.91-6.89 (m, 4H), 5.44-5.39 (m, IH)3 3.71 (s, 3H), 3.52 (s, 2H), 3.26 (IH, A of ABX, J = 14.1, 5.1Hz), 3.06 (IH B of ABX, J = 13.8, 8.4Hz), 2.80 (q, 2H, J = 8.1, 15.6Hz), 1.31 (t, 3H, J = 1.2Hz).
Figure imgf000050_0003
(5)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-methoxyphenyl)acetamido]ethyl}phenyl-sulfamic acid: 1H NMR (CD3OD) δ 8.58 (d, IH, J = 8.1Hz), 7.21 (t, IH, J = 7.8Hz), 7.12-7.02 (m, 4H), 6.81 (s, 2H), 6.72 (d, IH, J = 7.5Hz), 5.45-5.40 (m, IH), 3.79 (s, 3H), 3.50 (s, 2H), 3.29 (IH, A of ABX, obscured by solvent), 3.08 (IH, B of ABX, J = 11.8. 5. IHz), 2.80 (q, 2H, J = 15, 7.5Hz), 1.31 (t, 3H, J = 6.6Hz).
Figure imgf000051_0001
(5)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-phenylpropanamido)ethyl)phenylsulfamic acid: 1H NMR (CD3OD) δ 8.56 (d, IH, J = 8.4Hz), 7.25-6.98 (m, 9H), 5.43-5.38 (m, IH), 3.26 (IH, A of ABX, J = 14.1, 9.6Hz), 2.97 (IH, B of ABX, J = 10.9, 3Hz), 2.58-2.76 (m, 3H), 2.98 (q, 2H, J = 13.8, 7.2Hz), 1.29 (t, 3H, J = 8.7Hz).
Figure imgf000051_0002
(-S)-4-(2-(2-(3,4-Diτnethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)- phenylsulfamic acid: 1H NMR (CD3OD) δ 7.12-7.03 (m, 3H), 6.91 (d, IH, J = 8.4Hz), 6.82 (s, IH), 6.66 (d, IH, J = 2.1Hz), 6.63 (d, IH, J = 2.1Hz), 5.43 (m, IH), 3.84 (s, 3H), 3.80 (s, 3H), 3.45 (s, 2H), 3.30 (IH), 3.03 (IH, B of ABX, J = 14.1, 9.6Hz), 2.79 (q, 2H, J => 15.1, 7.2Hz), 1.30 (t, 3H, J = 7.2Hz).
Figure imgf000051_0003
(-S)-4-(2-(2-(2,3-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)- phenylsulfamic acid: 1H NMR (CD3OD) δ 8.31 (d, IH, J = 7.8Hz), 7.11-6.93 (m, 6H), 6.68 (d, IH, J = 7.5Hz), 5.49-5.40 (m, IH), 3.87 (s, 3H), 3.70 (s, 3H), 3.55 (s, 2H), 3.26 (IH, A of ABX, obscured by solvent), 3.06 (IH, B of ABX, J = 13.9, 9Hz), 2.80 (q, 2H, J = 14.8, 7.5Hz), 1.31 (t, 3H, J = 7.5Hz).
Figure imgf000052_0001
(S)-4-(2-(3-(3-Chlorophenyl)propanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid: 1H NMR (CD3OD) δ 7.27-7.18 (m, 3H), 7.13-7.08 (m, 5H), 7.01 (s, IH), 5.39 (q, IH, J = 5.1, 9.4Hz), 3.28 (IH, A of ABX, J = 5.1, 14.1Hz), 2.97 (IH, B of ABX, J = 9.3, 13.9Hz), 2.88- 2.76 (m, 4H), 2.50 (t, 2H, J - 8.1Hz), 1.31 (t, 3H, J = 7.8Hz).
Figure imgf000052_0002
(5)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(2-methoxyphenyl)propanamido)ethyl)phenyl- sulfamic acid: 1H NMR (CD3OD) δ 7.18-7.08 (m, 6H), 6.92 (d, IH, J = 8.1Hz), 6.82 (t, IH, J = 7.5Hz), 5.40-5.35 (m, IH), 3.25 (IH, A of ABX, J = 15, 5.4Hz), 3.00 (IH, B of ABX, J = 10.5, 7.5Hz), 2.88-2.76 (m, 4H), 2.47 (q, 2H, J = 9.1, 6Hz), 1.31 (t, 3H, J = 7.8Hz).
Figure imgf000052_0003
(.S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(3-methoxyphenyl)propanamido)ethyl)phenyl- sulfamic acid: 1H NMR (CD3OD) δ 7.19-7.00 (m, 5H), 6.75 (s, IH), 6.73 (s, IH), 5.42-5.37 (m, IH), 3.76 (s, 3H), 3.25 (IH5 A of ABX, J = 13.9, 5.4Hz), 2.98 (IH, B of ABX, J = 14.1, 9.6Hz), 2.86-2.75 (m, 4H), 2.48 (q, 2H, J = 11.7, 1.2Hz), 1.31 (t, 3H, J = 7.5Hz).
Figure imgf000052_0004
(5)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(4-methoxyphenyl)propanamido)ethyl)phenyl- sulfamic acid: 1H NMR (CD3OD) 8 7.13-6.99 (m, 7H), 6.82-6.78 (m. 2H)3 5.42-5.37 (m, IH), 3.33 (s, 3H), 3.23 (IH)5 2.97 (IH, B of ABX, J = 13.3, 11.4Hz)3 2.83-2.75 (m, 4H)5 2.49 (q, 2H5 J = 6.4, 3.3Hz), 1.31 (t, 3H5 J = 7.5Hz).
Figure imgf000053_0001
(5)-4-{2-[2-(4-Ethyl-2,3-dioxopiperazin-l-yl)acetamido]-2-(4-ethylthiazol-2- yl)ethyl}phenylsulfamic acid: 1H NMR (CD3OD) δ 7.14 (s, 4H), 7.08 (s, IH), 5.56-5.51 (m, IH)5 4.34 (d5 2H5 J = 16.2Hz), 3.88 (d, 2H5 J = 17.6Hz), 3.59-3.40 (m, 3H)5 3.26-3.14 (m, 3H), 2.98 (IH5 B ofABX, J = 10.8, 13.9Hz)5 2.82 (q, 2H, J = 6.9, 15Hz), 1.32 (t, 3H, J = 7.5Hz)5 1.21 (t, 3H5 J = 7.2Hz).
Figure imgf000053_0002
(5)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(5-methyl-254-dioxo-3,4-dihydropyrimidin-l(2H)- yl)acetamido]ethyl}phenylsulfamic acid: 1H (CD3OD ): δ 7.13 (s, IH), 7.06-7.02 (m, 4H), 6.95 (s, IH), 5.42-5.31 (m, IH), 4.43-4.18 (dd, 2H, J=16.5 Hz), 3.24-2.93 (m, 2H), 2.74-2.69 (q, 2H, J=7.3 Hz)5 1.79 (S5 3H), 1.22 (t, 3H5 J=7.5 Hz).
Figure imgf000053_0003
(5)-4-[2-(benzo[(f][l,3]dioxole-5-carboxamido)-2-(4-ethylthiazol-2-yl)ethyl]- phenylsulfamic acid: 1H NMR (CD3OD) δ 7.25 (d, IH, J=6.5 Hz)5 7.13 (s, IH)5 7.06 (d, 2H, J=8.5 Hz), 7.00 (d, 2H, J=8.5 Hz), 6.91 (s, IH), 6.76 (d, IH, J=8.1 Hz), 5.90 (s, 2H), 5.48 (q, IH, J=5.0 Hz), 3.32-3.24 (m, 2H)3 3.07-2.99 (m, 2H), 2.72 (q, 2H, J=7.5 Hz), 1.21 (t, 3H, J=7.5 Hz).
Figure imgf000054_0001
(5^-4-{2-[2-(2,5-Dimethylthiazol-4-yl)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}- phenylsulfamic acid: 1H (CD3OD): δ 7.10-7.01 (m, 5H), 5.41 (t, IH, J=6.9 Hz), 3.58 (s, 2H), 3.33-3.01 (m, 2H), 2.82-2.75 (q, 2H, J=I.5 Hz), 2.59 (s, 3H), 2.23 (s, 3H), 1.30 (t, 3H, J=7.5 Hz).
Figure imgf000054_0002
(6)-4-{2-[2-(2,4-Dimethylthiazol-5-yl)acetamido]-2-(4-methylthiazol-2- yl)ethyl}phenylsυlfamic acid: !H (CD3OD): δ 8.71-8.68 (d, IH, J=8.4 Hz), 7.10-7.03 (m, 4H), 7.01 (s, IH), 5.41 (m, IH), 3.59 (s, IH)5 3.34-2.96 (m, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 2.23 (s, 3H).
Figure imgf000054_0003
(5)-4-{2-(4-Ethylthiazol-2-yl)-2-[3-(thiazol-2-yl)propanamido]ethyl}phenyl-sulfamic acid: 1H (CD3OD): 67.67-7.65 (m, IH), 7.49-7.47 (m, IH), 7.14-7.08 (m, 4H), 7.04 (s, IH), 5.46-5.41 (q, IH5 J=5.1 Hz)5 3.58 (s, 2H), 3.30-3.25 (m, 3H), 3.02-2.67 (m, 5H), 1.31 <t, 3H5 J=7.5 Hz).
Figure imgf000055_0001
(5)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(4-ethylthiazol-2-yl)acetamido]ethyl}phenyl-sulfamic acid: 1H(CD3OD ): δ 7.04-6.91 (m, 6H), 5.32 (t, IH, J=5.4 Hz), 3.25-2.90 (m, 2H), 2.71-2.61 (m, 4H) 1.93 (s, 2H) 1.22-1.14 (m, 6H).
The second aspect of Category I of the present disclosure relates to 2-(thiazol-4-yl) compounds having the formula:
Figure imgf000055_0002
wherein R , R , and L are further defined herein in Table II herein below.
TABLE II
Figure imgf000055_0003
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0003
The compounds encompassed within the second aspect of Category I of the present disclosure can be prepared by the procedure outlined in Scheme II and described in Example 2 herein below.
Scheme II
Figure imgf000059_0001
Reagents and conditions: (a)(i) (wo-butyl)OCOCl, Et3N, THF; 0 0C, 20 min. (ii) CH2N2; room temp for 3 hours.
Figure imgf000059_0002
6 7
Reagents and conditions: (b) 48% HBr, THF; 0 0C, 1.5 hr.
Figure imgf000060_0001
Reagents and conditions: (c) CH3CN; reflux 5 hr.
Figure imgf000060_0002
8 9
Reagents and conditions: (d) (3-Cl)C6H4CO2H, EDCI, HOBt, DIPEA, DMF; rt, 18 hr.
Figure imgf000060_0003
9 10
Reagents and conditions: (e) (i) H2:Pd/C, MeOH; (ii) SO3-pyτidine, NH4OH3 rt, 18 hr.
EXAMPLE 2
4-((5)-2-(2-(3-chloroρhenyl)acetamido)-2-(2-(thiophene-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid (10) Preparation of (S)-[3-diazo-l-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid terr-butyl ester (6): To a 0 0C solution of 2-(5)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g, 4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4.4 mmol) followed by wo-butyl chloroformate (0.57 mL, 4.4 mmol). The reaction mixture is stirred at 0 0C for 20 minutes and filtered. The filtrate is treated with an ether solution of diazomethane (~16 mmol) at 00C. The reaction mixture is stirred at room temperature for 3 hours then concentrated in vacuo. The resulting residue is dissolved in EtOAc and washed successively with water and brine, dried (Na2SO4), filtered and concentrated. The residue is purified over silica (hexane/EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product as a slightly yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J= 8.7 Hz5 2H), 7.39 (d, J= 8.7 Hz, 2H), 5.39 (s, IH), 5.16 (d, J= 6.3 Hz, IH), 4.49 (s, IH), 3.25 (dd, J= 13.8 and 6.6, IH), 3.06 (dd, J= 13.5 and 6.9 Hz, IH), 1.41 (s, 9H).
Preparation of (S)-tert-bvιtyl 4-bromo-l-(4-nitrophenyl)-3-oxobutan-2-yl carbamate (7): To a 0 0C solution of (5)-[3-diazo-l-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-bυtyl ester, 6, (0.350 g, 1.04 mmol) in THF (5 mL) is added dropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture is stirred at 00C for 1.5 hours then the reaction is quenched at 0 0C with sat. Na2CO3. The mixture is extracted with EtOAc (3x 25 mL) and the combined organic extracts are washed with brine, dried (Na2SO4), filtered and concentrated to obtain 0.400 g of the product which is used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.20 (d, J= 8.4 Hz, 2H), 7.39 (d, J= 8.4 Hz, 2H), 5.06 (d, J= 7.8 Hz, IH), 4.80 (q, J= 6.3 Hz, IH), 4.04 (s, 2H), 1.42 (s, 9H).
Preparation of 0S)-2-(4-nitrophenyl)-l -[(thiophene-2-yl)thiazol-4-yl]ethanamine hydrobromide salt (8): A mixture of (5)-tert-butyl 4-bromo-l-(4-nitrophenyl)-3-oxobutan-2- ylcarbamate, 7, (7.74g, 20mmol), and thiophene-2-carbothioic acid amide (3.14g, 22mmol) in CH3CN (200 mL) is refluxed for 5 hours. The reaction mixture is cooled to room temperature and diethyl ether (50 mL) is added to the solution. The precipitate which forms is collected by filtration. The solid is dried under vacuum to afford 7.14 g (87 % yield) of the desired product. ESI+ MS 332 (M+l). Preparation of 2-(3-chlorophenyl)-W- {(,S)-2-(4-nitrophenyl)- 1 - [2-(thiophene-2-yl)thiazol- 4-yl]ethyl}acetarnide (9): To a solution of 2-(4-nitrophenyl)-l-(2-thiophene2-ylthiazol-4- yl)ethylamine, 8, (0.41 g, lmmol) 3-chlorophenylacetic acid (0.17Og, lmmol) and 1- hydroxybenzotriazole (HOBt) (0.07Og, 0.50mmol) in DMF ( 5 mL) at 0°, is added l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.19Og, lmmol) followed by triethylamine (0.42mL, 3mmol). The mixture is stirred at 00C 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 HCl, 5 % aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.290 g (60 % yield) of the desired product which is used without further purification. ESI- MS 482 (M-I).
Preparation of {4-[2-(3-chlorophenyl)acetylamino]-2-(2-thiophen-2-ylthiazol-4- yl)ethyl]phenyl} sulfamic acid (10): 2-(3-chlorophenyl)-N-{(5)-2-(4-nitrophenyl)-l-[2- (thiophene2-yl)thiazol-4-yl]ethyl}acetamide, 9, (0.290 g) is dissolved in MeOH (4 mL). 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 CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with Sθ3-pyridine (0.157 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.078 g of the desired product as the ammonium salt. 1H NMR (CD3OD) δ 7.61 (d, IH, J = 3.6Hz), 7.58 (d, IH, J = 5.1Hz), 7.41-7.35 (m, IH), 7.28-7.22 (m, 2H), 7.18-6.98 (m, 6H), 5.33 (t, IH, J = 6.6Hz), 3.70 (d, 2H, J = 3.9Hz), 3.23 (IH, A of ABX, J = 6.6, 13.8Hz), 3.07 (IH, B of ABX, J = 8.1, 13.5Hz).
The following are non-limiting examples of compounds encompassed within the second aspect of Category I of the present disclosure.
Figure imgf000062_0001
4-((-S)-2-(2-(3-Methoxyphenyl)acetamido)-2-(2-(thiophene2-yl)thiazol-4-yl)ethyl)- phenylsulfamic acid: 1H NMR (CD3OD) δ 8.35 (d, IH5 J = 8.7Hz), 7.61-7.57 (m, 2H), 7.25- 7.20 (m, 2H)3 7.25-7.20 (m, 2H), 7.09 (s, IH), 7.05 (d, 2H, J = 4.2Hz), 6.99 (d, IH, J = 8.7Hz), 6.81 (d, IH, J = 7.8Hz), 6.77 (s, IH), 5.30-5.28 (m, IH), 3.76 (s, 3H), 3.51 (s, 2H), 3.20 (IH, A ofABX, J = 6.3, 13.6Hz), 3.06 (IH, B of ABX, J = 8.1, 13.8Hz).
Figure imgf000063_0001
4-{(-S)-2-(3-Phenylpropanamido)-2-[2-(thiophene2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic acid: 1H NMR (CD3OD) δ 8.30 (d, IH, J = 9Hz), 7.61-7.56 (m, 2H), 7.26-7.14 (m, 7H), 7.12 (d, IH, J = 1.5Hz), 7.09 (d, IH, J = 2.1Hz), 6.89 (s, IH), 5.28-5.26 (m, IH), 3.18 (IH, A of ABX, J = 6.2, 13.8Hz), 2.96 (IH, B of ABX, J = 8.4, 13.6Hz).
Figure imgf000063_0002
4-{(5)-2-(3-(3-Chlorophenyl)propanamido)-2-[2-(thiophene2-yl)thiazol-4- yl]ethyl}phenylsulfamic acid: 1H NMR (CD3OD) δ 7.61-7.56 (m, 3H), 7.22-7.14 (m, 6H), 7.08 (d, IH), 7.00 (d, IH, J = 77.5Hz), 6.870 (s, IH), 5.25 (t, IH, J = 7.8Hz), 3.18 (IH, A of ABX, J = 6.6, 13.8Hz), 2.97 (IH, B of ABX, J = 7.8, 13.8Hz), 2.87 (t, 2H, J = 7.5Hz), 2.51 (t, 2H, J = 7.2Hz).
Figure imgf000063_0003
4-{(<S)-2-[2-(3-Fluorophenyl)acetamido]-2-[2-(thiophene-2-yl)thiazol-4- yl]ethyl}phenylsulfamic acid: 1H NMR (CD3OD) δ 7.61-7.57 (m, 2H), 7.32-7.28 (m, IH), 7.19- 7.16 (m, 2H), 7.08 (t, IH, J = 4.5Hz)5 7.02-6.95 (m, 6H), 5.29 (t, IH, J = 8.1Hz), 3.53 (s, 2H), 3.22 (IH, A ofABX, J = 6.6, 13.9Hz), 3.06 (IH, B of ABX, J = 8.4, 13.6Hz).
Figure imgf000064_0001
(5)-4-{2-[2-(3-Methyl-l,2,4-oxadiazol-5-yl)acetamido]-2-(2-phenylthiazoI-4- yl)ethyl}phenylsulfamic acid: 1H (CD3OD): δ 7.98-7.95 (m, 2H), 7.48-7.46 (m, 3H), 7.23 (s, IH), 7.09-7.05 (m, 4H), 5.33 (t, IH, J=7.2 Hz), 3.33-3.06 (m, 2H), 2.35 (s, 3H).
Figure imgf000064_0002
4-{(5)-2-[2-(4-ethyl-2,3-dioxopiperazin-l-yl)acetamido]-2-[2-(thiophene-2-yl)thiazol-4- yl]ethyl}phenylsulfamic acid: 1H NMR (CD3OD) δ 7.62 (d, IH, J = 3Hz), 7.58 (d, IH, J = 15.6Hz), 7.27 (s, IH), 7.16 (t, IH, J = 1.5Hz), 5.42-5.32 (m, IH), 4.31 (d, IH, J = 15.6Hz), 3.91 (d, IH, J = 15.9Hz), 3.60-3.50 (m, 4H), 3.30-3.23 (m, 2H), 2.98 (IH, B of ABX, J = 9.9, 13.8Hz), 1.21 (t, 3H, J = 6.9Hz).
The third aspect of Category I of the present disclosure relates to compounds having the formula:
Figure imgf000064_0003
wherein the linking unit L comprises a phenyl unit, said linking group having the formula:
-C(O)[(CR6aH)][(C H2)]- R is phenyl or substituted phenyl and non-limiting examples of the units R , R 5 and R 6a are further exemplified herein below in Table III.
TABLE III
Figure imgf000065_0001
The compounds encompassed within the third aspect of Category I of the present disclosure can be prepared by the procedure outlined in Scheme III and described in Example 3 herein below.
Scheme III
Figure imgf000066_0001
3 11
Reagents and conditions: (a) diphenylpropionic acid, EDCI, HOBt, TEA, DMF;
O 0C tO It, 18 hr.
Figure imgf000066_0002
11 12
Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH; it, 18 hr.
EXAMPLE 3
(5)-4-(2-(2,3-Diphenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)- phenylsulfamic acid (12)
Preparation of (5)-N-[l-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-diphenyl- propanamide (11): To a solution of l-(ιS)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.95 g, 2.65 mmol), diphenylpropionic acid (0.60 g, 2.65 mmol) and 1- hydroxybenzotriazole (HOBt) (0.180 g, 1.33 mmol) in DMF ( 10 mL) at 0°, is added l-(3- dimethylaminoρropyl)-3-ethylcarbodiimide (EDCI) (0.502 g, 2.62 mmol) followed by triethylamine (1.1 mL, 7.95 mmol). The mixture is stirred at 0 0C 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 HCl, 5 % aqueous NaHCO3, water and brine, and dried over Na2SO.*. The solvent is removed in vacuo to afford 0.903 g (70% yield) of the desired product which is used without further purification.
Preparation of (iS)-4-(2-(2,3-diphenylpropanamido)-2-(4-ethylthiazol-2- yl)ethyl)phenylsulfamic acid (12) (5)-jY-[l-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3- diphenyl-propanamide, 11, (0.903 g) is dissolved in MeOH (10 mL). 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 abed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (30 mL) and treated with SO3- pyridine (0.621 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.415 g of the desired product as the ammonium salt. 1H NMR (CD3OD) δ 8.59-8.52 (m, IH), 7.37-7.04 (m, 9H), 6.97-6.93 (m, IH), 6.89-6.85 (m, 2H), 5.36-5.32 (m, IH), 3.91-3.83 (m, IH), 3.29 (IH, A of ABX, obscured by solvent), 3.15 (IH, B of ABX, J = 5.4, 33.8Hz), 2.99-2.88 (m, 2H), 2.81-2.69 (m, 2H), 1.32-1.25 (m, 3H).
The precursors of many of the Z units which comprise the third aspect of Category I are not readily available. The following procedure illustrates an example of the procedure which can be used to provide different R6a units according to the present disclosure. Using the procedure outlined in Scheme IV and described in Example 4 the artisan can make modifications without undue experimentation to achieve the R5a units encompassed by the present disclosure.
Scheme IV
Figure imgf000067_0001
13
Reagents and conditions: (a) methyl 2-(2-methoxyphenyl)acetate, LDA, THF;
0 °C to rt l8 hr.
Figure imgf000068_0001
13 14
Reagents and conditions: (b)
EXAMPLE 4 2-(2-Methoxyphenyl)-3-phenylpropanoic acid (14)
Preparation of methyl 2-(2-methoxyphenyl)-3-phenylpropanoate (13): A 50OmL round- bottom flask is charged with methyl 2-(2-methoxyphenyl)acetate (8.496 g, 47 mmol, leq) and THF (20OmL). The homogeneous mixture is cooled to 0 0C in an ice bath. Lithium diisopropyl amide (23.5mL of a 2.0M solution in heptane/THF) is added, maintaining a temperature less than 30C. The reaction is stirred 45 minutes at this reduced temperature. Benzyl bromide (5.6mL, 47mmol, leq) is added dropwise. The reaction is allowed to gradually warm to room temperature and is stirred for 18 hours. The reaction is quenched with IN HCl and extracted 3 times with equal portions of EtOAc. The combined extracts are washed with H-O and brine, dried over Na2SO4, filtered, and concentrated. The residue is purified over silica to afford 4.433 g (35%) of the desired compound. ESI+ MS 293 (M+Na).
Preparation of 2-(2-methoxyphenyl)-3-phenylpropanoic acid (14): Methyl 2-(2- methoxyphenyl)-3-phenylpropanoate (4.433g, 16mmol, leq) is dissolved in 10OmL of a 1 :1 (v:v) mixture of THF and methanol. Sodium hydroxide (3.28g, 82mmol, 5eq) is added and the reaction mixture is stirred 18 hours at room temperature. The reaction is then poured into H2O and the pH is adjusted to 2 via addition of IN HCl. A white precipitate forms which is removed by filtration. The resulting solution is extracted with 3 portion of diethyl ether. The extracts are pooled, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified over silica to afford 2.107g (51%) of the desired compound. ESI- MS 255 (M-I), 21 1 (M-CO2H).
Intermediate 14 can be carried forward according to the procedure outlined in Scheme III and described in Example 3 to produce the following compound according to the third aspect of Category I.
Figure imgf000069_0001
(-S}-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(2-methoxyphenyl)-3-phenylpropanamido]- ethyl}ρhenylsulfamic acid: 1H NMR (CD3OD) δ 7.32-7.12 (m, 7H), 7.05-7.02 (m, IH), 6.99- 6.83 (m, 4H), 6.80-6.75 (m, 2H), 5.35-5.31 (m, IH)5 4.31-4.26 (m, IH), 3.75 (s, 3H), 3.20-2.90 (m, 4H), 2.79-2.74 (m, 2H), 1.32-1.25 (m, 3H).
The following are further non-limiting examples of compounds according to the third aspect of Category I of the present disclosure.
Figure imgf000069_0002
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-fluorophenyl)-3-phenylpropanamido]- ethyl}phenylsulfamic acid: 1H NMR (CD3OD) δ 7.33-6.87 (m, 14H), 5.39-5.25 (ra, IH), 3.95- 3.83 (m, IH), 3.31-3.10 (m, IH), 3.05-2.88 (m, 2H), 2.80-2.70 (m, 2H), 1.32-1.23 (m, 3H). 19F NMR δ 47.59.
Figure imgf000070_0001
(-S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-methoxyphenyl)-3-phenylpropanamido]- ethyl}phenylsulfamic acid: 1H NMR (CD3OD) δ 7.85 (d, IH, J = 8.4Hz), 7.25-7.20 (m, IH), 7.11-7.02 (m, 4H)5 7.01 (s, IH)5 6.90-6.79 (m, 2H)3 5.45-5.40 (m, IH), 4.09 (s, 2H)5 3.79 (s, 3H)5 3.12-3.08 (m, 2H), 1.10 (s, 9H).
The fourth aspect of Category I of the present disclosure relates to compounds having the formula:
Figure imgf000070_0002
wherein the linking unit L comprises a phenyl unit, said linking group having the formula:
-C(O)[(CR6aH)][(CH2]-
R5a is substituted or unsubstituted heteroaryl and the units R2, R3, and R5a are further exemplified herein below in Table IV.
TABLE IV
Figure imgf000070_0003
Figure imgf000071_0002
The compounds encompassed within the fourth aspect of Category I of the present disclosure can be prepared by the procedure outlined in Scheme V and described in Example 5 herein below.
Scheme V
Figure imgf000071_0001
3 • 15 Reagents and conditions: (a) 2-benzyl-3-ethoxy-3-oxopropanoic acid, EDCI, HOBt, DIPEA,
DMF; rt, 18 hr.
Figure imgf000072_0001
15 16
Reagents and conditions: (b) CH3C(=NOH)NH2, K2CO3, toluene; reflux, 18 hr
Figure imgf000072_0002
16 17
Reagents and conditions: (c) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH; rt, 18 hr.
EXAMPLE 5
4.{(5)_2-(4-Ethylthiazol-2-yl)-2-[2-(3-methyl-l,2,4-oxadiazol-5-yl)-3- phenylpropanamido]ethyl}phenylsulfamic acid (17):
Preparation of ethyl-2-benzyl-3-[rø- 1 -(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)- ethylamino]-3-oxopropanoate (15): To a solution of 1 -(5}-(4-ethylthiazol-2-yl)-2-(4- nitrophenyl)ethyl amine hydrobromide, 3, (0.406 g, 1.13 mmol), 2-benzyl-3-ethoxy-3- oxopropanoic acid (0.277 g) and 1-hydroxybenzotriazole (HOBt) (0.191 g, 1.41 mmol) in DMF ( 10 mL) at 0°, is added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.240 g, 1.25 mmol) followed by diisopropylethylamine (DIPEA) (0.306 g). The mixture is stirred at 0 0C 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 HCl, 5 % aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.169 g (31 % yield) of the desired product which is used without further purification.
Preparation of iV-[(5)-l-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-(3-methyl-l ,2,4- oxadiazol-5-yl)-3-phenylpropanamide (16): Ethyl 2-benzyl-3-((S)-l-(4-ethylthiazol-2-yl)-2-(4- nitrophenyl)ethylamino)-3-oxoproρanoate is dissolved in toluene (5 mL) and heated to reflux. Potassium carbonate (80 mg) and acetamide oxime (43 mg) are added, and treated with 80 mg potassium carbonate and 43 mg acetamide oxime at reflux. The reaction mixture is cooled to room temperature, filtered and concentrated. The residue is chromatographed over silica to afford 0.22 Ig (94%) of the desired product as a yellow oil.
Preparation of 4- {0S)-2-(4-ethylthiazol-2-yl)-2-[2-(3-methyl- 1 ,2,4-oxadiazol-5-yl)-3- phenylpropanamido]ethyl}phenylsulfamic acid (17): N-[(S)-l-(4-ethylthiazol-2-yl)-2-(4- nitrophenyl)ethyl]-2-(3-methyl-l,2,4-oxadiazol-5-yl)-3-phenylpropanamide, 16, (0. 221 g) and tin (II) chloride (507 mg, 2.2 mmol) are dissolved in EtOH (25 mL) and the solution is brought to reflux 4 hours. The solvent is removed in vacuo and the resulting residue is dissolved in EtOAc. A saturated solution OfNaHCO3 (50 mL) is added and the solution is stirred 1 hour. The organic layer is separated and the aqueous layer extracted twice with EtOAc. The combined organic layers are dried (NaaSO-O, filtered and concentrated to a residue which is dissolved in pyridine (0.143 g) and treated with Sθ3-pyridine (0.143 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.071g of the desired product as the ammonium salt. 1H (CD3OD): δ 7.29-6.87 (m, 10H), 5.38- 5.30 (m, IH), 4.37-4.30 (m, IH)5 3.42-2.74 (m, 6H), 2.38-2.33 (m, 3H), 1.34-1.28 (m, 3H).
Category II of the present disclosure relates to 2-(thiazol-2-yl) compounds having the formula:
Figure imgf000074_0001
wherein R1 , R2 , R3 , and L are further defined herein in Table V herein below.
TABLE V
Figure imgf000074_0002
Figure imgf000075_0002
The compounds encompassed within Category II of the present disclosure can be prepared by the procedure outlined in Scheme VI and described in Example 6 herein below.
Scheme VI
Figure imgf000075_0001
3 18
Reagents and conditions: (a) 3-benzoylpropionic acid, TsCl, TV-methyl imidazole, CH2Cl2; rt, 18 hr.
Figure imgf000076_0001
18 19
Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH.
EXAMPLE 6
(^)_4_[2-(4-Ethylthiazol-2-yl)-2-(4-oxo-4-phenylbutanamido)ethyl]- phenylsulfamic acid (19)
Preparation of (S)-N-[I -(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-4-oxo-4- phenylbutanamide (18): 3-Benzoylpropionic acid (0.250 g) is dissolved in CH2Cl2 (5 mL), N- methyl imidazole (0.333 mL) is added and the resulting solution is cooled to 0 0C after which a solution of jσ-toluenesulfonyl chloride (0.320 g) in CH2Cl2 (2 mL) is added dropwise. After 0.5 hours (5)-l-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethanamine, 3, (0.388 g) is added. The reaction is stirred forl 8 hours at room temperature and then concentrated in vacuo. The resulting residue is dissolved in EtOAc and washed with IN HCl and brine. The solution is dried over Na2SO4, filtered, and concentrated and the crude material purified over silica to afford 0.415 g of the desired product.
Preparation of (S)-4-[2-(4-ethylthiazol-2-yl)-2-(4-oxo-4-phenylbutanamido)- ethyl]phenylsulfamic acid (19): (iS)-ΛT-[l-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3- diphenyl-propanamide, 18, (0.2 g) is dissolved in MeOH (15 mL). 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 CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (5 mL) and treated with SO3- pyridine (0.153 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.090 g of the desired product as the ammonium salt. 1H NMR (CD3OD) δ 8.68 (d, IH, J=8.2 Hz), 8.00 (d, 2H, 1=1.2 Hz)5 7.80-7.50 <m, 3H), 7.12 (s, 4H), 7.03 (s, IH), 5.46-5.38 (m, IH), 3.29-3.14 (m, 2H), 3.06-2.99 (m, 2H), 2.83 (q, 2H, J=7.5 Hz), 2.69-2.54 (m, 2H), 1.33 (t, 3H, J=7.5 Hz).
The following are non-limiting examples of compounds encompassed within Category II of the present disclosure. The 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 I.
Figure imgf000077_0001
(-S)-4-(2-(4-Ethylthiazol-2-yl)-2-(5-methyl-4-oxohexanamido)ethyl)phenyl-sulfamic acid: 1H NMR (CD3OD) δ 8.59 (d, IH5 J=8.1 Hz), 7.14 (s, 4H), 7.08 (t, IH, J=13.0 Hz), 5.40-5.35 (m, IH), 3.37-3.27 (m, 2H), 3.04-2.97 (m, IH), 2.83-2.61 (m, 4H), 2.54-2.36 (m, 3H), 1.33 (t, 2H, J=7.3 Hz), 1.09 (dd, 6H, J=7.0, 2.2 Hz).
Figure imgf000077_0002
(-S)-4-{2-[4-(3,4-Dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-4-oxobutanamido]-2-(4- ethylthiazol-2-yl)ethyl}phenylsulfamic acid: 1H NMR(CD3OD) δ 8.64 (d, IH, J=8.4 Hz)5 7.60 (d, 2H, J=I 0.6 Hz), 7.11 (s, 3H), 7.04 (d, 2H5 J=5.5 Hz)5 5.42-5.40 (m, IH), 4.30-4.22 (m, 4H), 3.20-2.98 (m, 4H), 2.82 (q, 2H, J=7.3 Hz), 2.67-2.48 (m, 2H), 2.23 (t, 2H5 J=5.5 Hz), 1.32 (t, 3H, J=7.3 Hz).
Figure imgf000078_0001
(5)-4-{2-[4-(2,3-Dimet oxyphenyl)-4-oxo yl)ethyl}phenylsulfamic acid: 1H NMR (CD3OD), δ 8.64.(d, IH, J=8.1 Hz), 7.21-7.11 (m, 7H), 7.02 (s, IHi, 5.42 (q, IH5 J=5.9 Hz), 3.90 (d, 3H, J=3.3 Hz), 3.88 (d, 3H, J=2.9 Hz), 3.22-3.18 (m, 2H), 3.07-2.99 (m, 2H), 2.83 (q, 2H, J=7.3 Hz), 2.63-2.54 (m, 2H), 1.34 (t, 3H, J=7.69 Hz).
Figure imgf000078_0002
(5}-4- {2-(4-Ethylthiazol-2-yl)-2-[4-oxo-4-(pyridin-2-yl)butanamido]ethyl } - phenylsulfamic acid: 1H NMR (CD3OD) δ 8.60 (d, IH, J=12.8 Hz), 7.91-7.81 (m, 2H), 7.48- 7.44 (m, IH), 7.22-7.21 (m, IH), 6.99 (s, 3H), 6.91 (s, IH), 5.30 (q, IH, J=5.4 Hz), 3.36 (q, 2H, J=7.0 Hz), 3.21-3.15 (m, IH), 2.91-2.85 (m, IH), 2.74 (q, 2H, J=10.4 Hz), 2.57-2.50 (m, 2H), 1.20 (t, 3HJ=7.5 Hz).
Figure imgf000078_0003
(S)-4-{2-[4-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-4-oxobutanamido]-2-(4-ethylthiazol- 2-yl)ethyl}phenylsulfamic acid: 1H NMR (CD-3OD) δ 1.52-1 Al ( m,2 H), 7.1 l(s,4H), 7.03 (s,lH), 6.95 (d, IH, J=8.4 Hz), 5.41 (q, IH, J=3.7 Hz), 4.31 (d, 4H, J=5.5 Hz), 3.24-3.12 (m, 2H), 3.06-2.98 (m, 2H), 2.83 (q, 2H, J=7.3 Hz), 2.62-2.53 (m, 2H), 1.33 (t, 3H, J=7.3 Hz).
Figure imgf000079_0001
(iS)-4-[2-(4-tert-butoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yϊ)ethyl]phenyl-sulfamic acid: 1H NMR (CD3OD), δ 7.10 (s 4H), 7.02 (s, IH), 5.41 (q, IH, J=3.7 Hz), 3.30-3.25 (m, IH), 3.06-2.99 (m, IH), 2.83 (q, 2H, J=7.3 Hz), 2.52-2.40 (m, 4H), 1.42 (s, 9H), 1.33 (t, 3H, J=7.3 Hz).
Figure imgf000079_0002
(<S)-4-[2-(4-ethoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic acid: 1H NMR (CD3OD) δ 8.62 (d, IH, J=8.4 Hz), 7.10 (s, 4H)5 7.02 (s, IH), 5.40 (q, IH, 3.7 Hz), 4.15 (q, 2H, J=7.3 Hz), 3.28-3.25 (m, IH), 3.05-3.02 (m, IH), 2.82 (q, 2H, J=4.4 Hz), 2.54-2.48 (m, 2H), 1.33 (t, 3H, J=7.3 Hz), 1.24 (t, 3H, J=7.0 Hz).
The first aspect of Category III of the present disclosure relates to 2-(thiazol-2-yl) compounds having the formula:
Figure imgf000079_0003
wherein non-limiting examples of R , 1 , r R>2 , and R are further described herein below in Table VI.
TABLE VI
Figure imgf000079_0004
19
Figure imgf000080_0002
The compounds encompassed within Category III of the present disclosure can be prepared by the procedure outlined in Scheme VIII and described in Example 7 herein below.
Scheme VII
Figure imgf000080_0001
3 20
Reagents and conditions: (a) benzyl isocyanate, TEA, CH2CI2; it, 18 hr.
Figure imgf000081_0001
20 21
Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH.
EXAMPLE 7 (S)-4-(2-(3-Benzyl\ireido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamic acid (21)
Preparation of (S)-I -benzyl-3-[ 1 -(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]urea (20): To a solution of l-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.360 g, 1 mmol) and Et3N (0.42 mL, 3mmol ) in 10 mL CH2Cl2 is added benzyl isocyanate (0.12 mL, 1 mmol). The mixture is stirred at room temperature for 18 hours. The product is isolated by filtration to afford 0.425 g (96% yield) of the desired product which is used without further purification.
Preparation of (S)-4-(2-(3-benzylureido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid (21): (5)-l-benzyl-3-[l-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]urea, 20, (0.425 g) is dissolved in MeOH (4 mL). 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 CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SO3-pyridine (0.220 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH4OH 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. 1H NMR (CD3OD) δ 7.32-7.30 (m, 2H), 7.29-7.22 (m, 3H), 7.12-7.00 (m, 4H)3 6.84 (d, IH, J = 8.1Hz), 5.35-5.30 (m, IH), 4.29 (s, 2H), 3.27-3.22 (m, 3H), 3.11-3.04 (m, 3H), 2.81 (q, 2H, J = 10.2, 13.0Hz), 1.31 (t, 3H, J = 4.5Hz). The following is a non-limiting examples of compounds encompassed within the first aspect of Category III of the present disclosure.
4-{[(,S)-2-(2-Ethylthiazol-4-yl)-2-(3-(Λ)-methoxy-l-oxo-3-phenylpropan-2- yl)ureido]ethyl}phenylsulfamic acid: 1H NMR (CD3OD) δ 7.36-7.26 (m, 3H), 7.19-7.17 (m, 2H), 7.10-7.06 (m, 2H), 6.90-6.86 (m, 3H), 5.12-5.06 (m, IH), 4.60-4.55 (m, IH)5 3.69 (s, 3H) 3.12-2.98 (m, 6H), 1.44-1.38 (m, 3H).
The second aspect of Category III of the present disclosure relates to 2-(thiazol-4-yl) compounds having the formula:
Figure imgf000082_0001
wherein non-limiting examples of R1 and R4 are further described herein below in Table VII.
TABLE VII
Figure imgf000082_0002
Figure imgf000083_0001
Figure imgf000084_0002
The compounds encompassed within the second aspect of Category III of the present disclosure can be prepared by the procedure outlined in Scheme VIII and described in Example 8 herein below.
Scheme VIII
Figure imgf000084_0001
Reagents and conditions (a) benzyl isocyanate, TEA3 CH2Cl2; it, 18 hr.
Figure imgf000085_0001
Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH.
EXAMPLE 8
4- {(S)-2-(3-Benzylureido)-2-[2-(thiophen-2-yl)thiazol-4-yl] ethyl } - phenylsulfamic acid (23)
Preparation of l-benzyl-3-{(iS)-2-(4-nitrophenyl)-l-[2-(thiophen-2-yl)thiazol-4- yl]ethyl}urea (22): To a solution of (S)-2-(4-nitrophenyl)-l-[(2-thiophene-2-yl)thiazol-4- yl)ethan-amine hydrobromide salt, 8, and Et3N (0.42mL, 3mmol ) in 10 mL DCM is added benzyl isocyanate (0.12mL, lmmol). The mixture is stirred at room temperature for 18 hours. The product is isolated by filtration to afford 0.445 g (96% yield) of the desired product which is used without further purification.
Preparation of 4- {(S)-2-(3-benzylureido)-2-[2-(miophen-2-yl)thiazol-4-yl]ethyl}phenyl- sulfamic acid (23): l-Benzyl-3-{(5)-2-(4-nitrophenyl)-l-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}urea, 22, (0.445g) is dissolved in MeOH (10 mL) and CH2Cl2 (5 mL). A catalytic amount of PdVC (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 CELITE and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with Sθ3-pyridine (0.110 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH4OH 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. 1H NMR (CD3OD) δ 7.61 (d, IH, J = 2.1Hz), 7.58 (d, IH5 J = 6Hz), 7.33-7.22 (m, 4H), 7.17-7.14 (m, IH), 7.09-6.94 (m, 6H), 5.16 (t, IH, J = 6.6Hz), 4.13 (s, 2H), 3.14-3.11 (m, 2H). Category IV of the present disclosure relates to 2-(thiazol-4-yl) compounds having the formula:
Figure imgf000086_0001
wherein R , 1 , R , and L are further defined herein in Table VIII herein below.
TABLE VIII
Figure imgf000086_0002
Figure imgf000087_0001
Figure imgf000088_0003
The compounds encompassed within Category IV of the present disclosure can be prepared by the procedure outlined in Scheme IX and described in Example 9 herein below.
Scheme IX
Figure imgf000088_0001
8 24
Reagents and conditions: (a) C6H4CH2SO2Cl, DIPEA, CH2Cl2; 00C to rt, 14 hr.
Figure imgf000088_0002
24 25
Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH.
EXAMPLE 9
{4-(-?)-[2-Phenylmethanesulfonylamino-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamic acid (25)
Preparation of (S)- //-{2-(4-nitrophenyl)-l-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-l- phenylmethanesulfonamide (24): To a suspension of 2-(4-nitrophenyl)-l-(2-thiophene2- ylthiazol-4-yl)ethylamine, 8, (330 mg, 0.80 mmol) in CH2Cl2 (6 mL) at O 0C 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 CH2Cl2 and washed with sat. NaHCO3 followed by brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is purified over silica to afford 210 mg of the desired product as a white solid.
Preparation of {4-(5)-[2-phenylmethanesulfonylamino-2-(2-thiophen-2-ylthiazol-4- yl)ethyl]phenyl} sulfamic acid (25): (S)- N- {2-(4-nitrophenyl)-l -[2-(thiophen-2-yl)thiazol-4- yl]ethyl}-l-phenylmethanesulfonamide, 24, (210 mg, 0.41 mmol) is dissolved in MeOH (4 mL). 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 CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with Sθ3-pyridine (197 mg, 1.23 mmol). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH4OH 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. 1H NMR (300 MHz, MeOH-d4) δ 7.52-7.63 (m, 6.70- 7.28 (m, 11H), 4.75 (t, J = 7.2 Hz, IH), 3.95-4.09 (m, 2H), 3.20 (dd, J= 13.5 and 7.8 Hz, IH), 3.05 (dd, J= 13.5 and 7.8 Hz, IH). 1013770
Intermediates for use in Step (a) of Scheme DC can be conveniently prepared by the procedure outlined herein below in Scheme X and described in Example 10.
Scheme X
Figure imgf000089_0001
26 Reagents and conditions: (a) Na2SO3, H2O; microwave @ 200°C, 20 min.
NaO
Figure imgf000089_0002
26 27
Reagents and conditions: (b) PCl5, POCl3; 50 0C, 3 hrs.
EXAMPLE 10 (2-Methylthiazol-4-yl)methanesulfonyl chloride (27)
Preparation of sodium (2-methylthiazol-4-yl)methanesulfonate (26): 4-Chloromethyl-2- methylthiazole (250 mg, 1.69 mmol) is dissolved in H2O (2 mL) and treated with sodium sulfite (224 mg, 1.78 mmol). The reaction mixture is subjected to microwave irradiation for 20 minutes at 2000C. The reaction mixture is diluted with H2O (30 mL) and washed with EtOAc (2 x 25 mL). The aqueous layer is concentrated to afford 0.368g of the desired product as a yellow solid. LC/MS ESI+ 194 (M+l, free acid).
Preparation of (2-methylthiazol-4-yl)methanesulfonyl chloride (27): Sodium (2- methylthiazol-4-yl)methanesulfonate (357 mg, 1.66 mmol) is dissolved in phosphorous oxychloride (6 mL) and is treated with phosphorous pentachloride (345 mg, 1.66 mmol). The reaction mixture is stirred at 50 0C for 3hours, then allowed to cool to room temperature. The solvent is removed under reduced pressure and the residue is re-dissolved in CH2Cl2 (40 mL) and is washed with sat. NaHCO3 and brine. The organic layer is dried over MgSO4, filtered, and the solvent removed in vacuo to afford 0.095 g of the desired product as a brown oil. LC/MS ESI+ 21 1 (M+l). Intermediates are obtained in sufficient purity to be carried forward according to Scheme IX without the need for further purification.
4-{(S)-2-[(2-methylthiazol-4-yl)methylsulfonamido]-2-[2-(thiophen-2-yl)thiazol-4- yl]ethyl}phenylsulfamic acid: 1H (CD3OD): δ 7.71-7.66 (m, 2H)3 7.27-7.10 (m, 7H), 4.87 (t, IH, J=7.3 Hz), 4.30-4.16 (q, 2H5 J=I 3.2 Hz), 3.34-3.13 (m, 2H), 2.70 (s, 3H).
The following are non-limiting examples of compounds encompassed within Category IV of the present disclosure.
Figure imgf000091_0001
{4-(5)-[2-Phenylmethanesulfoπylamino-2-(2-ethylthiazol-4-yl)ethyl]phenyl}-sulfamic acid: 1H NMR (300 MHz, MeOH-d4) δ 7.27-7.32 (m, 3H), 7.16-7.20 (m, 3H)3 7.05-7.6 (m, 2H), 6.96 (d, J = 8.4 Hz, 2H)5 4.70 (t, J= 9.0 Hz, IH), 3.91-4.02 (m, 2H), 2.95-3.18 (m, 4H), 1.41 (t, J= 7.5 Hz, 3H).
Figure imgf000091_0002
{4-(5)-[2-(3-Methoxyphenyl)methanesulfonylamino-2-(2-ethylthiazol-4- yl)ethyl]phenyl} sulfamic acid: 1H NMR (300 MHz, MeOH-d4) δ 7.20 (t, J= 8.1 Hz. IH), 6.94- 7.08 (m,4H), 6.88-6.94 (m, 3H), 6.75-6.80 (m, IH), 4.67 (t, J= 7.2 Hz, IH), 3.90-4.0 (m, 2H), 3.76 (s, 3H), 2.95-3.16 (m, 4H), 1.40 (t, J= 7.5 HZ, 3H).
Figure imgf000091_0003
(-S)-4- { [ 1 -(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylsulfamoyl]methyl} -benzoic acid methyl ester: 1H NMR (300 MHz, MeOH-d4) δ 7.90-7.94- (m, 2H), 7.27-7.30 (m, 2H), 7.06-7.11 (m, 3H), 6.97-7.00 (m, 2H), 4.71 (t, J= 7.2 Hz, IH), 3.95-4.08 (4, 2H), 3.92 (s, 3H), 2.80-3.50 (m, 4H), 1.38-1.44 (m, 3H).
Figure imgf000092_0001
(5)-4-[2-(2-Ethylthiazol-4-yl)-2-(l-methyl-l/7-imidazol-4-sulfonamido)ethyl]- phenylsulfamic acid: 1H NMR (300 MHz, MeOH-d4) δ 7.54 (s, IH3 7.20 (s, IH), 7.09 (s, IH), 6.92-7.00 (m, 4H)3 4.62 (t, J= 5.4 Hz, IH)5 3.70 (s, 3H), 2.98-3.14 (m,3H)5 2.79 (dd, 7= 9.3 and 15.O Hz5 IH), 1.39 (q, J= 7.5 Hz3 3H).
Figure imgf000092_0002
4-{(5)-2-[2-(Thiophen-2-yl)thiazol-4-yl]-2-(232,2-trifluoroethylsulfonamido)- ethyl}phenylsulfamic acid: 1H (CD3OD): δ 7.62-7.56 (m, 2H), 7.22 (s, IH)3 7.16-7.06 (m, 5H), 4.84 (t, IH, J=7.6 Hz), 3.71-3.62 (m, 2H), 3.32-3.03 (m, 2H).
Figure imgf000092_0003
{4-(5)-[2-(Phenylethanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyl]- phenyl} sulfamic acid: 1H NMR (300 MHz, MeOH-d4) δ 7.56-7.62 (m, 2H), 7.04-7.19(m, 9H), 6.94-6.97 (m, 2H), 4.78 (t, J= 7.8 Hz, IH), 3.22-3.30 (m, 2H)), 3.11 (dd, J = 13.5 and 7.8 Hz, IH), 2.78-2.87 (m, 4H).
Figure imgf000093_0001
{4-(iS)-[3-(Phenylpropanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyl]- phenyl}sulfamic acid: 1H NMR (300 MHz, MeOH-Cl4) δ 7.56-7.62 (m, 2H), 6.99-7.17 (ra, 10H), 4.72 (t, J = 7.8 Hz, IH), 3.21 (dd, J= 13.5 and 7.2 Hz, IH), 3.02 (dd, J = 13.5 and 7.2 Hz, IH), 2.39-2.64 (m, 4H), 1.65-1.86 (m, 2H).
Figure imgf000093_0002
(S)- {4-[2-(4-Methyl-3,4-dihydro-2H-benzo[ 1 ,4]oxazine-7-sulfonylamino)-2-(2-thiophen- 2-ylthiazol-4-yl)ethyl]phenyl}sulfamic acid: 1H NMR (300 MHz, MeOH-d^ 6 7.53 (d, J= 5.1 Hz, IH) 7.48 (d, J=5.1 Hz, IH), 7.13-7.10 (m, IH), 7.04 (d, J = 8.4 Hz, 2H), 6.93-6.88 (ra, 3H), 6.75 (d, J = 8.1 Hz5 IH). 6.54 (d, J= 8.1 Hz, IH), 4.61 (t, J = 7.5 Hz, IH), 4.20-4.08 (m, 2H), 3.14-3.00 (m, 4H), 2.69 (s, 3H).
Figure imgf000093_0003
4-{(-St)-2-(4-acetamidophenylsulfonamido)-2-[2-(thiophen-2-yl)thiazol-4- yl]ethyl}phenylsulfamic acid: 1H (CD3OD): δ 7.67-7.52 (m, 6H), 7.24-7.23 (m, IH), 7.12-7.09 (m, 3H), 7.02-6.99 (m, 2H), 4.70 (t, IH, J=7.3 Hz)5 3.25-3.00 (m, 2H), 2.24 (s, 3H). The first aspect of Category V of the present disclosure relates to compounds having the formula:
Figure imgf000094_0001
wherein R1 is a substituted or unsubstituted heteroaryl and R4 is Ci-C6 linear, branched, or cyclic alkyl as further described herein below in Table IX.
TABLE DC
Figure imgf000094_0002
Figure imgf000095_0001
Compounds according to the first aspect of Category V which comprise a substituted or unsubstituted thiazol-4-yl unit for R1 can be prepared by the procedure outlined in Scheme XI and described herein below in Example 11. Scheme XI
Figure imgf000096_0001
7 28
Reagents and conditions: (a) CHaCN, reflux; 24 hr.
Figure imgf000096_0002
28 29
Reagents and conditions: (b) thiophosgene, CaCO3, CCU, H2O; rt, 18 hr.
Figure imgf000096_0003
Reagents and conditions: (c) KOtBu, THF; rt, 2hr.
Figure imgf000096_0004
Reagents and conditions: (d) (i) SnCl2-2H2O, EtOH; reflux, 4 hours (ii) SO3-pyridine, NH4OH. EXAMPLE Il
(5)-4-(2-(2-Phenylthiazol-4-yl)2-(4-(methoxycarbonyl)thiazole-5-ylamino)ethyl)phenylsulfamic acid (31)
Preparation of (5)-2-(4-nitrophenyl)-l -(2-phenylthiazol-4-yl)ethanamine hydrobromide salt (28): A mixture of (S)-tert-butyl 4-bromo-l-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (1.62 g, 4.17 mmol) and thiobenzamide (0.63 g, 4.60 mmol) in CH3CN (5 mL) is refluxed for 24 hours. The reaction mixture is cooled to room temperature and diethyl ether (50 mL) is added to the solution. The precipitate which forms is collected by filtration. The solid is dried under vacuum to afford 1.2 g (67 % yield) of the desired product. LC/MS ESI+ 326 (M+l).
Preparation of (5)-4-(l-isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylthiazole (29): To a solution of (iS)-2-(4-nitrophenyl)-l-(2-phenylthiazol-4-yl)ethanamine hydrobromide salt, 29, (726 mg, 1.79 mmol) and CaCO3 (716 mg, 7.16 mmol) in H2O (2 mL) is added CCl4 (3 mL) followed by thiophosgene (0.28 mL, 3.58 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CH2CI2 and water. The layers are separated and the aqueous layer extracted with CH2Cl2. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated in vacuo to a residue which is purified over silica (CH2CI2) to afford 480 mg (73 %) of the desired product as a yellow solid. 1H NMR (300 MHz, CDC13) δ 8.15 (d, J = 8.7 Hz, 2H), 7.97-7.99 (m, 2H), 7.43-7.50 (m, 3H), 7.34 (d, J = 8.7 Hz, 2H), 7.15 (d, J= 0.9 Hz, IH)3 5.40-5.95 (m, IH), 3.60 (dd, J= 13.8 and 6.0 Hz, IH)3 3.46 (dd, J- 13.8 and 6.0 Hz).
Preparation of (»S)-methyl 5-[ 1 -(2-phenylthiazol-4-yl)-2-(4-nitrophenyl)- ethylamino]thiazole-4-carboxylate (30): To a suspension of potassium tert-butoxide (89 mg, 0.75 mmol) in THF (3 mL) is added methyl isocyanoacetate (65 μL, 0.68 mmol) followed by (.S)-2-phenyl-4-(l-isothiocyanato-2-(4-nitrophenyl)ethyl)thiazole, 29, (250 mg, 0.68 mmol). The reaction mixture is stirred at room temperature for 2 hours then poured into sat. NaHCO3. The mixture is extracted with EtOAc (3x 25 mL) and the combined organic layers are washed with brine and dried (Na2SO-t) and concentrated in vacuo. The crude residue is purified over silica to afford 323 mg (~ 100% yield) of the desired product as a slightly yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.09-8.13 (m, 2H)5 7.95-7 98 (m, 3H), 7.84 (d, J= 1.2 Hz, IH), 7.44-7.50 (m, 3H), 7.28-7.31(m, 2H), 7.96 (d, J= 0.6 Hz, IH)3 4.71-4.78(m, IH), 3.92 (s, 3H), 3.60 (dd, J = 13.8 and 6.0 Hz, IH), 3.45 (dd, J = 13.8 and 6.0 Hz, IH).
Preparation of (5)-4-(2-(2-phenylthiazol-4-yl)2-(4-(methoxycarbonyl)thiazole-5- ylamino)ethyl)phenylsulfamic acid (31): (5)-methyl 5-[l-(2-phenylthiazol-4-yl)-2-(4- nitrophenyl)-ethylamino]thiazole-4-carboxylate, 30, (323 mg, 0.68 mmol) and tin (II) chloride (612 mg, 2.72 mmol) are dissolved in EtOH and the solution is brought to reflux. The solvent is removed in vacuo and the resulting residue is dissolved in EtOAc. A saturated solution of NaHCO3 is added and the solution is stirred 1 hour. The organic layer is separated and the aqueous layer extracted twice with EtOAc. The combined organic layers are dried (Na2SO4), filtered and concentrated to a residue which is dissolved in pyridine (10 mL) and treated with SO3-pyridine (130 mg, 0.82 mmol). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 0.071 g of the desired product as the ammonium salt 1H NMR (300 MHz, MeOH-d4) δ 7.97-8.00 (m, 3H), 7.48-7.52 (m, 3H), 7.22 (s, IH), 7.03-7.13 (m, 4H), 4.74 (t, J= 6.6 Hz, IH), 3.88 (s, 3H), 3.28-3.42 (m, • 2H).
Compounds according to the first aspect of Category V which comprise a substituted or unsubstituted thiazol-2-yl unit for R can be prepared by the procedure outlined in Scheme XII and described herein below in Example 12. Intermediate 32 can be prepared according to Scheme II and Example 2 by substituting cyclopropane-carbothioic acid amide for thiophene-2- carbothioic acid amide.
Scheme XII
Figure imgf000098_0001
32 33 Reagents and conditions: (a) thiophosgene ,CaCO3, CCI4/H2O; rt, 18 hr.
Figure imgf000099_0001
Reagents and conditions: (b)
Figure imgf000099_0002
34 35
Reagents and conditions: (c) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH.
EXAMPLE 12
4-{(5)-2-(2-Cyclopropylthiazol-4-yl)-2-[4-(3-methoxyphenyl)thiazol-2- ylamino]ethyl}phenylsulfamic acid (35)
Preparation of (S)-I -(I -(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)-thiourea (33): To a solution of (S)-I -(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethan-amine hydrobromide hydrobromide salt, 32, (4.04 g, 10.9 mmol) and CaCO3 (2.18 g, 21.8 mmol) in CCU/water (25 mL/20 mL) is added thiophosgene (1.5 g, 13.1 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CH2Cl2 and water. The layers are separated and the aqueous layer extracted with CH2Cb- The combined organic layers are washed with brine, dried (Na2SO-O an(i concentrated in vacuo to a residue which is subsequently treated with ammonia (0.5M in 1,4-dioxane, 120 mL) which is purified over silica to afford 2.90 g of the desired product as a red-brown solid. LC/MS ESI- 347 (M-I).
Preparation of (5)-4-(3-methoxybenzyl)-N-(l -(2-cycloρroρylthiazol-4-yl)-2-(4- nitrophenyl)ethyl)thiazol-2-amine (34): (6)-l-(l-(2-Cyclopropylthiazol-4-yl)-2-(4- nitrophenyl)ethyl)-thiourea, 32, (350 mg, 1.00 mmol) and 2-bromo-3'-methoxy-acetophenone (253 mg, 1.10 mmol) are combined in 3 mL CH3CN and heated to reflux for 24 hours. The mixture is concentrated and chromatographed to afford 0.172 g of the product as a yellow solid. LC/MS ESI+ 479 (M+l).
Preparation of 4- {(S)-2-(2-cyclopropylthiazol-4-yl)-2-[4-(3-methoxyphenyl)-thiazol-2- ylamino]ethyl}phenylsulfamic acid: (35): (5)-4-(3-methoxybenzyl)-N-(l-(2-cyclopropylthiazol- 4-yl)-2-(4-nitrophenyl)ethyl)thiazol-2-amine, 34, (0.172 g) is dissolved in 10 mL MeOH. A catalytic amount of PdVC (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere for 18 hours. The reaction mixture is filtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in 5 mL pyridine and treated with S O3 -pyridine (114 mg). The reaction is stirred at room temperature for 5 minutes after which 10 mL of a 7% solution OfNH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse-phase chromatography to afford 0.033 g of the desired product as the ammonium salt. 1H (CD3OD): δ 7.33-7.22 (m, 3H), 7.10-6.97 (m, 5H), 6.84-6.80 (m, 2H), 5.02 (t, IH, J=6.9 Hz), 3.82 (s, IH), 3.18 (q, 2H, J=7.1 Hz), 2.36 (q, IH, J=4.6 Hz), 1.20-1.13 (m, 2H), 1.04-0.99 (m, 2H).
The following are non-limiting examples of compounds encompassed within the first aspect of Category V.
Figure imgf000101_0001
(.S)-4-(2-(4-((2-Methoxy-2-oxoethyl)carbamoyl)thiazole-5-ylaτnino)2-(2-ethylthiazole-4- yl)ethyl)phenylsulfamic acid: 1H NMR (300 MHz, MeOH-d4) δ 7.91 (s, IH)3 7.08-7.10 (m, 3H), 6.99 (d, J= 8.7 Hz, 2H), 4.58 (t, J= 6.9 Hz, IH)3 4.11 (d, J= 2.7 Hz, 2H), 3.78 (s, 3H), 3.14- 3.28 (m, 2H), 3.06 (q, J= 7.5 Hz, 2H), 1.41 (t, J= 7.5 Hz, 3H).
Figure imgf000101_0002
(S)-4-(2- {5 -[I -JV-(2-Methoxy-2-oxoethylcarbamoyl)-l -H"-indol-3-yl]oxazol-2-ylamino>- 2-(2-methylthiazol-4-yl)ethyl)phenylsulfamic acid: 1H NMR (300 MHz, MeOH-d4) δ 7.63 (d, J = 7.8 Hz, IH), 7.37 (s, IH), 7.18-7.29 (m, 4H), 7.02-7.16 (m, 4H), 6.85 (s, IH), 5.04-5.09 (m, IH), 4.85 (s, 3H), 3.27 (dd, J= 13.5 and 8.1 Hz, IH), 3.10 (m, J= 13.5 and 8.1 Hz, IH), 2.69 (s, 3H).
Figure imgf000101_0003
4-((S)-2-(5-(2-Methoxyphenyl)oxazol-2-ylamino)-2-(2-methylthiazol-4- yl)ethyl)phenylsulfamic acid: 1H NMR (300 MHz, MeOH-d4) δ 7.52 (dd, J= 7.5 and 1.2 Hz, IH), 6.95-1.24 (m, 10H), 5.04-5.09 (m, IH), 3.92 (s, 3H), 3.26 (dd, J= 13.8 and 8.4 Hz, IH), 3.10 (dd, J= 13.8 and 8.4 Hz, IH), 2.72 (s, 3H).
Figure imgf000102_0001
4-((5)-2-(5-((5)-l-(^rr-Butoxycarbonyl)-2-phenylethyl)oxazole-2-ylamino)-2-(2- methylthiazole-4-yl)ethyl)phenylsulfamic acid: 1H NMR (300 MHz5 MeOH-d4) δ 7.03-7.27 (m, 10 H), 6.50 (s, IH), 4.95-5.00 (m, IH), 4.76 (t, J= 6.9 Hz, IH), 3.22 (dd, J = 14.1 and 6.9 Hz, IH), 3.00-3.10 (m, 2H), 2.90 (dd, J = 14.1 and 6.9 Hz1 IH), 2.72 (s, 3H), 1.37 (s, 9H).
Figure imgf000102_0002
(5)-{4-{2-[5-(4-Methoxycarbonyl)phenyI]oxazol-2-ylamino}-2-(2-methylthiazol-4- yl)ethyl}phenylsulfamic acid: 1H NMR (300 MHz, MeOH-d4) δ 7.99 (d, J= 7.5 Hz, 2H), 7.56-7.59 (m, 2H)5 7.23-7.24 (m, IH)5 7.08-7.14 (m, 4H)5 6.83 (d, J= 10.2 Hz5 IH)5 5.08 (t5 J = 6.0 Hz, IH), 3.91 (s, 3H)5 3.25-3.35 (m, IH), 3.09-3.13 (m, IH), 2.73 (s, 3H).
Figure imgf000102_0003
(»S)-4-(2-(5-(3-Methoxybenzyl)oxazole-2-ylamino)-2-(2-methylthiazole-4- yl)ethyl)phenylsulfamic acid: 1H NMR (300 MHz, MeOH-C-4) δ 7.03-7.28 (m, 8H), 6.79-6.83 (m, IH), 5.70 (s, IH), 4.99-5.06 (m, 2H), 4.41 (d, J= 2.1 Hz, 2H), 3.80 (s, 3H), 3.27-3.37 (m, IH)5 3.03-3.15 (m, IH)5 2.71 (s, 3H).
Figure imgf000102_0004
(5)-4-(2-(2-Methylthiazole-4-yl)2-(5-phenyloxazole-2-ylamino)ethyl)phenyl-sulfamic acid i.: i 1H NMR (300 MHz5 MeOH-d4) δ 7.45 (d, J - 8.7 Hz, 2H), 7.33 (t, J= 7.8 Hz5 2H)5 7.18- 7.22 (m, IH), 7.10-7.14 (m, 6H), 7.04 (s, IH), 5.04-5.09 (m, IH), 3.26 (dd, J- 13.8 and 6.3 Hz, IH), 3.10 (dd, J= 13.8 and 6.3 Hz3 IH), 2.70 (s, 3H).
Figure imgf000103_0001
4-((S)-2-(2-Cyclopropylthiazol-4-yl)-2-(4-(3-methoxyphenyl)thiazol-2- ylamino)ethyl)phenylsulfamic acid: 1H (CD3OD): δ 7.33-7.22 (m, 3H), 7.10-6.97 (m, 5H), 6.84- 6.80 (m, 2H), 5.02 (t, IH, J=6.9 Hz), 3.82 (s, IH), 3.18 (q, 2H, J=7.1 Hz), 2.36 (q, IH, J=4.6 Hz), 1.20-1.13 (m, 2H), 1.04-0.99 (m, 2H).
Figure imgf000103_0002
(5)-4-(2-(2-cyclopropylthiazol-4-yl)-2-(4-(4-fluorophenyl)thiazol-2- ylamino)ethyl)phenylsulfamic acid: 1H (CD3OD): δ 7.79-7.74 (m, 2H), 7.14-7.03 (m, 7H), 7.21 (s, IH), 6.79 (s, IH), 5.08 (t, IH, J=6.6 Hz), 3.29-3.12 (m, 2H), 2.40 (q, 2.40, J=5.1 Hz), 1.23- 1.18 (m, 2H), 1.08-1.02 (m, 2H).
Figure imgf000103_0003
4-((5)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2-methoxyphenyl)thiazol-2- ylamino)ethyl)phenylsulfamic acid: 1H (CD3OD): δ 7.89-7.87 (d, IH, J=7.6 Hz), 7.28 (t, IH, J=7.0 Hz), 7.10-6.96 (m, 8H), 5.03 (t, IH5 J=6.9 Hz), 3.90 (s, IH), 3.19 (q, 2H, J=6.6 Hz), 2.38 (q, 1H, J=4.8 Hz), 1.21-1.14 (m, 2H), 1.06-1.00 (m, 2H).
Figure imgf000104_0001
4-((.S>2-(2-cyclopropylthiazol-4-yl)-2-(4-(2,4-difluorophenyl)thiazol-2- ylamino)ethyl)phenylsulfamic acid: 1H (CD3OD): δ 8.06-8.02 (q, 2H, J=6.9 Hz)3 7.12-6.95 (m, 7H), 6.88 (s, IH), 5.11 (t, IH, J=6.9 Hz), 3.22-3.15 (m3 2H), 2.38 (q, 1H, J=4.8 Hz), 1.22-1.15 (m, 2H)5 1.06-1.02 (m, 2H).
Figure imgf000104_0002
(5)-4-(2-(4-(3-methoxybenzyl)thiazol-2-ylamino)-2-(2-cyclopropylthiazol-4- yl)ethyl)phenylsulfamic acid: 1H (CD3OD): δ 7.22-7.17 (m, 3H), 7.09-6.97 (m, 5H), 6.78-6.66 (m, 3H), 3.77 (s, 2H), 3.75 (s, 3H), 3.20-3.07 (m, 2H), 2.35 (q, 1H, J=4.8 Hz), 1.19-1.13 (m, 2H), 1.03-1.00 (m, 2H).
Figure imgf000104_0003
(-S)-{5-[l-(2-Ethylthiazol-4-yl)-2-(4-sυlfoaminophenyl)ethylamino]-2-methyl-2H- [l,2,4]triazole-3-yl}carbamic acid methyl ester: 1H NMR (300 MHz, MeOH-d4) δ 6.97-7.08 (m, 5H), 3.71 (s, 3H), 3.51 (s, 3H), 3.15 (dd, J= 13.5 and 6.3 Hz, IH), 3.02-3.07 (m, 3H), 1.40 (t, J = 6.6 Hz, 3H).
The second aspect of Category V of the present disclosure relates to compounds having the formula:
Figure imgf000105_0001
wherein R1 is a substituted or unsubstituted heteroaryl and R4 is substituted or unsubstituted phenyl and substituted or unsubstituted heteroaryl as further described herein below in Table X.
TABLE X
Figure imgf000105_0002
Figure imgf000106_0001
Compounds according to the second aspect of Category V which comprise a substituted or unsubstituted thiazol-4-yl unit for R1 can be prepared by the procedure outlined in Schemes XIII5 XrV, and XV and described herein below in Examples 13, 14, and 15.
Scheme XIII
Figure imgf000107_0001
36
Reagents and conditions: (a)(i) (wø-butyl)OCOCl, Et3N, THF; 00C, 20 min. (ii) CH2N2; 0 0C to room temp for 3 hours.
Figure imgf000107_0002
36 37
Reagents and conditions: (b) 48% HBr, THF; 0 0C, 1.5 hr.
Figure imgf000107_0003
Reagents and conditions: (c) CH3CN; reflux 2hr.
Figure imgf000107_0004
38 39
Reagents and conditions: (d) thiophosgene, CaCO3, CCI4, H2O; it, 18 hr.
Figure imgf000108_0001
39 40
Reagents and conditions: (e)(i) CH3C(O)NHNH2, EtOH; reflux, 2 hr. (ii) POCl3, rt 18 hr; 500C 2 hr.
Figure imgf000108_0002
40 41
Reagents and conditions: (f) (i) H2:Pd/C, MeOH; (ii) SO3-ρyridine, NH4OH.
EXAMPLE 13
(S)-4-(2-(5-Methyl-l,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4- yl)ethyl)phenylsulfamic acid (41)
Preparation of [3-diazo-l-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-buty\ ester (36): To a 00C solution of 2-(-S)-/er?-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g, 4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4.4 mmol) followed by ?so-butyl chloroformate (0.57 mL, 4.4 mmol). The reaction mixture is stirred at 0 0C for 20 minutes then filtered. The filtrate is treated with an ether solution of diazomethane (~16 mmol) at 0 0C. The reaction mixture is stirred at room temperature for 3 hours and concentrated. The residue is dissolved in EtOAc and washed successively with water and brine, dried (Na2SO**), filtered and concentrated in vacuo. The resulting residue is purified over silica (hexane/EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product as a slightly yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J= 8.7 Hz, 2H), 7.39 (d, J= 8.7 Hz, 2H), 5.39 (s, IH), 5.16 (d, J= 6.3 Hz, IH), 4.49 (s, IH), 3.25 (dd, J= 13.8 and 6.6, IH), 3.06 (dd, J= 13.5 and 6.9 Hz, IH), 1.41 (s, 9H).
Preparation of [3-bromo-l-(4-nitro-benzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester (37): To a 0 0C solution of [3-diazo-l-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-bυtyl ester, 36, (0.350 g, 1.04 mmol) in THF (5 mL) is added dropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture is stirred at 0 0C for 1.5 hours and quenched at 00C with saturated aqueous Na2CO3. The mixture is extracted with EtOAc (3 x 25 mL) and the combined organic extracts are washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 0.400 g of the desired product that is used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.20 (d, J= 8.4 Hz, 2H), 7.39 (d, J= 8.4 Hz, 2H), 5.06 (d, J= 7.8 Hz, IH), 4.80 (q, J= 6.3 Hz, IH), 4.04 (s, 2H), 1.42 (s, 9H).
Preparation of (S)-2-(4-nitrophenyl)-l -(2-phenylthiazol-4-yl)ethanamine hydrobromide salt (38): A mixture of [3-bromo-l-(4-nitro-benzyl)-2-oxo-propyl]-carbarnic acid tert-hutyl ester, 37, (1.62 g, 4.17 mmol) and benzothioamide (0.630 g, 4.59 mmol), in CH3CN (5 mL) is refluxed for 24 hours. The reaction mixture is cooled to room temperature and diethyl ether (50 mL) is added to the solution and the precipitate that forms is collected by filtration. The solid is dried under vacuum to afford 1.059 g (63%) of the desired product. ESI+MS 326 (M+l).
Preparation of (5)-4-[l -isothiocyanato-2-(4-nitrophenyl)-ethyl]-2-phenylthiazole (39): To a solution of (iS)-2-(4-nitrophenyl)-l-(2-phenylthiazol-4-yl)ethanamine hydrobromide salt, 38, (2.03g, 5 mmol) and CaCO3 (1 g, 10 mmol) in CCLj/water (10:7.5 mL) is added thiophosgene (0.46 mL, 6 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CH2Cl2 and water. The layers are separated and the aqueous layer extracted with CH2Cl2. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated in vacuo to a residue that is purified over silica (CH2Cl2) to afford 1.7 Ig (93% yield) of the desired product. ESI+ MS 368 (M+l).
Preparation of (.?)-5-methyl-N-[2-(4-nitrophenyl)-l-(2-phenylthiazol-4-yl)ethyl]-l,3,4- thiadiazol-2 -amine (40): A solution of (5r)-4-[l-isothiocyanato-2-(4-nitrophenyl)-ethyl]-2- phenylthiazole, 39, (332 rag, 0.876 mmol) and acetic hydrazide (65 mg, 0.876 mmol) in EtOH (5 mL) is reftuxed for 2 hours. The solvent is removed under reduced pressure, the residue is dissolved in POCl3 (3 mL) and the resulting solution is stirred at room temperature for 18 hours after which the solution is heated to 50 0C for 2 hours. The solvent is removed in vacuo and the residue is dissolved in EtOAc (40 mL) and the resulting solution is treated with IN NaOH until the pH remains approximately 8. The solution is extracted with EtOAc. The combined aqueous layers are washed with EtOAc, the organic layers combined, washed with brine, dried over MgSO-J, filtered, and concentrated in vacuo to afford 0.345 g (93% yield) of the desired product as a yellow solid. 1H NMR (CDCl3) 8.09 (d, J = 8.4 Hz, 2H), 7.91 (m, 2H), 7.46 (m, 4H), 7.44 (s, IH), 5.23 (m, IH), 3.59 (m, 2H), 2.49 (s, 3H). ESI+ MS 424 (M+l).
Preparation of (iS)-4-[2-(5-methyl-l ,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4- yl)ethyl]phenylsulfamic acid (41): (S)-5-Methyl-N-[2-(4-nitrophenyl)-l-(2-phenylthiazol-4- yl)ethyl]-l,3,4-thiadiazol-2-amine, 40, (0.404 g, 0.954 mmol) is dissolved in MeOH (5 mL). Pd/C (50 mg, 10% w/w) is added and the mixture is stirred under a hydrogen atmosphere until the reaction is judged to be complete. The reaction mixture is filtered through a bed of CELITE™ and the solvent removed under reduced pressure. The crude product is dissolved in pyridine (4 mL) and treated with Sθ3-ρyridine (0.304 g, 1.91 mmol). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH4OH (5.0 mL) is added. The mixture is then concentrated and the resulting residue is purified by reverse phase preparative HPLC to afford 0.052 g (11% yield) of the desired product as the ammonium salt. 1H (CD3OD): δ 8.00-7.97 (m, 2H), 7.51-7.47 (m, 3H), 7.23 (s, IH), 7.1 1-7.04 (q, 4H, J=9.0 Hz), 5.18 (t, IH, J=7.2 Hz), 3.34-3.22 (m, 2H), 2.50 (s, 3H). ESI- MS 472 (M-I).
Scheme XIV
Figure imgf000110_0001
8 42
Reagents and conditions: (a) thiophosgene ,CaCθ3, CCWH2O; rt, 18 hr.
Figure imgf000111_0001
Reagents and conditions: (b) CH3CN, reflux, 5 hours
Figure imgf000111_0002
Reagents and conditions: (c) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH; rt, 18 hr.
EXAMPLE 14
4-{(S)-2-[4-(2-Methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiophen-2-yl)thiazol-4- yl] ethyl }phenylsulfamic acid (44)
Preparation of (S)-I -[l-(thiophen-2-ylthiazol-4-yl)-2-(4-nitrophenyl)ethyl]-thiourea (42): To a solution of (5)-2-(4-nitrophenyl)-l-(thiophen-2-ylthiazol-4-yl)ethanamine hydrobromide salt, 8, (1.23 g, 2.98 mmol) and CaCO3 (0.597 g, 5.96 mmol) in CCWwater (10 rnL/5 mL) is added thiophosgene (0.412g, 3.58 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CH2Cl2 and water. The layers are separated and the aqueous layer extracted with CH2CI2. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated in vacuo to a residue which is subsequently treated with ammonia (0.5M in 1,4- dioxane, 29.4 mL, 14.7 mmol) which is purified over silica to afford 0.490 g of the desired product as a red-brown solid. ESI+ MS 399 (M+l).
Preparation of 4-(2-methoxyphenyl)-Λr-{(S)-2-(4-nitrophenyl)-l-[2-(thiophen-2- yl)thiazol-4-yl]ethyl} thiazol-2-amine (43): (S)-I -[ 1 -(thiophen-2-ylthiazol-4-yl)-2-(4- nitrophenyl)ethyl] -thiourea, 42, (265 mg, 0.679 mmol) is treated with bromo-2'- methoxyacetophenone (171 mg, 0.746 mmol) to afford 0.221 g of the product as a yellow solid. ESI+ MS 521 (M+l).
Preparation on 4- {(S)-2-[4-(2-methoxyphenyl)tm"azol-2-ylamino)-2-[2-(thiophen-2- yl)thiazol-4-yl]ethyl}phenylsulfamic acid (44): 4-(2-methoxyphenyl)-N-{(S)-2-(4-nitrophenyl)- l-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}thiazol-2-amine, 43, (0.229 g) is dissolved in 12 mL MeOH. A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere for 18 hours. The reaction mixture is filtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in 6 mL pyridine and treated with SC>3-pyridine (140 mg). The reaction is stirred at room temperature for 5 minutes after which 10 mL of a 7% solution OfNH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse-phase chromatography to afford 0.033g of the desired product as the ammonium salt. 1H (CD3OD): δ 7.96-7.93 (m, IH), 7.60- 7.55 (m, 2H), 7.29-7.23 (m, IH), 7.18-6.95 (m, 9H), 5.15 (t, 1H, J=6.9 Hz), 3.90 (s, 3H), 3.35- 3.24 (m, 2H).
Compounds according to the second aspect of Category V which comprise a substituted or unsubstituted oxazol-2-yl unit for R1 can be prepared by the procedure outlined in Scheme XV and described herein below in Example 15. Intermediate 39 can be prepared according to Scheme XIII and Example 13.
Scheme XV
Figure imgf000113_0001
39 45
Reagents and conditions: (a) l-azido-l-(3-methoxyphenyl)ethanone, PPI13, dioxane, 90 °C 20 minutes.
Figure imgf000113_0002
Reagents and conditions: (b) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH; rt, 18 hr.
EXAMPLE 15
4-{(-S}-2-[5-(3-Methoxyphenyl)oxazole-2-ylamino]-2-(2-phenylthiazole-4- yl)ethyl}phenylsulfamic acid (46)
Preparation of [5-(3-methoxyphenyl)oxazol-2-yl]-[2-(4-nitrophenyl)-l-(2-phenylthiazole- 4-yl) ethyl]amine (45): A mixture of (<S)-4-(isothiocyanato-2-(4-nitrophenyl)ethyl)-2- phenylthiazole, 39, (300 mg, 0.81 πunol), l-azido-l-(3-methoxyphenyl)ethanone (382 mg, 2.0 ramol) and PPb.3 (0.8 g, polymer bound, ~3 mmol/g) in dioxane (6 mL) is heated at 90 0C for 20 minutes. The reaction solution is cooled to room temperature and the solvent removed in vacuo and the resulting residue is purified over silica to afford 300 mg (74% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, MeOH-d4) δ 8.02 (d, J = 7.2 Hz, 2H), 7.92-7.99 (m, 2H), 7.42-7.47 (m, 3H), 7.22-7.27 (m, 3H), 6.69-7.03 (m, 4H), 6.75-6.78 (m, IH), 5.26 (t, J = 6.3 Hz, IH), 3.83 (s, 4H), 3.42-3.45 (m, 2H).
Preparation of 4- {(S)-2-[5-(3-methoxyphenyl)oxazole-2-ylamino]-2-(2-phenylthiazole- 4-yl)ethyl}phenylsulfamic acid (46): [5-(3-methoxyphenyl)oxazol-2-yl]-[2-(4-nitrophenyl)-l-(2- phenylthiazole-4-yl) ethyl]amine, 45, (300 mg, 0.60 mmol) is dissolved in MeOH (15 mL). 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 CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (10 mL) and treated with SOβ-pyridine (190 mg, 1.2 mmol). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH4OH is added. The mixture is then concentrated and the resulting residue is purified by reverse-phase chromatography to afford 0.042 g of the desired product as the ammonium salt. 1H NMR (300 MHz, MeOH-d4) δ 7.99 (d, J= 7.5 Hz, 2H), 7.46-7.50 (m, 3H),7.23-7.29 (m, 3H), 7.04-7.12 (m, 6H), 6.78 (dd, J = 8.4 and 2.4 Hz, IH), 5.16 (t, J= 6.6 Hz5 IH), 3.81 (s, 3H), 3.29-3.39 (m, IH), 3.17 (dd, J= 13.8 and 8.1 Hz, IH).
Further to the preparation of compounds which encompass Category V of the present disclosure, compounds of the present disclosure comprising R1 units having non-exemplified units can be prepared by modifying the procedures described herein above. For example, compounds of Category V comprising substituted or unsubstituted [1 ,2,4]triazole-3-yl units can be prepared by s
The following are non-limiting examples of the second aspect of Category V of the present disclosure.
Figure imgf000114_0001
(5)-4-(2-(5-Phenyl-l,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)- phenylsulfamic acid: 1H (CD3OD): δ 7.97-7.94 (m, 2H), 7.73-7.70 (m, 2H)3 7.44-7.39 (m, 6H), 7.25 (s, IH), 7.12 (s, 4H), 5.29 (t, IH, J=6.9 Hz), 3.35-3.26 (m, 2H).
Figure imgf000115_0001
4-((-5)-2-(5-Propyl- 1 ,3 ,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4- yl)ethyl)phenylsulfamic acid: 1H (CD3OD): δ 7.59-7.54 (m, 2H)3 7.17-7.03 (m, 6H)3 5.13 (t, IH3 J=7.2 Hz), 3.32-3.13 (m, 2H), 2.81 (t, 2H, J=7.4 Hz), 1.76-1.63 (h, 6H, 7=7.4 Hz), 0.97 (t, 3H3 J-7.3 Hz).
Figure imgf000115_0002
4-((5)-2-(5-Benzyl-l,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4- yl)ethyl)phenylsulfamic acid: 1H (CD3OD): δ (m, 2H), 7.49-7.45 (m, 2H), 7.26-7.16 (m, 5H), 7.05-6.94 (m, 6H), 5.04 (t, IH5 J=7.1 Hz), 4.07 (s, 2H), 3.22-3.04 (m, 2H).
Figure imgf000115_0003
4-((5)-2-(5-(Naphthalen- 1 -ylmethyl)- 1 ,3 ,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2- yl)thiazol-4-yl)ethyl)phenylsulfamic acid: 1H (CD3OD): δ 8.08-8.05 (m, IH), 7.89-7.80 (m, 2H), 7.55-7.43 (m, 6H)3 7.11-7.00 (m, 6H)5 5.08 (t, IH, j=7.1 Hz), 4.63 (s, 2H), 3.26-3.08 (m3 2H).
Figure imgf000116_0001
4-((5)-2-(5-((Methoxycarbonyl)methyl)-l,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2- yl)thiazol-4-yl)ethyl)phenylsulfamic acid: 1H(CD3OD): δ 7.48-7.44 (m, 2H), 7.03-6.92 (m, 6H), 5.02 (t, IH, J=7.2 Hz), 4.30 (s, 2H), 3.55 (s, 3H), 3.22-3.02 (m, 2H).
Figure imgf000116_0002
4-((5)-2-(5-((2-Methylthiazol-4-yl)methyl)-l,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2- yl)thiazol-4-yl)ethyl)phenylsulfamic acid: 1H(CD3OD): δ 7.60-7.56 (m, 2H), 7.19 (s, IH), 7.15- 7.12 (m, 2H), 7.09-7.03 (q, 4H, J=8.7 Hz), 5.14 (t, IH, J=7.2 Hz), 4.28 (s, 2H), 3.33-3.14 (m, 2H), 2.67 (s, 3H).
Figure imgf000116_0003
4-{(5)-2-[4-(2,4-Difluorophenyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)thiazol-4- yl]ethyl}phenylsulfamic acid: 1H (CD3OD): δ 8.06-8.02 (q, IH, J=6.8 Hz), 7.59-7.54 (m, 2H), 7.16-7.08 (m, 6H), 7.01-6.88 (m, 4H), 5.20 (t, IH, J=7.0 Hz), 3.36-3.17 (m, 2H).
Figure imgf000116_0004
(jS)-4-{2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4- yl)ethyl}phenylsulfamic acid: 1H (CD3OD): δ 8.02-7.99 (m, 2H), 7.54-7.45 (m, 4H), 7.26 (s, IH), 7.08 (s, 4H), 5.26 (t, 1H, J=6.9 Hz), 4.35-4.28 (q, 2H3 j=6.9 Hz), 3.38-3.18 (m, 2H), 1.36 (t, 3H, J=7.2 Hz).
Figure imgf000117_0001
(5)-4-{2-[4-(2-Ethoxy-2-oxoethyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4- yl)ethyl}phenylsulfamic acid: 1H (CD3OD): δ 7.96 (m, 2H), 7.50-7.46 (m, 3H), 7.21 (s, IH), 7.10-7.04 (m, 4H), 6.37 (s, IH), 5.09 (t, IH, J=6.9 Hz), 4.17-4.10 (q, 2H, J=I Λ Hz), 3.54 (s, 2H), 3.35-3.14 (m, 2H), 1.22 (t, 3H, J=7.1 Hz).
Figure imgf000117_0002
(i!»)-4-{2-[4-(4-acetaniidophenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4- yl)ethyl}phenylsulfamic acid: 1H (CD3OD): δ 8.11 (m, 2H), 7.82-7.80 (m, 2H)3 7.71-7.61 (m, . 6H), 7.40 (s, IH), 7.23 (s, 4H), 5.32 (t, IH, J=7.0 Hz), 3.51-3.35 (m, 2H), 2.28 (s, 3H).
Figure imgf000117_0003
(S)-4-[2-(4-phenylthiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]phenyl-sulfaniic acid: 1H (CD3OD): δ 8.03-7.99 (m, 2H), 7.75-7.72 (d, 2H, J=8.4 Hz), 7.53-7.48 (m, 3H)5 7.42 (m, 4H), 7.12 (s, 4H), 6.86 (s, IH), 5.23 (t, IH, J=7.2 Hz), 3.40-3.27 (m, 2H).
Figure imgf000117_0004
(5)-4-{2-[4-(4-(methoxycarbonyl)phenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4- yl)ethyl}phenylsulfaτnic acid: 1H (CD3OD): δ 8.04-8.00 (m, 4H)5 7.92-7.89 (d, 2H, J=9.0 Hz), 7.53-7.49 (m, 3H), 7.30 (s, IH), 7.15 (s, 4H)5 7.05 (s, IH), 5.28 (t, 1H, J=6.9 Hz)5 3.93 (s, 3H)5 3.35-3.24 (m, 2H).
Figure imgf000118_0001
4-{(S)-2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)thiazol-4- yl]ethyl}phenylsulfamic acid: 1H (CD3OD): 67.43-7.38 (m, 2H), 7.26 (s, IH), 7.00-6.94 (m, 3H)5 6.89 (s, 4H)5 5.02 (t, IH5 J=7.0 Hz), 4.16-4.09 (q, 2H, J=7.1 Hz), 3.14-2.94 (m, 2H)5 1.17 (t5 3H, J=7.1 Hz).
Figure imgf000118_0002
(1S)-4-[2-(4-(Methoxycarbonyl)thiazol-5-ylamino)-2-(2-phenylthiazole-4- yl)ethyl]phenylsulfamic acid: 1H NMR (300 MHz, MeOH-d,,) δ 7.97-8.00 (m, 3H)5 7.48-7.52 (m, 3H)5 7.22 (s, IH), 7.03-7.13 (m, 4H)5 4.74 (t, J= 6.6 Hz5 IH)3 3.88 (s, 3H)5 3.28-3.42 (m, 2H).
Figure imgf000118_0003
(5)-4-[2-(5-Phenyloxazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]-phenylsulfamic acid: 1H NMR (300 MHz5 MeOH-d4) δ 7.94-7.96 (m, 2H)5 7.45-7.49 (m, 5H)5 7.32 (t5 J= 7.8 Hz5 2H)5 7.12 (s, IH), 7.19 (t, J= 7.2 Hz, IH), 7.12 (s, 4H), 7.05 (s, IH), 5.15 (t, J= 6.4 Hz5 IH)5 3.34 (dd, J= 14.1 and 8.4 Hz, IH)5 3.18 (dd, J= 14.1 and 8.4 Hz5 IH).
Figure imgf000119_0001
(5)-4-{2-[5-(4-Acetamidophenyl)oxazol-2-ylamino]-2-(2-phenylthiazol-4- yl)ethyl}phenylsulfamic acid: 1H NMR (300 MHz3 MeOH-d4) δ 7.92-7.94 (m, 2H), 7.55-7.58 (m, 2H)5 7.39-7.50 (m, 5H), 7.26 (s, IH)5 7.12 (s, 4H), 7.02 (s, IHO), 5.14 (t, J= 7.8 Hz, IH), 3.13-3.38 (m, 2H), 2.11 (s, 3H).
Figure imgf000119_0002
4-((.S)-2-(5-(2,4-Difluorophenyl)oxazole-2-ylamino)-2-(2-phenylthiazole-4- yl)ethyl)phenylsulfamic acid: 1H NMR (300 MHz5 MeOH-U4) δ 7.97-7.99 (m, 2H)3 7.54-7.62 (m, IH), 7.45-7.50 (m, 3H), 7.28 (s, IH), 7.12 (s, 4H), 6.97-7.06 (m, 3H), 5.15- 5.20 (m, IH), 3.28-3.40 (m, IH)3 3.20 (dd, J= 13.8 and 8.4 Hz, IH).
Figure imgf000119_0003
4-{(5)-2-[5-(3-Methoxyphenyl)oxazol-2-ylamino]-2-[(2-thiophen-2-yl)thiazole-4- yl]ethyl}phenylsulfamic acid: 1H NMR (300 MHz, MeOH-d4) δ 7.55-7.60 (m, 2H), 7.26 (t, J = 8.1 Hz, IH), 7.21 (s, IH)3 7.04-7.15 (m, 8H), 6.77-6.81 (m, IH)3 5.10 (t, J= 6.3 Hz, IH), 3.81 (s, 3H), 3.29-3.36(m, IH), 3.15 (dd, J= 14.1 and 8.4 Hz, IH).
Figure imgf000119_0004
(5)-4-[2-(4,6-Dimethylpyrimidin-2-ylamino)-2-(2-methylthiazole-4- yl)ethyl]phenylsulfamic acid: 1H NMR (300 MHz, MeOH-d4) δ 7.00-7.10 (m, 5H), 6.44 (s, IH), 5.50 (t, J= 7.2 Hz, IH), 3.04-3.22 (m, 2H), 2.73 (s, 3H), 2.27 (s, 6H).
Figure imgf000120_0001
(iS)-4-[2-(4-Hydroxy-6-methylpyrimidine-2-ylamino)-2-(2-methylthiazole-4- yl)ethyl]phenylsulfamic acid: 1H NMR (300 MHz, MeOH-d4) δ 7.44 (d, J= 8.4Hz,2H), 6.97-7.10 (m, 4H), 5.61 (s, IH), 5.40-5.49 (m, IH), 3.10-3.22 (m, 2H), 2.73 (s, 3H) , 2.13 (s, 3H).
The first aspect of Category VI of the present disclosure relates to compounds having the formula:
Figure imgf000120_0002
wherein R1 is heteroaryl and R4 is further described herein below in Table XI.
TABLE XI
Figure imgf000120_0003
Figure imgf000121_0001
Figure imgf000122_0003
Compounds according to the first aspect of Category VI .can be prepared by the procedure outlined in Scheme XVI and described herein below in Example 16.
Scheme XVI
Figure imgf000122_0001
47
Reagents and conditions: (a) CH3CN; reflux 2hr.
Figure imgf000122_0002
47 48
Reagents and conditions: (b) (3-Cl)C6H4CO2H, EDCI, HOBt5 DIPEA, DMF; rt, 18 hr.
Figure imgf000123_0001
48 49
Reagents and conditions: (c) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH, it, 18 hr.
EXAMPLE 16
4-((S)-2-(2-(3-Chlorophenyl)acetamido)-2-(2-(thiophene-2-yl)oxazol-4-yl)ethyl)phenylsulfamic acid (49)
Preparation of (5)-2-(4-nitrophenyl)-l -[(thiophene-2-yl)oxazol-4-yl]ethanamine hydrobromide salt (47): A mixture of (S)-tert-butyl 4-bromo-l -(4-nitrophenyl)-3-oxobutan-2- ylcarbamate, 7, (38.7 g, 100 mmol), and thiophene-2-carboxamide (14 g, 110 mmol) (available from Alfa Aesar) in CH3CN (500 mL) is refiuxed for 5 hours. The reaction mixture is cooled to room temperature and diethyl ether (200 mL) is added to the solution. The precipitate which forms is collected by filtration. The solid is dried under vacuum to afford the desired product which can be used for the next step without purification.
Preparation of 2-(3-chlorophenyl)-N-{(-S)-2-(4-nitrophenyl)-l-[2-(thiophene-2-yl)oxazol- 4-yl]ethyl}acetamide (48): To a solution of (5)-2-(4-nitrophenyl)-l-[(thiophene-2-yl)oxazol-4- yl]ethanamine HBr, 47, (3.15 g, 10 mmol) 3-chlorophenyl-acetic acid (1.70 g, 10 mmol) and 1- hydroxybenzotriazole (HOBt) (0.7Og, 5.0 mmol) in DMF ( 50 mL) at 0 0C, is added l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.90 g, 10 mmol) followed by triethylamine (4.2 mL, 30 mmol). The mixture is stirred at 0 0C 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 HCl, 5 % aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford the desired product which is used without further purification. Preparation of-((5r)-2-(2-(3-chlorophenyl)acetamido)-2-(2-(thiophene-2-yl)oxazol-4- yl)ethyl)phenylsulfamic acid (49): 2-(3-chlorophenyl)-7V-{(»S)-2-(4-nitrophenyl)-l-[2-(thiophene- 2-yl)oxazol-4-yl]ethyl}acetamide, 48, (3 g) is dissolved in MeOH (4 mL). 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 CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SO3- pyridine (0.157 g). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH4OH is added. The mixture is then concentrated and the resulting residue can be purified- by reverse phase chromatography to afford the desired product as the ammonium salt.
The second aspect of Category VI of the present disclosure relates to compounds having the formula:
Figure imgf000124_0001
wherein R1 is aryl and R2 and R3 are further described herein below in Table XII.
TABLE XII
Figure imgf000124_0002
Figure imgf000125_0002
Compounds according to the second aspect of Category VI .can be prepared by the procedure outlined in Scheme XVII and described herein below in Example 17.
Scheme XVII
Figure imgf000125_0001
50
Reagents and conditions: (a) CH3CN; reflux, 2 hr.
Figure imgf000126_0001
50 51
Reagents and conditions: (b) C6H4CO2H, EDCI, HOBt5 DIPEA, DMF; rt, 18 hr.
Figure imgf000126_0002
51 52
Reagents and conditions: (c) (i) H2:Pd/C, MeOH; (ii) SO3-pyridine, NH4OH, rt, 18 hr.
EXAMPLE 17
{4-[2-(5)-(4-Ethyloxazol-2-yl)-2-phenylacetylaminoethyl] -phenyl} sulfamic acid (52)
Preparation of (5)-l-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethanamine (50): A mixture of [l-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-butyl ester, 1, (1O g, 32.3τnmol) and 1 -bromo-2-butanone (90%, 4.1 mL, 36 mmol) in CH3CN (500 mL) is refluxed for 18 hours. The reaction mixture is cooled to room temperature and diethyl ether is added to the solution and the precipitate which forms is removed by filtration and is used without further purification.
Preparation of iV-[l-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide (51): To a solution of (5)-l-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethanamine, 50, (2.9 g, 11 mmol), phenylacetic acid (1.90 g, 14 mmol) and 1-hydroxybenzotriazole (HOBt) (0.94 g, 7.0 mmol) in DMF ( 100 mL) at 0 ° C, is added l-(3-dimethylamino-propyl)-3-ethylcarbodiimide (EDCI) (2.68g, 14 mmol) followed by triethylamine (6.0 mL, 42mmol). The mixture is stirred at 0 0C 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 HCl, 5 % aqueous NaHCO3, water and brine, and dried over Na2Sθ4. The solvent is removed in vacuo to afford the desired product which is used without further purification.
Preparation of {4-[2-(5)-(4-ethyloxazol-2-yl)-2-phenylacetylaminoethyl]- phenyl} sulfamic acid (52): N-[l-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl- acetamide, 51, (0.260 g) is dissolved in MeOH (4 mL). 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 CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with Sθ3-pyridine (0.177 g, 1.23). The reaction is stirred at room temperature for 5 minutes after which a 7% solution OfNH4OH (10 mL) is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford the desired product as the ammonium salt.
Regulation of HPTP-β provides a method for modulating the activity of angiopoietin receptor-type tyrosine kinase Tie-2, and thereby mediate, affect, or otherwise control disease states related to angiogenesis wherein angiogenesis is improperly regulated by the human body. The compounds of the present disclosure serve as a method for providing regulation of angiogenesis. As such the present disclosure addresses several unmet medical needs, inter alia;
1 ) Providing compositions effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors; and thereby providing a method for regulating angiogenesis in a disorder wherein angiogenesis is elevated;
2) Providing compositions effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors; and thereby providing a method for regulating angiogenesis in a disorder; and
3) Providing compositions effective human protein tyrosine phosphatase beta (HPTP-β) inhibitors; and thereby providing a method for regulating angiogenesis in a disorder wherein angiogenesis is decreased. For purposes of the present disclosure the term "regulate" is defined as including, but is not limited to, up-regulate or down-regulate, to fix, to bring order or uniformity, to govern, or to direct by various means. In one aspect, an antibody may be used in a method for the treatment of an "angiogenesis elevated disorder" or "angiogenesis reduced disorder". As used herein, an "angiogenesis elevated disorder" is one that involves unwanted or elevated angiogenesis in the biological manifestation of the disease, disorder, and/or condition; in the biological cascade leading to the disorder; or as a symptom of the disorder. Similarly, the "angiogenesis reduced disorder" is one that involves wanted or reduced angiogenesis in the biological manifestations. This "involvement" of angiogenesis in an angiogenesis elevated/reduced disorder includes, but is not limited to, the following:
1. The angiogenesis as a "cause" of the disorder or biological manifestation, whether the level of angiogenesis is elevated or reduced genetically, by infection, by autoimmunity, trauma, biomechanical causes, lifestyle, or by some other causes.
2. The angiogenesis as part of the observable manifestation of the disease or disorder. That is, the disease or disorder is measurable in terms of the increased or reduced angiogenesis. From a clinical standpoint, angiogenesis indicates the disease; however, angiogenesis need not be the "hallmark" of the disease or disorder.
3. The angiogenesis is part of the biochemical or cellular cascade that results in the disease or disorder. In this respect, regulation of angiogenesis may interrupt the cascade, and may control the disease. Non-limiting examples of angiogenesis regulated disorders that may be treated by the present disclosure are herein described below.
FORMULATIONS
The present disclosure also relates to compositions or formulations that comprise one or more human protein tyrosine phosphatase beta (HPTP-β) inhibitors as disclosed herein. In general, the disclosed compositions comprise: a) an effective amount of one or more phenylsufamic acids or salts thereof according to the present disclosure that are effective as human protein tyrosine phosphatase beta (HPTP-p) inhibitors; and b) one or more excipients. For the purposes of the present disclosure the term "excipient" and "carrier" are used interchangeably throughout the description of the present disclosure and said terms are defined herein as, "ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition."
The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present disclosure have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.
Non-limiting examples of disclosed compositions include: a) from about 0.001 mg to about 1000 mg of one or more phenylsulfamic acids or salts thereof according to the present disclosure; and b) one or more excipients.
Another example of disclosed compositions includes: a) from about 0.01 mg to about 100 mg of one or more phenylsulfamic acids or salts thereof according to the present disclosure; and b) one or more excipients.
A further example of disclosed compositions includes: a) from about 0.1 mg to about 10 mg of one or more phenylsulfamic acids or salts thereof according to the present disclosure; and b) one or more excipients.
The term "effective amount" as used herein means "an amount of one or more phenylsulfamic acids, effective at dosages and for periods of time necessary to achieve the desired or therapeutic result." An effective amount may vary according to factors known in the art, such as the disease state, age, sex, and weight of the human or animal being treated. Although particular dosage regimes may be described in examples herein, a person skilled in the art would appreciated that the dosage regime may be altered to provide optimum therapeutic response. Thus, it is not possible to specify an exact "effective amount." For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. In addition, the compositions of the present disclosure can be administered as frequently as necessary to achieve a therapeutic amount.
METHOD OF USE
The present disclosure relates to methods for regulating angiogenesis in a human comprising administering to a human one or more of the disclosed compounds.
One example of the disclosed methods includes a method for treating an angiogenesis regulated disorder in a subject, wherein the angiogenesis regulated disorder is an angiogenesis elevated disorder, and said disorder is chosen from diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein ■ occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, EaI es1 disease, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, trauma and post-laser complications, diseases associated with rubeosis, and proliferative vitreoretinopathy.
Another example of the disclosed methods includes a method for treating an angiogenesis regulated disorder in a subject, wherein the angiogenesis regulated disorder is an angiogenesis elevated disorder, and said disorder is chosen from inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Osler-Weber-Rendu disease, or hereditary hemorrhagic telangiectasia, solid or blood borne tumors and acquired immune deficiency syndrome.
A further example of the disclosed methods includes a method for treating an angiogenesis regulated disorder in a subject wherein the angiogenesis regulated disorder is an angiogenesis reduced disorder and chosen from skeletal muscle and myocardial ischemia, stroke, coronary artery disease, peripheral vascular disease, coronary artery disease.
A yet further example of the disclosed methods includes a method of vascularizing ischemic tissue. As used herein, "ischemic tissue," means tissue that is deprived of adequate blood flow. Examples of ischemic tissue include, but are not limited to, tissue that lack adequate blood supply resulting from myocardial and cerebral infarctions, mesenteric or limb ischemia, or the result of a vascular occlusion or stenosis. In one example, the interruption of the supply of oxygenated blood may be caused by a vascular occlusion. Such vascular occlusion may be caused by arteriosclerosis, trauma, surgical procedures, disease, and/or other etiologies. Also included within the methods of treatment of the present disclosure is the treatment of skeletal muscle and myocardial ischemia, stroke, coronary artery disease, peripheral vascular disease, coronary artery disease.
A still further example of the disclosed methods includes a method of repairing tissue. As used herein, "repairing tissue" means promoting tissue repair, regeneration, growth, and/or maintenance including, but not limited to, wound repair or tissue engineering. One skilled in the art appreciates that new blood vessel formation is required for tissue repair. In turn, tissue may be damaged by, including, but not limited to, traumatic injuries or conditions including arthritis, osteoporosis and other skeletal disorders, and burns. Tissue may also be damaged by injuries due to surgical procedures, irradiation, laceration, toxic chemicals, viral infection or bacterial infections, or burns. Tissue in need of repair also includes non-healing wounds. Examples of non-healing wounds include non-healing skin ulcers resulting from diabetic pathology; or fractures that do not heal readily.
The disclosed compounds are also suitable for use in effecting tissue repair in the context of guided tissue regeneration (GTR) procedures. Such procedures are currently used by those skilled in the arts to accelerate wound healing following invasive surgical procedures.
A yet still further example of the disclosed methods includes a method of promoting tissue repair characterized by enhanced tissue growth during the process of tissue engineering. As used herein, "tissue engineering" is defined as the creation, design, and fabrication of biological prosthetic devices, in combination with synthetic or natural materials, for the augmentation or replacement of body tissues and organs. Thus, the present methods may be used to augment the design and growth of human tissues outside the body for later implantation in the repair or replacement of diseased tissues. For example, antibodies may be useful in promoting the growth of skin graft replacements that are used as a therapy in the treatment of burns. Other examples of the tissue engineering example of the disclosed methods includes in cell-containing or cell-free devices that induce the regeneration of functional human tissues when implanted at a site that requires regeneration. As discussed herein, biomaterial-guided tissue regeneration may be used to promote bone re-growth in, for example, periodontal disease. Thus, antibodies may be used to promote the growth of reconstituted tissues assembled into three-dimensional configurations at the site of a wound or other tissue in need of such repair.
A yet further example of the tissue engineering example of the disclosed methods, the compounds disclosed herein can be included in external or internal devices containing human tissues designed to replace the function of diseased internal tissues. This approach involves isolating cells from the body, placing them with structural matrices, and implanting the new system inside the body or using the system outside the body. For example, antibodies may be included in a cell-lined vascular graft to promote the growth of the cells contained in the graft. It is envisioned that the methods of the disclosure may be used to augment tissue repair, regeneration and engineering in products such as cartilage and bone, central nervous system tissues, muscle, liver, and pancreatic islet (insulin-producing) cells.
The present disclosure also relates to the use of the disclosed phenylsulfamic acids in the manufacture of a medicament for promoting the growth of skin graft replacements.
The present disclosure also relates to the use of the disclosed phenylsulfamic acids according to the present disclosure in the manufacture of a medicament for use in effecting tissue repair in the context of guided tissue regeneration (GTR) procedures.
The disclosed compounds can be used in the manufacture of one or more medicaments, non-limiting examples of these medicaments are: l
Medicaments for the treatment an angiogenesis regulated disorder in a subject, wherein the angiogenesis regulated disorder is an angiogenesis elevated disorder.
Medicaments for the treatment an angiogenesis regulated disorder in a subject, wherein the angiogenesis regulated disorder is an angiogenesis elevated disorder chosen from Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Osler- Weber-Rendu disease, or hereditary hemorrhagic telangiectasia, solid or blood borne tumors and acquired immune deficiency syndrome.
Medicaments useful for the purposes of tissue engineering thereby inducing enhanced tissue growth. Medicaments for the treatment an angiogenesis regulated disorder in a subject, wherein the angiogenesis regulated disorder is an angiogenesis reduced disorder.
PROCEDURES Screening Assays using in vitro and in vivo models of angiogenesis
Antibodies of the disclosed compounds maybe screened in angiogenesis assays that are known in the art. Such assays include in vitro assays that measure surrogates of blood vessel growth in cultured cells or formation of vascular structures from tissue explants and in vivo assays that measure blood vessel growth directly or indirectly (Auerbach,R., et al. (2003). Clin Chem 49, 32-40, Vailhe,B., et al. (2001). Lab Invest 81, 439-452).
1. In vitro models of angiogenesis
The in vitro models which are suitable for use in the present disclosure employ cultured endothelial cells or tissue explants and measure the effect of agents on "angiogenic" cell responses or on the formation of blood capillary-like structures. Non-limiting examples of in vitro angiogenesis assays include but are not limited to endothelial cell migration and proliferation, capillary tube formation, endothelial sprouting, the aortic ring explant assay and the chick aortic arch assay.
2. In vivo models of angiogenesis
The in vivo agents or antibodies which are suitable for use in the present disclosure are administered locally or systemically in the presence or absence of growth factors (i.e. VEGF or angiopoietin 1) and new blood vessel growth is measured by direct observation or by measuring a surrogate marker such as hemoglobin content or a fluorescent indicator. Non-limiting examples of in vitro angiogenesis assays include but are not limited to chick chorioallantoic membrane assay, the corneal angiogenesis assay, and the MATRIGEL™ plug assay.
3. Procedures for Determining Vascularization of Ischemic Tissue.
Standard routine techniques are available to determine if a tissue is at risk of suffering ischemic damage from undesirable vascular occlusion. For example, in myocardial disease these methods include a variety of imaging techniques (e.g., radiotracer methodologies, x-ray, and MRI) and physiological tests. Therefore, induction of angiogenesis as an effective means of preventing or attenuating ischemia in tissues affected by or at risk of being affected by a vascular occlusion can be readily determined.
A person skilled in the art of using standard techniques can measure the vascularization of tissue. Non-limiting examples of measuring vascularization in a subject include SPECT (single photon emission computed tomography); PET (positron emission tomography); MRI (magnetic resonance imaging); and combination thereof, by measuring blood flow to tissue before and after treatment. Angiography maybe used as.an assessment of macroscopic vascularity. Histologic evaluation may be used to quantify vascularity at the small vessel level. These and other techniques are discussed in Simons, et al., "Clinical trials in coronary angiogenesis," Circulation, 102, 73-86 (2000).
The following are non-limiting examples of HPTPβ (IC5O μM) and PTPlB (IC50 μM) activity is listed herein below in Table A.
TABLE A
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
The dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as "40 mm" is intended to mean "about 40 mm."
All documents cited in the Detailed Description of the Invention are, in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention. To the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.
While particular embodiments of the present disclosure have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this disclosure.

Claims

WHAT IS CLAIMED IS:
1. A compound having the formula:
Figure imgf000140_0001
wherein R is a substituted or unsubstituted thiazolyl unit having the formula:
Figure imgf000140_0002
R2 and R3 are each independently chosen from: i) hydrogen; ii) substituted or unsubstituted Cj-C6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv) substituted or unsubstituted heteroaryl; or
R2 and R3 can be taken together to form a saturated or unsaturated ring having from 5 to
7 atoms; said substitutions are independently chosen from one or more Ci-C6 linear, branched, or cyclic alkyl, halogen, hydroxyl, or cyano units;
R4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-C6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; and iv) substituted or unsubstituted heteroaryl;
Z is a unit having the formula: (L)-R1
R1 is chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-C6 linear, branched or cyclic alkyl; iii) substituted or unsubstituted aryl; iv) substituted or unsubstituted heterocyclic rings; or v) substituted or unsubstituted heteroaryl rings;
L is a linking unit chosen from: i) -C(O)NH[C(R53R513)]^-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O>-; iv) -SO2[C(R8aR8b)]z-;
R5a, R5b, R6a, R6b, R7a, R7b, R8a, and R8b are each independently: i) hydrogen; ii) C1-C4 substituted or unsubstituted linear or branched alkyl; iii) substituted or unsubstituted aryl; iv) substituted or unsubstituted heterocyclic rings; v) substituted or unsubstituted heteroaryl rings; the index n is 0 or 1 ; the indices w, x, y, and z are each independently from 1 to 4.
2. A compound according to Claim 1 wherein R has the formula:
Figure imgf000141_0001
3. A compound according to Claim 2 wherein R2 and R3 are each hydrogen or substituted or unsubstituted Ci-C6 linear, branched, or cyclic alkyl.
4. A compound according to Claim 3 wherein R2 is chosen from methyl, ethyl, n-propyl, wσ-propyl, n-butyl, wo-butyl, sec-butyl, and tert-bυtyl; and R3 is hydrogen.
5. A compound according to Claim 4 wherein R2 is methyl or ethyl.
6. A compound according to Claim 2 wherein R2 is substituted or unsubstituted phenyl and R3 is hydrogen.
7. A compound according to Claim 2 wherein R2 is substituted or unsubstituted heteroaryl and R3 is hydrogen.
8. A compound according to Claim 7 wherein R2 is a heteroaryl unit chosen from 1,2,3,4- tetrazol-1-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, pyτrol-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, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [l,2,4]thiadiazol-3-yl, [l,2,4]thiadiazol-5-yl, and [l,3,4]thiadiazol-2-yl.
9. A compound according to Claim 8 wherein R2 is thiophene-2-yl or thiophene-3-yl.
10. A compound according to Claim 1 wherein R has the formula:
Figure imgf000142_0001
1 1. A compound according to Claim 10 wherein R4 is hydrogen or substituted or unsubstituted Ci-Cβ linear, branched, or cyclic alkyl.
12. A compound according to Claim 11 wherein R4 is chosen from methyl, ethyl, n-propyl, iso-pτopyl, n-butyl, iso-butyl, sec-butyl, and (ert-butyl; and R3 is hydrogen.
13. A compound according to Claim 12 wherein R4 is methyl or ethyl.
14. A compound according to Claim 10 wherein R4 is substituted or unsubstituted phenyl and R3 is hydrogen.
15. A compound according to Claim 10 wherein R4 is substituted or unsubstituted heteroaryl.
16. A compound according to Claim 15 wherein R2 is a heteroaryl unit chosen from 1 ,2,3,4- tetrazol-1-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, furan-3-yl, thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [l,2,4]thiadiazol-3-yl, [l,2,4]thiadiazol-5-yl, and [l,3,4]thiadiazol-2-yl.
17. A compound according to Claim 16 wherein R4 is thiophene-2-yl or thiophene-3-yl.
18. A compound according to Claim 1 wherein L has the formula:
Figure imgf000143_0001
R6a is hydrogen, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl; the index x is 1 or 2.
19. A compound according to Claim 18 wherein R1 is chosen from phenyl, 2-fluorophenyl, - 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5- difluorophenyl, 2-chlorophenyl, 3-chlorophenyϊ, 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.
20. A compound according to Claim 19 wherein R has the formula:
Figure imgf000143_0002
21. A compound according to Claim 20 wherein R2 is methyl or ethyl, R3 is hydrogen, and L has the formula -C(O)CH2-.
22. A compound according to Claim 20 wherein R2 is methyl or ethyl, R3 is hydrogen, and L has the formula -C(O)CH2CH2-.
23. A compound according to Claim 19 wherein R has the formula:
Figure imgf000144_0001
24. A compound according to Claim 23 wherein R4 is methyl, ethyl, phenyl, thiophene-2-yl, thiazol-2-yl, oxazol-2-yl, and isoxazol-3-yl; and L has the formula — C(O)CH2— .
25. A compound according to Claim 23 wherein R4 is methyl, ethyl, phenyl, thiophene-2-yl, thiazol-2-yl, oxazol-2-yl, and isoxazol-3-yl; and L has the formula — C(O)CHaCH2-.
26. A compound according to Claim 1 wherein R1 is a substituted or unsubstituted heteroaryl unit, said substitutions chosen from: i) Cj-C6 linear, branched, and cyclic alkyl; ii) substituted or unsubstituted phenyl and benzyl; iii) substituted of unsubstituted heteroaryl; iv) -C(O)R9; and v) -NHC(O)R9;
R9 is Ci-Ce linear and branched alkyl; Ci-C6 linear and branched alkoxy; or —
NHCH2C(O)R10; R10 is chosen from hydrogen, methyl, ethyl, and tert-butyl.
27. A compound according to Claim 26 wherein said R1 substituted or unsubstituted heteroaryl unit is substituted by an alkyl unit chosen from methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.
28. A compound according to Claim 26 wherein said R1 substituted or unsubstituted heteroaryl unit is substituted by substituted or unsubstituted phenyl and benzyl, said phenyl and benzyl substitutions are chosen from one or more: i) halogen; ii) Ci-C3 alkyl; iii) C1-C3 alkoxy; iv) -CO2R11; and v) -NHCOR12; wherein R1 ' and R12 are each independently hydrogen, methyl, or ethyl.
29. A compound according to Claim 26 wherein said R1 substituted or unsubstituted heteroaryl unit is substituted by a carboxy unit having the formula -C(O)R9; R9 is chosen from methyl, methoxy, ethyl, and ethoxy.
30. A compound according to Claim 26 wherein said R1 substituted or unsubstituted heteroaryl unit is substituted by an amide unit having the formula -NHC(O)R9; R9 is chosen from methyl, methoxy, ethyl, ethoxy, tert-bvityl, and tert-butoxy.
31. A compound according to Claim 1 having the formula:
Figure imgf000145_0001
wherein R2 is methyl or ethyl, R3 is hydrogen, R6a is chosen from phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difiuorophenyl, 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.
32. A compound according to Claim 1 having the formula:
Figure imgf000145_0002
wherein R2 is methyl or ethyl, R3 is hydrogen, R6a is chosen from 3 -methyl- 1,2,4- oxadiazol-5-yl, thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and isoxazol-3-yl.
33. A compound according to Claim 1 having the formula:
Figure imgf000146_0001
wherein R4 is methyl, ethyl, phenyl, or thiophene-2-yl, R a is 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, A- hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3- dimethoxyphenyl, 3,4-dimethoxyphenyl, and 3,5-dimethoxyphenyl.
34. A compound according to Claim 1 having the formula:
Figure imgf000146_0002
wherein R4 is methyl, ethyl, phenyl, or thiophene-2-yl, R6a is chosen from 3-methyl- l,2,4-oxadiazol-5-yl, thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5- yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and isoxazol-3-yl.
35. A compound according to Claim 1 having the formula:
Figure imgf000146_0003
wherein R2 is chosen from methyl, ethyl, phenyl, and thiophene-2-yl, R3 is hydrogen or methyl; R1 is chosen from phenyl, thiophene-2-yl, thiophene-3-yl, thiazol-2-yl, thiazol-4- yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and isoxazol-3-yl.
36. A compound according to Claim 1 having the formula:
Figure imgf000147_0001
wherein R2 and R3 are each independently hydrogen, methyl or ethyl; R1 is chosen from phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4- difmorophenyl, 3,5-difluorophenyl, 2-chlorophenyl5 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.
37. A compound having the formula:
Figure imgf000147_0002
wherein L is -SO2[CH2]Z-; R4 is Ci-C4 linear of branched alkyl, or thiophene-2-yl; R1 is substituted or unsubstituted Ci-C6 linear, branched or cyclic alkyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl rings, the index z is 0, 1 or 2.
38. A compound according to Claim 37 wherein R1 is methyl, trifluoromethyl, ethyl, 2,2,2- trifluoroethyl, phenyl, 4-fluorophenyl, 4-acetamidophenyl, (4-methyl- carboxyphenyl)methyl, 3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl, l-methyl-l//- imidazol-4-yl, and (2-methylthiazol-4-yl)methyl.
39. A compound having the formula:
Figure imgf000148_0001
wherein R1 is a substituted or unsubstituted heteroaryl unit chosen from: i) 1 ,2,3,4-tetrazol-l-yl and 1 ,2,3,4-tetrazol-5-yl having the respective formulae:
Figure imgf000148_0002
ii) [l,2,3]triazol-4-yl, [l,2,3]triazol-5-yl, [l,2,4]triazol-4-yl, and [l,2,4]triazol-5-yl having the respective formulae:
Figure imgf000148_0003
iii) imidazol-2-yl and imidazol-4-yl having the respective formulae:
Figure imgf000148_0004
iv) pyrrol-2-yl and pyrrol-3-yl having the respective formulae:
Figure imgf000148_0005
v) oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl having the respective formulae:
vi)
vii)
Figure imgf000148_0006
viii) [l,3,4]oxadiazol-2-yl having the formula:
Figure imgf000149_0001
ix) furan-2-yl and furan-3-yl having the respective formulae:
Figure imgf000149_0002
x) thiophene-2-yl and thiophene-3-yl having the respective formulae:
Figure imgf000149_0003
xi) isothiazol-3-yl, isothiazol-4-yl and isothiazol-5-yl having the respective formulae:
xii)
Figure imgf000149_0004
xiii) [l,2,4]thiadiazol-3-yl and [l,2,4]thiadiazol-5-yl having the respective formulae:
Figure imgf000149_0005
said heteroaryl unit substitutions chosen from: i) Ci-C6 linear, branched, and cyclic alkyl; ii) substituted or unsubstituted phenyl and benzyl; iii) substituted of unsubstituted heteroaryl; iv) -C(O)R9; and v) -NHC(O)R9;
R9 is Ci-C6 linear and branched alkyl; C)-C6 linear and branched alkoxy; or NHCH2C(O)R10; R10 is chosen from hydrogen, methyl, ethyl, and tert-bυtyl; R4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted Ci-C6 linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; and iv) substituted or unsubstituted heteroaryl.
40. A compound according to Claim 39 wherein said R1 substituted or unsubstituted heteroaryl unit is substituted by an alkyl unit chosen from methyl, ethyl, n-propyl, iso- propyl, n-butyl, wo-butyl, sec-butyl, and tert-bυty\.
41. A compound according to Claim 39 wherein said R1 substituted or unsubstituted heteroaryl unit is substituted by substituted or unsubstituted phenyl and benzyl, said phenyl and benzyl substitutions are chosen from one or more: i) halogen; ii) C1-C3 alkyl; iii) Ci -C3 alkoxy; iv) -CO2R11; and v) -NHCOR12; wherein R! ' and R12 are each independently hydrogen, methyl, or ethyl.
42. A compound according to Claim 39 wherein said R1 substituted or unsubstituted heteroaryl unit is substituted by a carboxy unit having the formula -C(O)R9; R9 is chosen from methyl, methoxy, ethyl, and ethoxy.
43. A compound according to Claim 39 wherein said R1 substituted or unsubstituted heteroaryl unit is substituted by an amide unit having the formula -NHC(O)R9; F chosen from methyl, methoxy, ethyl, ethoxy, ter/-butyl, and tert-butoxy.
44. A compound according to Claim 39 wherein R1 is chosen from 4-(methoxy- carbonyl)thiazol-5-yI, 4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl, 5-[ 1 -7V-(2- methoxy-2-oxoethyl)-l -H-indol-3-yl]oxazol-2-yl, 5-(2-methoxyphenyl)oxazol-2-yl, 5- [(5)-l-(ter/-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl5 5-[4-(methyl- carboxy)phenyl]oxazol-2-yl, 5-(3-methoxybenzyl)oxazol-2-yl, 5-(4-phenyl)-oxazol-2-yl. 5-(2-methoxyphenyl)thiazol-2-yl, 5-(3-methoxyphenyl)thiazol-2-yl, 5-(4- fluorophenyl)thiazol-2-yl, 5-(2,4-difiuorophenyl)thiazol-2-yl, 5-(3-methoxy- benzyl)thiazol-2-yl, 4-(3-methoxyphenyl)thiazol-2-yl, and 4-(4-fluorophenyl)-thiazol-2- yi.
45. A compound according to Claim 39 wherein R4 is chosen from methyl, ethyl, cyclopropyl, phenyl, and thiophene-2-yl.
46. A compound chosen from:
(S)- {4-[2-(4-Ethylthiazol-2-yl)-2-phenylacetylaminoethyl]-phenyl } sulfamic acid; (,S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-fluorophenyl)acetamido)ethyl)phenyl-sulfamic acid; (AS)-4.(2-(4-Ethylthiazol-2-yl)-2-(2-(3-fluorophenyl)acetaniido)ethyl)phenyl-siιlfamic acid; (5)-4-(2-(2-(2,3-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid; (5r)-4-(2-(2-(3,4-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid; (5)-4-(2-(2-(2-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid; (-S)-4-(2-(2-(3-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid; (5)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)phenyl-sulfamic acid; (-S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-methoxyphenyl)acetamido)ethyl)phenyl-sulfamic acid; (5)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-methoxyphenyl)acetamido)ethyl)phenyl-sulfamic acid;
(iS)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-phenylpropanamido)ethyl)phenylsulfamic acid; (-S)-4-(2-(2-(3,4-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)- phenylsulfamic acid; (5)-4-(2-(2-(2,3-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)- phenylsulfamic acid; (iS}-4-(2-(3-(3-Chlorophenyl)propanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid; (,S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(2-methoxyphenyl)propanamido)ethyl)phenyl- sulfamic acid; (5)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(3-methoxyphenyl)proρanamido)ethyl)phenyl- sulfamic acid; (5)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(4-methoxyphenyl)propanamido)ethyl)phenyl- sulfamic acid; (_?)-4-{2-[2-(4-Ethyl-2,3-dioxopiperazin-l-yl)acetamide]-2-(4-ethylthiazol-2- yl)ethyl}phenylsulfamic acid; (5)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)- yl)acetamide]ethyl}phenylsulfamic acid; and (5)-4-[2-(Benzo[t/][l,33dioxole-5-carboxamido)-2-(4-ethylthiazol-2-yl)ethyl]- phenylsulfamic acid.
47. A compound chosen from:
4-((1S)-2-(2-(2-Chlorophenyl)acetamido)-2-(2-(thiophene2-yl)thiazol-4- yl)ethyl)phenylsulfamic acid; 4-((1S)-2-(2-(3-Methoxyphenyl)acetamido)-2-(2-(thiophene2-yl)thiazol-4-yl)ethyl)- phenylsulfamic acid; 4-{(5)-2-(3-Phenylpropanamido)-2-[2-(thiophene2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic acid; 4-{(,S)-2-(3-(3-Chlorophenyl)propanamido)-2-[2-(thiophene2-yl)thiazol-4- yl]ethyl}phenylsulfamic acid; 4-{(iS)-2-[2-(3-Fluorophenyl)acetamide]-2-[2-(thiopheaie2-yl)thiazol-4- yl]ethyl}phenylsulfamic acid; (5)-4-{2-[2-(2,5-Dimethylthiazol-4-yl)acetamide]-2-(4-ethylthiazol-2-yl]ethyl>- phenylsulfamic acid; (5)-4-{2-[2-(2,4-Dimethylthiazol-5-yl)acetamide]-2-(4-methylthiazoI-2- ylethyl}phenylsulfamic acid; (-S)-4-{2-(4-Ethylthiazol-2-yl)-2-[3-(thiazol-2-yl)propanamido]ethyl}phenyl-sulfamic acid; (5)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(4-ethylthiazol-2-yl)acetamide]ethyl}phenyl-sulfamic acid; (-S)-4-{2-[2-(3-Methyl-l,2,4-oxadiazol-5-yl)acetamide]-2-(2-phenylthiazol-4- yl)ethyl}phenylsulfamic acid; and 4- {(5)-2-[2-(4-Ethyl-2,3-dioxopiperazin- 1 -yl)acetamide]-2-[2-(thiophen-2-yl)thiazol-4- yl]ethyl}phenylsulfamic acid.
48. A compound chosen from:
(iS)-4-(2-(2,3-Diphenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamic acid; (iS)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(2-methoxyphenyl)-3-phenylpropanamido]- ethyl)phenylsulfamic acid; (5)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-fluorophenyl)-3-phenylpropanamido]- ethyl}phenylsulfamic acid; (-S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-methoxyphenyl)-3-phenylpropanamido]- ethyl} phenylsulfamic acid; 4-{(5)-2-(4-Ethylthiazol-2-yl)-2-[2-(3-methyl-l,2,4-oxadiazol-5-yl)-3- phenylpropanamido] ethyl } phenylsulfamic acid;
(5)-4-[2-(4-Ethylthiazol-2-yl)-2-(4-oxo-4-phenylbutanamido)-ethyl]phenylsulfamic acid; (1S)-4-(2-(4-Ethylthiazol-2-yl)-2-(5-methyl-4-oxohexanamido)ethyl)phenyl-sulfamic acid; (iS)-4-{2-[4-(3,4-Dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-4-oxobutanamido]-2-(4- ethylthiazol-2-yl)ethyl}phenylsulfamic acid; (-?)-4-{2-[4-(2,3-Dimethoxyphenyl)-4-oxobutanamido]-2-(4-ethylthiazol-2- yl)ethyl} phenylsulfamic acid; (S)-A- {2-(4-Ethylthiazol-2-yl)-2-[4-oxo-4-(pyridin-2-yl)butanamido]ethyl } - phenylsulfamic acid; (S)-4-{2-[4-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)-4-oxobutanamido]-2-(4-ethylthiazol-
2-yl)ethyl}phenylsulfamic acid; (5)-4-[2-(4-fert-Butoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenyl-sulfamic acid; (5)-4-[2-(4-Ethoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic acid;
(S)-4-(2-(3-Benzylureido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid;
4- {[(S)-2-(2-Ethylthiazol-4-yl)-2-(3-CK)- 1 methoxy- 1 -oxo-3-phenylpropan-2- yl)ureido]ethyl}phenylsulfamic acid; and 4-{(5)-2-(3-Benzylureido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic acid.
49. A compound chosen from: {4-(5)-[2-Phenylmethanesulfonylamino-2-(2-thiophen-2-ylthiazol-4- yl)ethyl]phenyl} sulfamic acid; 4-{(S)-2-[(2-Methylthiazol-4-yl)methylsulfonamido]-2-[2-(thiophen-2-yl)thiazol-4- yl]ethyl}phenylsulfamic acid; {4-(5)-[2-Phenylmethanesulfonylamino-2-(2-ethylthiazol-4-yl)ethyl]phenyl}-sulfamic acid; {4-(iS)-[2-(3-Methoxyphenyl)methanesulfonylamino-2-(2-ethylthiazol-4- yl)ethyl]phenyl} sulfamic acid; (6)-4-{[l-(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylsulfamoyl]methyl}-benzoic acid methyl ester; (,S)-4-[2-(2-Ethylthiazol-4-yl)-2-(l-methyl-lH'-imidazol-4-sulfonamido)ethyl]- phenylsulfamic acid; 4-{(5)-2-[2-(Thiophen-2-yl)thiazol-4-yl]-2-(2,2,2-trifluoroethylsulfonamido)- ethyl}phenylsulfamic acid; {4-(5)-[2-(Phenylethanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyl]- phenyl} sulfamic acid; {4-(iS)-[3-(Phenylpropanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyl]- phenyl} sulfamic acid; (S)- {4-[2-(4-Methyl-3 ,4-dihydro-2H-benzo[ 1 ,4]oxazine-7-sulfonylamino)-2-(2-thiophen-
2-ylthiazol-4-yl)ethyl]phenyl} sulfamic acid; and 4-{(5)-2-(4-Acetamidophenylsulfonamido)-2-[2-(thiophen-2-yl)thiazol-4- yl]ethyl}phenylsulfamic acid.
50. A compound chosen from: 4-{(S)-2-(2-cyclopropylthiazol-4-yl)-2-[4-(3-methoxyphenyl)-thiazol-2- ylamino]ethyl}phenylsulfamic acid; (5)-4-(2-(4-((2-Methoxy-2-oxoethyl)carbamoyl)thiazole-5-ylamino)2-(2-ethylthiazole-4- yl)ethyl)phenylsulfamic acid; 4-((5)-2-(5-(l-N-(2-Methoxy-2-oxoethyl)-l-H-indol-3-yl)oxazole-2-ylamino)-2-(2- methylthiazol-4-yl)ethyl))phenylsulfamic acid; 4-((S)-2-(5-(2-Methoxyphenyl)oxazol-2-ylamino)-2-(2-methylthiazol-4- yl)ethyl)phenylsulfamic acid; 4-((5)-2-(5-((-S)-l-(/ert-Butoxycarbonyl)-2-phenylethyl)oxazole-2-ylamino)-2-(2- methylthiazole-4-yl)ethyl)phenylsulfamic acid; (5)-4-(2-(5-(4-Methoxycarbonyl)phenyl)oxazole-2-ylamino)2-(2-methylthiazole-4- yl)ethyl)phenylsulfamic acid; (5)-4-(2-(5-(3-Methoxybenzyl)oxazole-2-ylamino)-2-(2-methylthiazole-4- yl)ethyl)phenylsulfamic acid; (5)-4-(2-(2-Methylthiazole-4-yl)2-(5-phenyloxazole-2-ylamino)ethyl)phenyl-sulfamic acid; 4-((S)-2-(2-Cyclopropylthiazol-4-yl)-2-(4-(3-methoxyphenyl)thiazol-2- ylamino)ethyl)phenylsulfamic acid; (5)-4-(2-(2-cycloρroρylthiazol-4-yl)-2-(4-(4-flυorophenyl)thiazol-2- ylamino)ethyl)phenylsulfamic acid; 4-((5)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2-methoxyphenyl)thiazol-2- ylamino)ethyl)phenylsulfamic acid; 4-((-S)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2,4-difluorophenyl)thiazol-2- ylamino)ethyl)phenylsulfamic acid; (-5)-4-(2-(4-(3-methoxybenzyl)thiazol-2-ylamino)-2-(2-cyclopropylthiazol-4- yl)ethyl)phenylsulfamic acid; (S)- {5-[ 1 -(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylamino]-2-methyl-2H-
[l,2,4]triazole-3-yl}carbamic acid methyl ester; 4-{(S)-2-[4-(2-Methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiophen-2-yl)thiazol-4- yl] ethyl }phenylsulfamic acid; 4-{(iS)-2-[5-(3-Methoxyphenyl)oxazole-2-ylamino]-2-(2-phenylthiazole-4- yl)ethyl}phenylsulfamic acid; 4-{(5)-2-[4-(2,4-Diflυorophenyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)thiazol-4- yl] ethyl }phenylsulfamic acid; (-S)-4-{2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4- yl)ethyl}phenylsulfamic acid; (-S)-4-{2-[4-(2-Ethoxy-2-oxoethyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4- yl)ethyl}phenylsulfamic acid; (<S)-4-{2-[4-(4-Acetamidophenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4- yl)ethyl}phenylsulfamic acid; (S)-4-[2-(4-Phenylthiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]phenyl-sυlfamic acid; (5)-4-{2-[4-(4-(Methoxycarbonyl)phenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4- yl)ethyl}phenylsulfamic acid; 4-{(S)-2-[4-(Ethoxycarbonyl)thiazol-2-ylaτnino]-2-[2-(thiophen-2-yl)thiazol-4- yl] ethyl }phenylsulfamic acid; (iS)-4-[2-(4-(Methoxycarbonyl)thiazol-5-ylamino)-2-(2-phenylthiazole-4- yl)ethyl]phenylsulfamic acid;
(5)-4-[2-(5-Phenyloxazole-2-ylamino)]-2-(2-phenylthiazole-4-yl)phenylsulfamic acid; (5)-4-{2-[5-(4-Acetamidophenyl)oxazole-2-ylamino]-2-(2-phenylthiazole-4- yl)ethyl}phenylsufamic acid; 4-((<S)-2-(5-(2,4-Difluorophenyl)oxazole-2-ylamino)-2-(2-phenylthiazole-4- yl)ethyl)phenylsυlfamic acid; 4-{(5)-2-[5-(3-Methoxyphenyl)oxazol-2-ylamino]-2-[(2-thiophen-2-yl)thiazole-4- yl] ethyl }phenylsulfamic acid; (jS)-4-[2-(4,6-Dimethylpyrimidene-2-ylamino)-2-(2-methylthiazole-4- yl)ethyl]phenylsulfamic acid; and (iS)-4-[2-(4-Hydroxy-6-methylpyrimidine-2-ylamino)-2-(2-methylthiazole-4- yl)ethyl]phenylsulfamic acid.
51. Composition comprising: A) one or more compounds according to Claim 1 , or a pharmaceutically acceptable salt thereof; and
B) one or more excipients or carriers.
52 A method for treating a disease chosen from from diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales1 disease, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, trauma and post-laser complications, diseases associated with rubeosis, and proliferative vitreoretinopathy comprising administering to a human a compound according to Claim 1.
53. A method for treating a disease , comprising administering to a human diagnosed as needing such treatment an amount of one or more compounds according to Claim 1, or a pharmaceutically effective salt thereof, in an amount effective to treat the disease, wherein the disease is chosen from Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas, Osier- Weber-Rendu disease, or hereditary hemorrhagic telangiectasia, solid or blood borne tumors and acquired immune deficiency syndrome.
54. A method for treating a disease , comprising administering to a human diagnosed as needing such treatment an amount of one or more compounds according to Claim 1, or a pharmaceutically effective salt thereof, in an amount effective to treat the disease, wherein the disease is chosen from skeletal muscle and myocardial ischemia, stroke, coronary artery disease, peripheral vascular disease, coronary artery disease.
55. A method for regulating angiogenesis in a human comprising administering to a human a compound according to Claim 1.
56. A method for vascularizing ischemic tissue in a human comprising administering to a human a compound according to Claim 1.
57. A method for promoting the growth of skin graft replacements comprising administering to a human a compound according to Claim 1.
58. A method for promoting tissue repair in the context of guided tissue regeneration (GTR) procedures comprising administering to a human a compound according to Claim 1.
59. A compound, or a pharmaceutically acceptable salt thereof, having the formula:
Figure imgf000158_0001
wherein R is chosen from: i) substituted or unsubstituted heterocyclic rings having from 5 to 10 ring atoms; or ii) substituted or unsubstituted heteroaryl rings having from 5 to 10 ring atoms; Z is a unit having the formula:
-(L)n-R1 R1 is chosen from: i) hydrogen; ii) substituted or unsubstituted linear, branched or cyclic alkyl; iii) substituted or unsubstituted aryl; iv) substituted or unsubstituted heterocyclic rings; or v) substituted or unsubstituted heteroaryl rings; L is a linking unit chosen from: i) -C(O)NH[C(R5aR5b)]w-; ii)
Figure imgf000158_0002
iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R88R8")]^; R5a, R5b, R6a, R6b, R7a, R7b, R8a, and R8b are each independently: i) hydrogen; ii) Ci -C4 substituted or unsubstituted linear or branched alkyl; iii) substituted or unsubstituted phenyl; iv) substituted or unsubstituted heterocyclic rings having from 5 to 10 ring atoms; or v) substituted or unsubstituted heteroaryl rings having from 5 to 10 ring atoms; the index n is 0 or 1 ; the indices w, x, y, and z are each independently from 1 to 4.
60. A compound according to Claim 59, wherein R is a 5-member heteroaryl ring.
61. A compound according to Claim 60, wherein R is chosen from pyrrolyl, pyrazolyl, imidazolyl, [l,2,3]triazolyl, 1,2,3,4-tetrazolyl, oxazolyl, isoxazolyl, [l,2,4]oxadiazolyl, [l,3,4]oxadiazolyl, furanyl, thiopheneyl, isothiazolyl, thiazolyl, [l,2,4]thiadiazolyl, and [1 ,3,4]thiadiazolyl.
62. A compound according to Claim 59, wherein R is a 5-member heterocyclic ring.
63. A compound according to Claim 62, wherein R is chosen from pyrrolidinyl, 4,5- dihydroimidazolyl, pyrrolidinonyl, imidazolidinonyl, lH-imidazol-2(3H)-only, imidazolidine-2,4-dionyl, thiazolidin-2-only, and 2-thioxothiazolidin-4-only.
61. A compound according to Claim 59, wherein R is a unit chosen from thiazolyl, imidazolyl, or oxazolyl.
62. A compound according to Claim 61 , wherein R has the formula:
Figure imgf000159_0001
wherein R2 and R3 are each independently chosen from: i) hydrogen; ii) substituted or unsubstituted linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv) substituted or unsubstituted heteroaryl; or
R2 and R3 can be taken together to form a saturated or unsaturated ring having from 5 to
7 atoms; the substitutions are independently chosen from one or more Ci-Ce linear, branched, or cyclic alkyl, halogen, hydroxyl, or cyano units.
63. A compound according to Claim 61, wherein R has the formula:
Figure imgf000160_0001
wherein R4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; and iv) substituted or unsubstituted heteroaryl; the substitutions are independently chosen from one or more Ci-C6 linear, branched, or cyclic alkyl, halogen, hydroxyl, or cyano units.
64. A compound according to Claim 61 , wherein R has the formula:
Figure imgf000160_0002
wherein R and R are each independently chosen from: i) hydrogen; ii) substituted or unsubstituted linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv) substituted or unsubstituted heteroaryl; or
O 1X
R and R can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms; the substitutions are independently chosen from one or more Ci-C6 linear, branched, or cyclic alkyl, halogen, hydroxyl, or cyano units.
65. A compound according to Claim 61, wherein R has the formula:
Figure imgf000161_0001
wherein R4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; and iv) substituted or unsubstituted heteroaryl; the substitutions are independently chosen from one or more Ci-C6 linear, branched, or cyclic alkyl, halogen, hydroxyl, or cyano units.
66. A compound according to Claim 61 , wherein R has the formula:
Figure imgf000161_0002
wherein R2 and R3 are each independently chosen from: i) hydrogen; ii) substituted or unsubstituted linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv) substituted or unsubstituted heteroaryl; or
R2 and R3 can be taken together to form a saturated or unsaturated ring having from 5 to
7 atoms; the substitutions are independently chosen from one or more C]-Cg linear, branched, or cyclic alkyl, halogen, hydroxyl, or cyano units.
67. A compound according to Claim 61, wherein R has the formula:
Figure imgf000161_0003
wherein R4 is a unit chosen from: i) hydrogen; ii) substituted or unsubstituted linear, branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; and iv) substituted or unsubstituted heteroaryl; the substitutions are independently chosen from one or more CJ-CO linear, branched, or cyclic alkyl, halogen, hydroxyl, or cyano units.
68. A compound according to any of Claims 62, 64, or 66 wherein R and R are each independently hydrogen or substituted or unsubstituted methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-hvΛγ\, sec-butyl, tert-buty\, phenyl, 1,2,3,4-tetrazolyl, [l,2,3]triazolyl, [l,2,4]triazolyl, imidazolyl, pyrrolyl, oxazolyl, isoxazolyl, isoxazolyl, [l,2,4]oxadiazolyl, [l,3,4]oxadiazolyl, furanyl, thiopheneyl, isothiazolyl, thiazolyl, thiazolyl, [l,2,4]thiadiazolyl, and [l,3,4]thiadiazolyl.
69. A compound according to any of Claims 63, 65, or 67 wherein R and R are each independently hydrogen or substituted or unsubstituted methyl, ethyl, n-propyl, iso- propyl, n-butyl, ώo-butyl, see-butyl, rert-butyl, phenyl, 1,2,3,4-tetrazolyl, [l,2,3]triazolyl, [l,2,4]triazolyl, imidazolyl, pyrrolyl, oxazolyl, isoxazolyl, isoxazolyl, [l,2,4]oxadiazolyl, [l,3,4]oxadiazolyl, furanyl, thiopheneyl, isothiazolyl, thiazolyl, thiazolyl, [l,2,4]thiadiazolyl, and [l,3,4]thiadiazolyl.
70. A compound according to Claim 59, wherein R is a 6-member heteroaryl ring.
71. A compound according to Claim 70, wherein R is chosen from pyridinyl, pyrimidinyl, pyrazinyl, and triazinyl.
72. A compound according to Claim 59, wherein R is a 6-member heterocyclic ring.
73. A compound according to Claim 72, wherein R is chosen from morpholinyl, piperidinyl, piperazinyl, and piperidinonyl.
74. A compound according to Claim 59, wherein R is lf/-indolyl,lH'-pyrrolo[2,3- 6]pyridinyl, 7//-pyrrolo[2,3-cT]pyrimidinyl, 5-H-pyrrolo[2,3-&]pyrazinyl, 7/-r-pyrrolo[2,3- c]pyridazinyl, 5H-PyIToIo[S, 2-c]pyridazinyl, liZ-άenzo^imidazolyl, 7H-imidazo[4,5- c]pyridazinyl, liJ-imidazo[4,5-6]pyrazinyl, 7i7-purinyl, 9/7-purinyl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, isoquinolin-1-yl, isoquinolin-3-yl, and isoquinolin-4-yl.
A compound, or pharmaceutically acceptable salt thereof, having the formula:
Figure imgf000163_0001
wherein A is a substituted or unsubstituted heterocyclic or heteroaryl ring having from 5 to 10 ring atoms;
R15 represents one or more optional substitutions for hydrogen, the substitutions are each independently chosen from: i) linear, branched, or cyclic alkyl, alkenyl, and alkynyl; ii) substituted or unsubstituted aryl; iii) substituted or unsubstituted heterocyclic; iv) substituted or unsubstituted heteroaryl; v) -(CR173R17b)qOR16; vi) -(CR17aR17b)qC(O)R16; vii) -(CR17aR! 7b)qC(O)OR!6; viii) -(CRl7aR17b)qC(O)N(Rl6)22; ix) -(CR17aR17b)qN(RI6)2; x) halogen; xi) — CΗmXn; wherein X is halogen, m is from 0 to 2, m+n =3 ; xii) -CCR17aR17b)qSO2R16; and xiii) -<CR17aRl 7b); each R16 is independently chosen from hydrogen, substituted or unsubstituted linear, branched, or cyclic alkyl; or two R16 units can be taken together to form a ring comprising 3-7 atoms; R!7a and R17b are each independently hydrogen or linear or branched alkyl; the index q is from 0 to 4; wherein further when R is a unit chosen from: i) linear, branched, or cyclic alkyl, alkenyl, and alkynyl; ii) substituted or unsubstituted aryl; iii) substituted or unsubstituted heterocyclic; iv) substituted or unsubstituted heteroaryl ;
R15 can be further substituted by one or more optional R18 units that are substitutions for hydrogen, each R18 unit is independently chosen from: i) linear, branched, or cyclic alkyl, alkenyl, and alkynyl; ii) -(CR20aR20b)pOR19; iii) -(CR20aR20b)pC(O)R19; iv) -(CR20aR20b)pC(O)OR19; v) -(CR20aR20b)pC(O)N(R19)2; vi) -(CR20aR20b)pN(R19)2; vii) halogen; viii) — CHmXn; wherein X is halogen, m is from 0 to 2, m-t-n =3; ix) -(CR201R20OpSO2R19; and x) -(CR20aR20b)pSO3R19; each R19 is independently chosen from hydrogen, substituted or unsubstituted linear, branched, or cyclic alkyl; or two R19 units can be taken together to form a ring comprising 3-7 atoms; R20a and R20b are each independently hydrogen or linear or branched alkyl; the index p is from 0 to 4; and
Z is a unit containing one or more units chosen from: ii) substituted or unsubstituted linear, branched or cyclic alkyl; iii) substituted or unsubstituted aryl; iv) substituted or unsubstituted heterocyclic rings; or v) substituted or unsubstituted heteroaryl rings; each substitution on a Z unit is independently chosen from halogen, C1-C4 linear, branched alkyl, or cyclic alkyl, -OR11, -CN, -N(Rπ)2, -CO2R11, -C(O)N(Rπ)2, -
NR1 1C(O)R1 ', -NO2, and -SO2R1 '; each R1 ' is independently hydrogen; substituted or unsubstituted C1-C4 linear, branched, cyclic alkyl, alkenyl, or alkynyl; substituted or unsubstituted phenyl or benzyl; or two R units can be taken together to form a ring comprising from 3-7 atoms.
76. A compound according to Claim 75, wherein A is a ring chosen from pyrrolyl, pyrazolyl, imidazolyl, [l,2,3]triazolyl, 1,2,3,4-tetrazolyl, oxazolyl, isoxazolyl, [l,2,4]oxadiazolyl, [l,3,4]oxadiazolyl, furanyl, thiopheneyl, isothiazolyl, thiazolyl, [l,2,4]thiadiazolyl, [l,3,4]thiadiazolyl, pyrrolidinyl, 4,5-dihydroimidazolyl, pyrrolidinonyl, imidazolidinonyl, l//-imidazol-2(3//)-only, imidazolidine-2,4-dionyl, thiazolidin-2-only, 2- thioxothiazolidin-4-only, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl, piperidinyl, piperazinyl, piperidinonyl, lH-indolyl,lHr-pyrrolo[2,3-£»]ρyridinyl, IH- pyrrolo[2,3-cT|pyrimidinyl, 5i/-pyrrolo[2,3-6]pyrazinyl, 7H-pyrrolo[2,3-c]pyridazinyl, 5H-pyrrolo[3,2-c]pyridazinyl, lH-&enzo[rf]imidazolyl, 7H-imidazo[4,5-c]pyridazinyl, lH-imidazo[4,5-fe]pyrazinyl, 7H-purinyl, 9i7-purinyl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, isoquinolin-1-yl, isoquinolin-3-yl, and isoquinolin-4-yl.
77. A compound according to either of Claim 59 or 75, wherein Z has the formula:
Figure imgf000165_0001
wherein R1 is a substituted or unsubstituted phenyl or naphthyl; the substitutions are each independently chosen from: i) Ci-C]2 linear, branched, or cyclic alkyl, alkenyl, and alkynyl; ii) substituted or unsubstituted C6 or C1O aryl; iii) substituted or unsubstituted C1-C9 heterocyclic rings; iv) substituted or unsubstituted C1-C9 heteroaryl rings; v) -(CR14aR14b)2OR' 3; vi) -(CR14aR14b)zC(O)R13; vii) -(CR14aR14b)2C(O)OR13; viii) -(CR148R 14b)zC(O)N(RI3)2; ix) -(CR14aRI4b)zN(R13)2; x) halogen; xi) -(CR14aR14b)zCN; xii) -(CR14aR14b)zNO2; xiii) -CHjXk; wherein X is halogen, j is from 0 to 2, j + k = 3; xiv) -(CRl4aR14b)zSR13; xv) -(CR14aR14b)2SO2R13; and xiii) -(CR14aR14b)zSO3R13; wherein each R13 is independently hydrogen, substituted or unsubstituted Ci -C4 linear, branched, or cyclic alkyl; or two R13 units can be taken together to form a ring comprising 3-7 atoms; R14a and R14b are each independently hydrogen or C1-C4 linear or branched alkyl; the index p is from 0 to 4.
77. A compound according to Claim 75, wherein Z is a ring chosen from pyrrolyl, pyrazolyl, imidazolyl, [l,2,3]triazolyl, 1,2,3,4-tetrazolyl, oxazolyl, isoxazolyl, [l,2,4]oxadiazolyl, [l,3,4]oxadiazolyl, furanyl, thiopheneyl, isothiazolyl, thiazolyl, [l,2,43thiadiazolyl, [l,3,4]thiadiazolyl, pyrrolidinyl, 4,5-dihydroimidazolyl, pyrrolidinonyl, imidazolϊdinonyl, lH-iniidazol-2(3H)-only, imidazolidine-2,4-dionyl, thiazolidin-2-only, 2- thioxothiazolidin-4-only, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, moφholinyl, piperidinyl, piperazinyl, piperidinonyl, l//-indolyl,lH-pyrrolo[2,3-6]pyridinyl, 7H- pyrrolo[2,3-cf]pyrimidinyl, 5H-pyrrolo[2,3-Z>]pyrazinyl, 7H-pyrrolo[2,3-c]pyridazinyl, 5H-pyrrolo[3,2-c]pyridazinyl, lH-6enzo[αT]imidazolyl, 7H-imidazo[4,5-c]pyridazinyl, lH-imidazo[4,5-&]pyrazinyl, 7H-purinyl, 9H-purinyl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, isoquinolin-1-yl, isoquinolin-3-yl, and isoquinolin-4-yl
78. A pharmaceutically acceptable salt of the compounds of any of Claims 1, 2, 10, 31-39, 46-50, 59 and 75.
79. A compound according to Claim 78 wherein the compounds are salts comprising anions chosen from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, and citrate.
80. A compound according to Claim 78 wherein the compounds are salts comprising cations chosen from sodium, lithium, potassium, calcium, magnesium, and bismuth.
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