WO2008002576A2 - Prolyl hydroxylase inhibitors and methods of use - Google Patents

Prolyl hydroxylase inhibitors and methods of use Download PDF

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Publication number
WO2008002576A2
WO2008002576A2 PCT/US2007/014832 US2007014832W WO2008002576A2 WO 2008002576 A2 WO2008002576 A2 WO 2008002576A2 US 2007014832 W US2007014832 W US 2007014832W WO 2008002576 A2 WO2008002576 A2 WO 2008002576A2
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WO
WIPO (PCT)
Prior art keywords
carbonyl
amino
pyridine
acetic acid
hydroxy
Prior art date
Application number
PCT/US2007/014832
Other languages
French (fr)
Other versions
WO2008002576A3 (en
Inventor
Richard Masaru Kawamoto
Shengde Wu
Namal Chithranga Warshakoon
Artem G. Edokimov
Kenneth Donald Greis
Angelique Sun Boyer
Original Assignee
The Procter & Gamble Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=38728868&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2008002576(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to AT07835890T priority Critical patent/ATE485264T1/en
Priority to EP20070835890 priority patent/EP2044005B8/en
Priority to CA 2659682 priority patent/CA2659682C/en
Priority to KR1020097001697A priority patent/KR101130592B1/en
Priority to EP18158907.8A priority patent/EP3357911B1/en
Priority to CN2007800307200A priority patent/CN101506149B/en
Priority to SI200730449T priority patent/SI2044005T1/en
Priority to JP2009518232A priority patent/JP5113838B2/en
Priority to BRPI0713350-2A priority patent/BRPI0713350B1/en
Priority to RU2009102220/04A priority patent/RU2429226C9/en
Priority to PL07835890T priority patent/PL2044005T3/en
Priority to PL15191470T priority patent/PL3026044T3/en
Priority to EP15191470.2A priority patent/EP3026044B8/en
Priority to DK07835890T priority patent/DK2044005T3/en
Priority to AU2007265460A priority patent/AU2007265460B2/en
Priority to DE200760009992 priority patent/DE602007009992D1/en
Priority to EP22172062.6A priority patent/EP4095127A1/en
Priority to MX2009000286A priority patent/MX2009000286A/en
Application filed by The Procter & Gamble Company filed Critical The Procter & Gamble Company
Publication of WO2008002576A2 publication Critical patent/WO2008002576A2/en
Publication of WO2008002576A3 publication Critical patent/WO2008002576A3/en
Priority to IL196127A priority patent/IL196127A/en
Priority to HK09108318A priority patent/HK1129369A1/en

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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Definitions

  • the present disclosure relates, in some aspects, to HIF- l ⁇ prolyl hydroxylase inhibitor compounds and pharmaceutically acceptable salts thereof, compositions comprising the HIF- l ⁇ prolyl hydroxylase inhibitor compounds, and to methods for treating or controlling, inter alia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, and anemia.
  • PVD Peripheral Vascular Disease
  • CAD Coronary Artery Disease
  • heart failure ischemia
  • ischemia ischemia
  • HIF- l ⁇ under normal healthy conditions wherein the cells have a sufficient supply of oxygen is readily converted to a degraded form by one of several prolyl hydroxylase enzymes, inter alia, EGLIN.
  • prolyl hydroxylase enzymes inter alia, EGLIN.
  • HIF-l ⁇ When cells undergo hypoxia, this enzymatic transformation is slow or entirely stopped and HIF-l ⁇ begins to build up in the cell.
  • this protein combines with another factor, HIF- l ⁇ which together form an active transcription factor complex.
  • This transcription factor then activates several biological pathways which are present as a response to and a means for alleviating the body's state of hypoxia. These responses include, inter alia, angiogenic, erythropoietic (EPO), glucose metabolism, and matrix alteration responses.
  • EPO erythropoietic
  • the substituted aryl or heteroaryl amide compounds of the present disclosure are a new class of compounds that can inhibit HIF- l ⁇ prolyl hydroxylase, thus resulting in improvement in blood flow, oxygen delivery and energy utilization in ischemic tissues, or upregulate the production of erythropoietin so as to treat anemia.
  • Disclosed herein are compounds and pharmaceutically acceptable salts thereof, and/or pharmaceutical compositions thereof comprising: a) an effective amount of one or more compounds according to the present disclosure; and b) an excipient.
  • the present disclosures also relate to methods for controlling, inter alia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, and/or anemia.
  • PVD Peripheral Vascular Disease
  • CAD Coronary Artery Disease
  • heart failure heart failure
  • ischemia ischemia
  • anemia anemia
  • the present disclosures also relate to methods for regulating blood flow, oxygen delivery and/or energy utilization in ischemic tissues, wherein the methods can comprise administering to a human an effective amount of one or more compounds or pharmaceutically acceptable salts disclosed herein.
  • FIGURES Figure 1 Immunoblot analysis of nuclear extracts demonstrating stabilization of HIF-I ⁇ in mouse liver by ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ -acetic acid
  • Figure 2. An example of how the erythropoietin level is elevated versus vehicle in mouse serum after oral dosing of ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]-amino ⁇ - acetic acid.
  • 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.
  • 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.
  • organic unit refers to groups or moieties that comprise one or more carbon atoms and which form a portion of one of the compounds or pharmacetucally acceptable salts thereof.
  • substitutent units referred to elsewhere herein are organic units.
  • the organic units should often have variable ranges of restricted size and/or molecular weight, so as to provide desired binding to the target enzymes, solublility, bioabsorption characteristics.
  • 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 units often have hydrogen bound to at least some of the carbon atoms of the organic units, and can optionally contain the common heteroatoms found in substituted organic compounds, such as oxygen, nitrogen, sulfur, and the like, or inorganic atoms such as halogens, phosphorus, and the like.
  • substituted organic compounds such as oxygen, nitrogen, sulfur, and the like
  • inorganic atoms such as halogens, phosphorus, and the like.
  • 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, alkyl carboxamido, substituted alkylcarboxamido, dialkylcarboxamido, substituted dialkylcarboxamido, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein.
  • organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals,
  • Substituted and unsubstituted linear, branched, or cyclic alkyl units include the followini non-limiting examples: methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), z ' so-propyl (C 3 ), cyclopropyl (Ci), n-butyl (C 4 ), sec-butyl (C 4 ), iso-buty ⁇ (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 (Ci), 1 -chloroethyl (C 2 ), 2 -hydroxy ethyl (C 2 ), 1,2-
  • Substituted and unsubstituted linear, branched, or cyclic alkenyl include, ethenyl (C 2 ), 3 propenyl (C 3 ), 1-propenyl (also 2-methyl ethenyl) (C 3 ), isopropenyl (also 2-methylethen-2-yl) (C3), buten-4-yl (C 4 ), and the like; substituted linear or branched alkenyl, non-limiting example: of which include, 2-chloroethenyl (also 2-chlorovinyl) (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 (C3), 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 (Cs), 5-hydroxy-5-ethylhept-3-ynyl (C 9 ), and the like.
  • alkoxy denotes a unit having the general formula -OR 100 wherein R 100 is an alkyl, alkylenyl, or alkynyl unit as defined herein above, for example, methoxy, methoxymethyl, methoxy methyl.
  • haloalkyl denotes an alkyl unit having a hydrogen atom substituted by one or more halogen atoms, for example, trifluoromethyl, 1 ,2- dicloroethyl, and 3,3,3-trifluoropropyl.
  • aryl denotes cyclic organic units that comprise at least one benzene ring having a conjugated and aromatic six-membered ring, non-limiting examples of which include phenyl (C 6 ), naphthylen-1-yl (C 10 ), 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 (Ce), 3- methylphenyl (Ce), 2-amino-4-fluorophenyl (C ⁇ ), 2-(iV,A/-diethylamino)phenyl (Ce), 2- cyanophenyl (C 6 ), 2,6-di-/erf-butylphenyl (C 6 ), 3-methoxyphenyl (C 6 ), 8-hydroxynaphthylen-2- yl (Cio), 4,5-dimethoxynaphthylen-l-yl (C 10 ), and 6-cyanonaphthylen-l-yl (C10).
  • heteroaryl denotes an organic unit comprising a five or six membered conjugated and aromatic ring wherein at least one of the ring atoms is a heteroatom selected from nitrogen, oxygen, or sulfur.
  • the heteroaryl rings can comprise 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, such as a pyridine ring, a furan ring, or thiofuran ring.
  • a “heteroaryl” can also be a fused multicyclic and heteroaromatic ring system having wherein at least one of the rings is an aromatic ring and at least one atom of the aromatic ring is a heteroatom including 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.
  • units which can substitute for hydrogen atoms on a hydrocarbyl or other unit 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 ), ⁇ o-butyl (C 4 ), sec-butyl (C 4 ), tert-butyl (C 4 ), cyclobutyl (C 4 ), n-pentyl (C 5 ), cyclopentyl (C 5 ), n-hexyl (C 6 ), and cyclohexyl (C 6 ); ii) substituted or unsubstituted aryl; for example, methyl (Ci),
  • compositions effective as inhibitors of human protein prolyl hydroxylase thereby stimulating an angiogenic response in human tissue, thereby providing a method for increasing blood flow, oxygen delivery and energy utilization in ischemic tissues;
  • compositions effective as human protein HIF- l ⁇ prolyl hydroxylase inhibitors and thereby increasing the concentration of HIF-I ⁇ leading to greater activation and sustaining the of various biological pathways that are the normal response to cellular hypoxia;
  • compositions effective in stimulating an erythropoietic (EPO) response in cell and thereby enhancing the maintenance of red blood cells by controlling the proliferation and differentiation of erythroid progenitor cells into red blood cells;
  • VEGF Vascular Endothelial Growth Factor
  • HIF- l ⁇ prolyl hydroxylase inhibitors of the present disclosure which are capable of regulating blood flow, oxygen delivery and energy utilization in ischemic tissues that are caused by insufficient regulation of HIF-I ⁇ prolyl hydroxylase.
  • HIF-I ⁇ prolyl hydroxylase enzymes will have other positive medical effects on human tissue and the alleviation of symptoms and disease states other than those symptoms or diseases states that are specifically pointed out in the present disclosure.
  • these yel undisclosed or yet unknown conditions will be positively affected by compositions which stimulate the body own response to hypoxia and other low blood oxygen conditions.
  • composition of matter stand equally well for the HIF- l ⁇ prolyl hydroxylase enzyme inhibitors described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms “compound,” “analog,” and “composition of matter” are used interchangeably throughout the present specification.
  • the compounds disclosed herein include all salt forms, for example, salts of both basic groups, inter alia, amines, as well as salts of acidic groups, inter alia, carboxylic acids.
  • anions that can form pharmaceutically acceptable salts with basic groups: chloride, bromide, iodide, sulfate, bisuifate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate, and the like.
  • cations that can form pharmaceutically acceptable salts of the anionic form of acidic substituent groups on the compounds described herein: sodium, lithium, potassium, calcium, magnesium, zinc, bismuth, and the like.
  • HIF- l ⁇ prolyl hydroxylase inhibitor compounds described herein are substituted aryl or heteroaryl amides, having the core structure shown in Formula (I) below.
  • X can be N or CH; L is an organic linking unit as further described, below, and Y, R, R 1 and R 2 can be any of the units further described below.
  • the compounds of the present disclosure are 2- arnidopyri dines and when X is CH the compounds of the present disclosure are arylamides, as shown below:
  • R and R 1 are optional substituent groups that can be independently chosen from a wide variety of inorganic (hydrogen, hydroxyl, amino, halogen or the like) or organic substituent units, such as alkyls, cycloalkyls, heterocyclic, heteroaryl s, and the like, wherein such substituent units can optionally have from 1 to 12 carbon atoms, or 1 to 10 carbon atoms, or 1 to six carbon atoms.
  • R and R 1 can each be independently a chosen from: i) hydrogen; ii) substituted or unsubstituted phenyl; and iii) substituted or unsubstituted heteroaryl.
  • the optional substitutent units for the phenyl and heteroaryl rings can be chosen from a wide variety of inorganic and Ci-C 4 organic radicals, and there are typically zero, one, two, or three of such substituent groups.
  • one, two, or three substituentsfor the above-mentioned phenyl and heteroaryl rings can be independently selected from: i) C 1 -C 4 linear, branched, or cyclic alkyl; ii) C 1 -C 4 linear, branched, or cyclic alkoxy; iii) C 1 -C 4 linear, branched, or cyclic haloalkyl; iv) halogen; v) -CN; vi) -NHC(O)R 4 vii) -C(O)NR 5a R ⁇ b ; viii) heteroaryl; or ix) two substitutions can be taken together to form a fused ring having from 5 to 7 atoms; wherein the above-
  • the R units can be chosen from substituted or unsubstituted phenyl; or substituted or unsubstituted heteroaryls; and the R 1 units are hydrogen.
  • R can be a substituted or unsubstituted phenyl, having one, two, or three optional inorganic or organic substitutents, which in some embodiments are chosen from: i) C 1 -C 4 linear, branched, or cyclic alkyl; ii) Ci-C 4 linear, branched, or cyclic alkoxy; iii) C 1 -C 4 linear, branched, or cyclic haloalkyl; iv) halogen; or v) -CN.
  • R units include 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-iso- propylphenyl, 3-z's ⁇ -propylphenyl, 4-wo-propylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4- cyanophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3- ethoxyphenyl, 4-ethoxyphenyl, 2- ⁇ .s ⁇ -propoxyphenyl, 3-2so-propoxyphenyl, 4-iso- propoxyphenyl, 2-cyanophenyl, 3-cyanophenyl,
  • the R units can have the formula -NH(C(O)R 4 wherein R 4 is C 1 -C4 linear, branched, or cyclic alkyl.
  • R 4 is C 1 -C4 linear, branched, or cyclic alkyl.
  • Non limiting examples of such R units include: i) -NH(C(O)CH 3 ; ii) -NH(C(O)CH 2 CH 3 ; ii) -NH(C(O)CH 2 CH 2 CH 3 ; ii) -NH(C(O)CH(CH 3 ) 2 ; ii) -NH(C(O)(cyclopropyl); and ii) -NH(C(O)CH 2 CH 2 CH 2 CH 3 .
  • R units can have the formula:
  • R 10 has the formula -C(O)NR 5a R 5b ; wherein R 5a and R 5b can be independently selected from hydrogen, Ci-C 4 linear or branched alkyls, or R 5a and R 5b are taken together to from a ring having 5 or 6 atoms.
  • the R 10 units can have the formula: — C(O)NR 5a R 5b wherein R 5a and R 5b are each independently selected from hydrogen, methyl, ethyl, n-propyl, /so-propyl, and cyclopropyl.
  • R 10 units include: i) -C(O)NH 2 ; ii) -C(O)NHCH 3 ; iii) -C(O)N(CH 3 ) 2 ; iv) -C(O)NH(CH 2 CH 3 ); v) -C(O)N(CH 2 CH 3 ) 2 ; vi) -C(O)N(CH 3 )(CH 2 CH 3 ).
  • R 5a and R 5b together to form a ring having 5 or 6 ring atoms
  • R 10 units are heteroaryl units chosen from pyrrol idin-1-yl, piperidin-1-yl, piperazin-1-yl, and morpholin-4-yl.
  • the R 10 units can be heteroaryl units, non limiting examples of which are thiazol-2-yl, thiazol-4-yl, l,2,3,4-tetrazol-5-yl, [l,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, 1,2,3,4- tetrazol-5-yl, [l,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, and isoquinolin-4-y
  • the R units can include substituted phenyl units wherein two substitutions can be taken together to form a fused ring having from 5 to 7 ring atoms, for example a 2,3-dihydro-benzo[l,4]dioxin-6-yl ring which would provide a compound having the formula:
  • R examples include units wherein R is hydrogen and R 1 is hydrogen.
  • R 2 , X, Y, L, and R 9 can be independently chosen in any manner as otherwise taught herein with respect to the compounds of Formula (I).
  • R 1 substituents for compounds of Formula (I) can be chosen from a wide variety of inorganic and organic units.
  • R 1 is a phenyl ring, which can optionally be substituted with 1, 2, or 3 substituent units, independently selected from inorganic or Ci -C 4 organic units.
  • substituent units independently selected from inorganic or Ci -C 4 organic units.
  • Ci -C 4 linear, branched, or cyclic alkyl ii) Ci-C 4 linear, branched, or cyclic alkoxy; iii) C 1 -C 4 linear, branched, or cyclic haloalkyl; iv) halogen; or v) -CN.
  • R 1 include 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-iso-propylphenyl, 3-iso- propylphenyl, 4- ⁇ opropylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4- ethoxyphenyl, 2-/so-propoxyphenyl, 3-isopropoxyphenyl, 4-wo-propoxyphenyl, 2- cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,
  • R 1 units includes compounds wherein R is hydrogen and R 1 units are hydrogen.
  • R is hydrogen and R 1 is a substituted or unsubstituted phenyl, wherein the substitutions are chosen from: i) C1-C 4 linear, branched, or cyclic alkyl; ii) C1-C4 linear, branched, or cyclic alkoxy; iii) C1-C4 linear, branched, or cyclic haloalkyl; iv) halogen; and v) -CN.
  • Y is a unit that can be chosen from a wide variety of inorganic units, such as H, —OH, -NH 2 , or a halogen, and C 1 -C4 organic units.
  • Y can be chosen from: i) hydrogen; ii) —OR 3 , wherein R 3 is hydrogen, or a lower alkyl, such as methyl, or ethyl.
  • the R 2 units can be chosen from a wide variety of inorganic units, such as -OH, or -NH 2 units, or a variety of organic units.
  • R 2 is chosen from: i) -OR 6 ; or ii) -NR 7a R 7b ; wherein R 6 is hydrogen or C1-C4 linear, branched, or cyclic alkyl; and R 7a andR 7b are each independently chosen from: i) hydrogen; ii) C 1 -C 4 linear, branched, or cyclic alkyl; or iii) R 7a and R 7b can be taken together to form a ring having from 3 to 7 atoms.
  • R 2 units are hydroxyl (—OH) wherein the compounds are carboxylic acids, or may also be present in the form of a salt as the corresponding hydroxyl/carboxylate anion, i.e. R2 can bea -O " unit, so as to form a compound having a carboxylate group, as shown below.
  • R, R 1 , R 2 , X, Y, L, and R 9 can be independently chosen in any manner as otherwise taught herein with respect to the compounds of Formula (I).
  • R 2 includes compounds wherein R 6 is C t -C 4 linear, branched, or cyclic alkyl providing R 2 units which are alkoxy wherein the compounds formed are organic esters having C1-C 4 linear, branched, or cyclic alkyl groups.
  • R 2 units are: i) -OCH 3 ; ii) -OCH 2 CH 3 ; and iii) -OCH 2 CH 2 CH 3 .
  • R 2 units include compounds wherein R 2 has the formula — NR 7a R 7b ; and R 7a and R 7b are each independently chosen from: i) hydrogen; and ii) C 1 -C 4 linear, branched, or cyclic alkyl.
  • R 2 units include: i) -NH 2 ; ii) -NHCH 3 ; iii) -N(CH 3 ) 2 ; iv) -NH(CH 2 CH 3 ); v) -N(CH 2 CH 3 ) 2 ; vi) -N(CH 3 )(CH 2 CH 3 ).
  • R 2 units includes compounds wherein R 2 has the formula — NR 7a R 7b ; and R 7a and R 7b are taken together to form a ring having from 3 to 7 atoms, wherein the non- limiting examples of R 2 units include aziridin-1-yl, axetidin-l-yl, pyrolidin-1-yl, piperidin- 1-yl, piperazin-1-yl, and morpholin-4-yl.
  • L is a unit that links the nitrogen atom of the carboxyamide group to the neighboring carbonyl group.
  • L is typically a Ci-C 6 or Ci-C 4 organic linking unit.
  • L comprises a one or more optionally substituted methylene units having the formula:
  • R 8a and R 8b are each independently hydrogen, Ci-C 6 linear or branched alkyl, or phenyl: and the index y is from 1 to 4.
  • L units includes units wherein R 8a and R 8b are both hydrogen and the index n is equal to 1 , the L unit has the formula:
  • R, R , R , X, Y, and R can be independently chosen in any manner as otherwise taught herein with respect to the compounds of Formula (I).
  • L units includes units wherein R 8a and R 8b are each hydrogen or methyl and the index n is equal to 1 , these units having the formula:
  • L units includes units wherein all R 8a and R 8b units are hydrogen and the index n is equal to 2, these units having the formula:
  • the R 9 substituent for the amide nitrogen atom can be hydrogen or a C1-C4 organic substituent, such as a C1-C4 alkyl group, such as methyl, or a Ci-C 4 haloalkyl, such as a trifluoromethyl group.
  • the compounds of Formula (I) can be organized into several categories for the strictly non-limiting purpose of describing alternatives for synthetic strategies for the preparation of subgenera of compounds within the scope of Formula (I) that are not expressly exemplified herein. This mental organization into categories does not imply anything with respect to increased or decreased biological efficacy with respect to any of the compounds or compositions of matter described herein.
  • R units can be substituted or unsubstituted phenyl, non-limiting examples of which are described in Table I herein below.
  • Reagents and conditions (a) C 6 H 5 OH, NaH, THF; microwave 190 0 C, 5 hr.
  • Reagents and conditions (c) GlyOMe.HCl, EDCI, HOBt, DMF; 0 0 C to rt, 3 days.
  • the resulting suspensior is heated in a sealed tube at 85 0 C for 16 hours. After this time, the mixture is cooled to room temperature and concentrated under reduced pressure. The residue is then treated with IM HCl (1 mL) and diluted with EtOAc. The organic layer is separated, washed with H 2 O, saturated aqueous NaCl and concentrated under reduced pressure. The crude material is purified over silica (EtOAc: heptane 3:7). The resulting solid can be crystallized from EtOAc/heptane to afforc 0.143g (53% yield) of the desired compound as a colorless solid.
  • step (f) can be modified by substituting in step (f) other reagents for 3-chlorophenylboronic acid.
  • Non-limiting examples include 4-chlorophenylboronic acid, 2-chlorophenylboronic acid, 2-fluorophenylboronic acid, 3-fluorophenylboronic acid, 4- fluorophenylboronic acid, 2-rnethylphenylboronic acid, 3-methylphenylboronic acid, and 4- methylphenylboronic acid.
  • the following heteroaryl substituted phenyl compound can be prepared from ⁇ [5-(3- • cyano-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino ⁇ acetic acid methyl ester by treatment with trimethylsilyl azide and di-butyl tin oxide in DME and heating the mixture to 140 0 C, 150 W 3 200 psi in a microwave reactor.
  • R units which are substituted or unsubstituted heteroaryl, non-limiting examples of which are described in Table II herein below.
  • step (f) can be modified by substituting in step (f) other reagents for 3-chlorophenylboronic acid.
  • substitutes include 3- (thiazol-2-yl)phenylboronic acid, 3-(thiazol-4-yl)phenylboronic acid, 4-(thiazol-2- yl)phenylboronic acid, 4-(thiazol-4-yl)phenylboronic acid, 3-(imidazol-2-yl)phenylboronic acid.
  • R units which are substituted or unsubstituted phenyl, non-limiting examples of which are described in Table III herein below.
  • Reagents and conditions (a) NaOH, H 2 O/THF; rt, 1 hr.
  • the fourth aspect of Category I of the present disclosure encompasses compounds having the formula:
  • R units are substituted or unsubstituted heteroaryl.
  • R units are described in Table IV herein below. TABLE IV
  • the compounds which encompass the fourth aspect of Category I of the present disclosure can be prepared by the procedure outlined in Scheme II and described in Example 2 herein beginning with compounds which are members of the first and second aspect of Category I.
  • the following are non-limiting examples of compound encompassed by the fourth aspect of Category I.
  • Category II of the present disclosure relates to compounds having the formula:
  • R units are substituted or unsubstituted phenyl. Non-limiting examples of these R units are described in Table V herein below.
  • the resulting suspension is heated to 80 0 C and stirred for 3 hours after which the reaction is cooled to room temperature and filtered through CeliteTM. The collected solids are washed with additional MeOH and the filtrate concentrated under reduced pressure.
  • the crude material is purified over silica (hexanes:EtOAc gradient 6: 1 to 4:1) to afforc 0.614 g (78% yield) of the desired product as orange crystals.
  • a further non-limiting example includes the following.
  • R units are substituted or unsubstituted phenyl.
  • R units are described in Table VI herein below. TABLE VI
  • Reagents and conditions (a) BBr 3 , CH 2 Cl 2 ; rt, 3 days.
  • Category III of the present disclosure relates to compounds having the formula:
  • the resulting suspension is heated to 90 0 C in a sealed rube for 22 hours.
  • the reaction is cooled to room temperature and additional 3-chlorophenyl boronic acid (0.055 g, 0.35 mmol) and Pd(dppf)Cl 2 (0.048 g, 0.06 mmol) is added and the reaction reheated to 90 0 C for an additional 22 hours.
  • the reaction solution is filtered through CeliteTM and the collected solids are washed with additional MeOH.
  • the filtrate and washings are concentrated under reduced pressure and the residue dissolved in CH 2 Cl 2 and washed with 10% citric acid.
  • the organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure.
  • Category IV of the present disclosure relates to compounds having the formula:
  • the resulting suspension is heated to 85 0 C in a sealed tube for 20 hours. After cooling, the reaction solution is filtered through CeliteTM and the collected solids are washed with additional MeOH. The filtrate and washings are concentrated under reduced pressure and the residue dissolved in CH 2 Cl 2 and washed with 10% citric acid. The organic layer is dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product is purified over silica (EtOAc:heptane 1:4) to afford 0.112 g (73% yield) of the desired compound as a colorless oil.
  • Reagents and conditions (a) LiOH, THF/H 2 O; rt, 3 days.
  • the second aspect of Category IV relates to compounds having the formula:
  • Reagents and conditions (a) CH 3 NH 2 HCl, EDCI, HOBt, DMF; 0 0 C to rt, 2 days.
  • R 1 units are substituted or unsubstituted phenyl.
  • R 1 units are substituted or unsubstituted phenyl.
  • Non-limiting examples of these units are described in Table X herein below.
  • the reaction is heated to 70 0 C in a sealed tube under N 2 for 16 hours.
  • the solvents are then removed under reduced pressure and the solid which remains is partitioned between CH 2 Cl 2 and IM K 2 CO 3 .
  • the aqueous phase is removed and the organic phase washed with H 2 O. sat. NaCl, dried (MgSO 4 ), filtered and concentrated under reduced pressure.
  • the crude material is purified over silica (EtOAc :heptane gradient 1 :4 to 3:7) to afford 0.113 g (85% yield) of the desired compound.
  • the second aspect of Category V encompasses compounds having the formula:
  • R 1 units are substituted or unsubstituted phenyl, non-limiting examples of which are described in Table XI herein below.
  • the compounds of the second aspect can be prepared by the procedure outlined in Scheme XIII and described in Example 11 herein below.
  • DIPEA DIPEA, DMF; rt, 48 hr.
  • Reagents and conditions (a) TFA, CH 2 Cl 2 ; rt, 16 hr.
  • DIPEA DIPEA, DMF; rt, 3 days.
  • DIPEA diisopropylethylamine
  • EDCI l-(3-dimethyl-aminopropyl)-3- ethylcarbodiimide
  • HOBt 1-hydroxybenzo-triazole
  • Category VII of the present disclosure relates to compounds having the formula:
  • Reagents and conditions (a) (4-ClC 6 H 4 )B(OH) 2 , Pd(dppf)Cl 2 , K 3 PO 4 , 1,4-dioxane, MeOH; 80 0C, 3 hr.
  • reaction is cooled to room temperature and filtered through CeliteTM.
  • the solids that form are collected and washed with additional MeOH before the filtrate 1 s concentrated under reduced pressure.
  • the crude material is purified over silica (hexanes:EtOAc; 6:1 to 4:1) to provide 0.615 g (78% yield) of the desired compound as orange crystals.
  • Reagents and conditions (a) LiOH, THF, H 2 O; reflux, 2 hr.
  • R 8a , R 8b , R 9 and R 6 are further described herein below in
  • Reagents and conditions (a) NaOH, THF, H 2 O; reflux, 3 hr.
  • Administration of one or more of the compounds of Formula (I), alone in the form of pharmaceutical compositions, optionally in combination with other pharmaceutically active compounds or compositions, can be effective in treatment of the following disease states or conditions: i) as human protein HIF- l ⁇ prolyl hydroxylase inhibitors; and thereby providing a means for regulating blood flow, oxygen delivery and energy utilization in ischemic tissues; ii) the compounds of the present disclosure are efficacious in regulating blood flow, oxygen delivery and energy utilization in ischemic tissues; and iii) the compounds of the present disclosure provide stabilized HIF-l ⁇ by blocking a degradation pathway mediated by HIF prolyl hydroxylase.
  • Each of the disease states or conditions which the formulator desires to treat may require differing levels or amounts of the compounds described herein to obtain a therapeutic level.
  • the formulator can determine this amount by any of the testing procedures known to the artisan or ordinary skil in the art.
  • the compounds of the present disclosure can be HIF- l ⁇ prolyl hydroxylase inhibitors when administered in pharmaceutically effective amounts, and thereby provide increased angiogenic response or cellular responses which are activated by transcription factors that are directly or indirectly affected by an increase in cellular HIF- l ⁇ concentration.
  • diseases or disease states are listed herein below, inter alia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, and anemia.
  • PVD Peripheral Vascular Disease
  • CAD Coronary Artery Disease
  • the compounds disclosed herein are especially effective in the treatment of anemia.
  • Stimulation of EPO production: anemia HIF-I is a transcription factor that also regulates the hypoxia-inducible EPO gene.
  • HIF-I is a transcription factor that also regulates the hypoxia-inducible EPO gene.
  • HIF- l ⁇ binds to the 3 1 hypoxia-response element of the EPO gene which results in the marked enhancement of EPO transcription (Semenza, G. L., et al. "Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1", J. Biol. Chem. Vol. 269, pp. 23757-63 (1994)).
  • EPO is essential for maintenance of red blood cells by controlling the proliferation and differentiation of erythroid progenitor cells into red blood cells (Krantz, S. B., "Erythropoietin,” Blood, Vol. 77, pp 419-434 (1991)).
  • the liver serves as the primary source of EPO.
  • production of EPO in the liver decreases and the kidney becomes the primary source of EPO.
  • other organs such as the liver and brain produce small but significant amounts of EPO.
  • a erythropoietin deficiency is associated with anemia.
  • the most prevalent form of anemia is associated with kidney failure.
  • EPO has been described in the treatment of anemia: associated with chemotherapy; that occurs as a consequence of AIDS; and due to prematurity and autologous blood donation.
  • EPO has even been suggested as a general use agent in pre-operative elective surgery.
  • 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, LX. ei al, 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.
  • 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 vesse 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 represen 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.
  • receptor tyrosine kinases on the endothelial cell surface and transduce signals that promote cell migration and proliferation.
  • unregulated or improperly regulated angiogenesis may either cause a particular disease or exacerbate an existing pathological condition.
  • 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
  • Peripheral vascular disease is the term used to describe the clinical syndrome of vascular insufficiency outside of the coronary circulation and typically involving the circulation to the lower extremities.
  • Atherosclerosis is by far the leading cause of peripheral vascular disease (PVD), although a number of discrete disease processes can contribute to its development and progression (i.e. diabetes, immune vasculitis and trauma).
  • Atherosclerotic PVD can present in three ways:
  • the present disclosure provides compounds which when administered in vivo inhibit HIF- l ⁇ prolyl hydroxylase thereby leading to increased expression of HIF-regulated genes, inter alia, angiogenic factors, erythropoietin, and glycolytic enzymes thereby resulting in improvement in blood flow, oxygen delivery and energy utilization in ischemic tissues.
  • HIF-regulated genes inter alia, angiogenic factors, erythropoietin, and glycolytic enzymes thereby resulting in improvement in blood flow, oxygen delivery and energy utilization in ischemic tissues.
  • 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.
  • the present disclosure further relates to forms of the present compounds, which under normal human or higher mammalian physiological conditions, release the compounds described herein.
  • One iteration of this aspect includes the pharmaceutically acceptable salts of the analogs described herein.
  • the formulator for the purposes of compatibility with delivery mode, excipients, and the like, can select one salt form of the present analogs over another since the compounds themselves are the active species which mitigate the disease processes described herein.
  • compositions or formulations which comprise the human protein HIF- l ⁇ prolyl hydroxylase inhibitors according to the present disclosure.
  • the compositions of the present disclosure comprise: a) an effective amount of one or more human protein HIF- l ⁇ prolyl hydroxylase inhibitor according to the present disclosure which are effective for treating PVD CAD, heart failure, ischemia, and anemia; 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.
  • compositions according to the present disclosure include: a) from about 0.001 mg to about 1000 mg of one or more human protein HIF-l ⁇ prolyl hydroxylase inhibitor according to the present disclosure; and b) one or more excipients.
  • Another example according to the present disclosure relates to the following compositions: a) from about 0.01 mg to about 100 mg of one or more human protein prolyl HIF-
  • a further example according to the present disclosure relates to the following compositions: a) from about 0.1 mg to about 10 mg of one or more human protein HIF- l ⁇ prolyl hydroxylase inhibitor according to the present disclosure; and b) one or more excipients.
  • an effective amount means "an amount of one or more HIF- l ⁇ prolyl hydroxylase inhibitors, 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. 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 further relates to the use of one or more of the HIF-I ⁇ prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating anemia.
  • the present disclosure further relates to the use of one or more of the HIF- l ⁇ prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating angiogenesis.
  • the present disclosure further relates to the use of one or more of the HIF- l ⁇ prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating peripheral vascular disease.
  • the present disclosure further relates to the use of one or more of the HIF- l ⁇ prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating wounds.
  • the present disclosure further relates to the use of one or more of the HIF- l ⁇ prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating atherosclerotic lesions.
  • the present disclosure further relates to the use of one or more of the HIF- l ⁇ prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating diabetes.
  • the present disclosure further relates to the use of one or more of the HIF-I ⁇ prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating hypertension.
  • the present disclosure further relates to the use of one or more of the HIF- l ⁇ prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating a disease affected by the level of VEGF, GAPDH and erythropoietin.
  • the present disclosure further relates to the use of one or more of the HIF- l ⁇ prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating a disorder 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.
  • the present disclosure further relates to the use of one or more of the HIF- l ⁇ prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating a disorder 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, 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-
  • the HIF-l ⁇ prolyl hydroxylase inhibitors of the present disclosure provide a method for increasing the vascularization of tissue in a subject.
  • vascularization of tissue means a pro- angiogenic response whereby blood vessels or other vessels or ducts develop at or around the afflicted tissue.
  • the afflicted tissue need not be hypoxic or ischemic per se, but rather the HIF- l ⁇ prolyl hydroxylase inhibitors help to sustain or further stimulate the body's pro-angiogenic response to hypoxia.
  • a non-limiting example of "vascularization” includes capillary proliferation in a non-healing wound or along the border of ischemic tissue.
  • tissue include: cardiac tissue, such as myocardium and cardiac ventricles; skeletal muscle; neurological tissue, such as from the cerebellum; internal organs, such as the stomach, intestine, pancreas, liver, spleen, and lung; and distal appendages such as fingers and toes.
  • cardiac tissue such as myocardium and cardiac ventricles
  • neurological tissue such as from the cerebellum
  • internal organs such as the stomach, intestine, pancreas, liver, spleen, and lung
  • distal appendages such as fingers and toes.
  • VEGF Vascular Endothelial Growth Factor
  • Oxygen tension has been shown to be a key regulator of VEGF gene expression, both in vitro and in vivo.
  • VEGF induction it is demonstrated that VEGF induces the formation of functional neo-vessels in the mouse cornea and enhanced blood flow in a dog model of coronary artery disease.
  • the HIF- l ⁇ prolyl hydroxylase inhibitors of the present disclosure provide enhancement in the expression of multiple hypoxia inducible genes including VEGF, GAPDH and erythropoietin (EPO).
  • HIF- l ⁇ prolyl hydroxylase inhibitors of the present disclosure provide enhanced the accumulation of HIFl - ⁇ in the cytoplasm and nucleus.
  • Transgenic mice expressing a constitutively active HIF- l ⁇ in the skin have increased dermal vascularity and had a 13-fold increase in VEGF levels
  • the present disclosure also relates to a method for controlling human protein HIF- l ⁇ prolyl hydroxylase.
  • the present method comprises the step of administering to a human or higher mammal an effective amount of a composition comprising one or more human protein HIF- l ⁇ prolyl hydroxylase inhibitors according to the present disclosure.
  • the present disclosure also relates to the use of the human protein HIF- l ⁇ prolyl hydroxylase inhibitors according to the present disclosure in the manufacture of a medicament for the treatment of atrial arrhythmias and related disorders.
  • the present disclosure also relates to hypoxia inducible factor HIF-I ⁇ prolyl hydroxylase inhibition in myocardial remodeling and function, thereby providing means for inducing angiogenesis in a patient experiencing ischemia.
  • the present disclosure relates to a method for treating anemia comprising administering to a human or mammal in need of treatment an effective amount of one or more human protein HIF- l ⁇ prolyl hydroxylase inhibitors according to the present disclosure.
  • the present disclosure relates to a method for regulating anemia comprising administering to a human or mammal in need of treatment an effective amount of one or more human protein HIF- l ⁇ prolyl hydroxylase inhibitors according to the present disclosure.
  • the present disclosure relates to a method for preventing anemia comprising administering to a human or mammal in need of treatment an effective amount of one or more human protein HIF- l ⁇ prolyl hydroxylase inhibitors according to the present disclosure.
  • the EGLN-I (or EGLN-3) enzyme activity is determined using mass spectrometry (matrix-assisted laser desorption ionization, time-of-flight MS, MALDI-TOF MS - for assay details, see reference (Greis et al., 2006).
  • Recombinant human EGLN-1-179/426 is prepared as described above and in the Supplemental Data.
  • Full-length recombinant human EGLN-3 is prepared in a similar way, however it is necessary to use the His-MBP-TVMV-EGLN-3 fusion for the assay due to the instability of the cleaved protein.
  • the HIF- l ⁇ peptide corresponding to residues 556-574 (DLDLEALAPYIP ADDDFQL) is used as substrate.
  • the reaction is conducted in a total volume of 50 uL containing TrisCl (5 mM, pH 7.5), ascorbate (120 ⁇ M), 2-oxoglutarate (3.2 ⁇ M), HIF-l ⁇ (8.6 ⁇ M), and bovine serum albumin (0.01%).
  • TrisCl 5 mM, pH 7.5
  • ascorbate 120 ⁇ M
  • 2-oxoglutarate 3.2 ⁇ M
  • HIF-l ⁇ 8.6 ⁇ M
  • bovine serum albumin 0.01%
  • reaction is stopped by transferring 10 ⁇ L of reaction mixture to 50 ⁇ L of a mass spectrometry matrix solution ( ⁇ - cyano-4-hydroxycinnamic acid, 5 mg/mL in 50% acetonitrile/0.1% TFA, 5 mM NH4PO4).
  • a mass spectrometry matrix solution ⁇ - cyano-4-hydroxycinnamic acid, 5 mg/mL in 50% acetonitrile/0.1% TFA, 5 mM NH4PO4
  • Two microliters of the mixture is spotted onto a MALDI-TOF MS target plate for analysis with an Applied Biosystems (Foster City, CA) 4700 Proteomics Analyzer MALDI-TOF MS equipped with a Nd: YAG laser (355 nm, 3 ns pulse width, 200 Hz repetition rate). Hydroxylated peptide product is identified from substrate by the gain of 16 Da. Data defined as percent conversion of substrate to product is analyzed in GraphPad Prism 4 to
  • HEK293 cells are seeded in 96-well poly-lysine coated plates at 20,000 cells per well in DMEM (10% FBS, 1% NEAA, 0.1% glutamine). Following overnight incubation, the cells are washed with 100 uL of Opti-MEM (Gibco, Carlsbad, CA) to remove serum. Compound in DMSO is serially diluted (beginning with 100 ⁇ M) in Opti-MEM and added to the cells. The conditioned media is analyzed for VEGF with a Quantikine human VEGF immunoassay kit (R&D Systems, Minneapolis, MN). Optical density measurements at 450nm are recorded using the Spectra Max 250 (Molecular Devices, Sunnyvale, CA). Data defined as % of DFO stimulation is used to calculate EC 50 values with GraphPad Prism 4 software (San Diego, CA).
  • mice All animal work is conducted in accordance with the Guide for the Care and Use of Laboratory Animals (National Academy of Sciences; Copyright ⁇ 1996) and the Institutional Animal Care and Use Committee guidelines at Procter and Gamble Pharmaceuticals.
  • vehicle aqueous carbonate buffer, 50 mM; pH 9.0
  • compound 1 in vehicle at 50 mg/kg or 100 mg/kg.
  • the animals are dosed three times: day 1 at 8am and 5 pm, day 2 at 8am.
  • One hour after the first dose unilateral arterial ligation is performed under anesthesia using isoflurane.
  • the femoral artery is ligated proximal to the origin of the popliteal artery.
  • the contralateral limb underwent a sham surgical procedure. Ligation is performed in an alternating fashion between right and left hindlimbs. Two hours after 8am dosing on day 2, we obtained blood by ventricular stick while the mice are anesthetized with isoflurane. Serum samples for EPO analysis are obtained using gel clot serum separation tubes. Heart, liver, and gastrocnemius muscles are harvested, snap-frozen in liquid nitrogen, and stored in -8O 0 C until use.
  • Mouse Serum EPO assay The mouse serum EPO is detected using Mouse Quantikine Erythropoietin ELISA kit from R&D Systems according to manufacturer's instructions.
  • Tissues from mice stored at -8O 0 C are powdered with mortar and pestle chilled with liquid nitrogen.
  • Nuclear extracts are prepared using an NE-PER kit (Pierce Biotechnology).
  • HIF- let Novus, Littleton, CO
  • the suspension is incubated in a conical micro centrifuge tube for 4 hours at 4°C.
  • Protein A/G-coupled agarose beads (40 ul of a 50% suspension) are then added to the tube. Following overnight tumbling at 4°C, the beads are washed 3 times with ice-cold phosphate buffered saline.
  • the beads are then prepared for SDS- PAGE with 40 ul of Laemmli sample buffer. Proteins separated on SDS-PAGE are transferred onto nitrocellulose sheets with XCeIl-II Blot Module system (Invitrogen, Carlsbad, CA). The blots are blocked with 5% BSA prior to incubation with a rabbit antibody to HIF- l ⁇ at 1 :100 dilution (Novus). The blots are then washed with Tris-buffered saline/Tween-20 buffer and incubated with horseradish peroxidase-conjugated goat anti-rabbit secondary antibody (Pierce, Rockford, IL). Blots are developed with the ECL reagent (Amersham, Piscataway, NJ). Images of blots are captured with an Epson Expression 1600 scanner.
  • Table XV below provides non-limiting examples of the in vivo response for compounds according to the present disclosure.

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Abstract

The present disclosure relates to HIF-1α prolyl hydroxylase inhibitors, compositions which comprise the HIF-1α prolyl hydroxylase inhibitors described herein and to methods for controlling, inter alia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, and anemia.

Description

PROLYL HYDROXYLASE INHIBITORS AND METHODS OF USE
FIELD OF THE DISCLOSURE The present disclosure relates, in some aspects, to HIF- lα prolyl hydroxylase inhibitor compounds and pharmaceutically acceptable salts thereof, compositions comprising the HIF- lα prolyl hydroxylase inhibitor compounds, and to methods for treating or controlling, inter alia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, and anemia.
BACKGROUND OF THE DISCLOSURE
HIF- lα under normal healthy conditions wherein the cells have a sufficient supply of oxygen is readily converted to a degraded form by one of several prolyl hydroxylase enzymes, inter alia, EGLIN. When cells undergo hypoxia, this enzymatic transformation is slow or entirely stopped and HIF-lα begins to build up in the cell. When this build up of HIF-lα occurs, this protein combines with another factor, HIF- lβ which together form an active transcription factor complex. This transcription factor then activates several biological pathways which are present as a response to and a means for alleviating the body's state of hypoxia. These responses include, inter alia, angiogenic, erythropoietic (EPO), glucose metabolism, and matrix alteration responses.
In patients where there is a need for stimulating one or more of these responses, for example, in patients in need of increased tissue oxygen due to peripheral vascular disease (PVD), inhibiting the EGLIN enzyme will stimulate the body's own angiogenic response without the consequences of oxygen deficiency. In addition, in diseases of ischemia, inter alia, CAD and anemia, stimulation of angiogenic, erythropoietic, and metabolic adaptation would be expected to provide therapeutic benefits.
Therefore there continues to be a long felt need for compounds that inhibit prolyl hydroxylase enzymes and thereby regulate the concentration of HIF-I α in cells so as to induce angiogenic or erythropoietic responses and therefore treat diseases related to hypoxia or anemia.
SUMMARY OF THE DISCLOSURE
The substituted aryl or heteroaryl amide compounds of the present disclosure are a new class of compounds that can inhibit HIF- lα prolyl hydroxylase, thus resulting in improvement in blood flow, oxygen delivery and energy utilization in ischemic tissues, or upregulate the production of erythropoietin so as to treat anemia.
Disclosed herein are compounds and pharmaceutically acceptable salts thereof, and/or pharmaceutical compositions thereof comprising: a) an effective amount of one or more compounds according to the present disclosure; and b) an excipient.
The present disclosures also relate to methods for controlling, inter alia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, and/or anemia.
The present disclosures also relate to methods for regulating blood flow, oxygen delivery and/or energy utilization in ischemic tissues, wherein the methods can comprise administering to a human an effective amount of one or more compounds or pharmaceutically acceptable salts 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 herein 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.
BRIEF DESCRIPTION OF THE FIGURES Figure 1. Immunoblot analysis of nuclear extracts demonstrating stabilization of HIF-I α in mouse liver by {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} -acetic acid Figure 2. An example of how the erythropoietin level is elevated versus vehicle in mouse serum after oral dosing of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}- acetic acid.
DETAILED DESCRIPTION OF THE DISCLOSURE
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:
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.
"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, W 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 i5 are disclosed, then 11, 12, 13, and 14 are also disclosed.
The term "organic unit" as described herein refers to groups or moieties that comprise one or more carbon atoms and which form a portion of one of the compounds or pharmacetucally acceptable salts thereof. For example, many of the substitutent units referred to elsewhere herein are organic units. In order to effectively function in the context of their presence in the compounds and/or salts disclosed herein, the organic units should often have variable ranges of restricted size and/or molecular weight, so as to provide desired binding to the target enzymes, solublility, bioabsorption characteristics. For example, 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 units often have hydrogen bound to at least some of the carbon atoms of the organic units, and can optionally contain the common heteroatoms found in substituted organic compounds, such as oxygen, nitrogen, sulfur, and the like, or inorganic atoms such as halogens, phosphorus, and the like.. 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, alkyl carboxamido, substituted alkylcarboxamido, dialkylcarboxamido, substituted dialkylcarboxamido, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.
Substituted and unsubstituted linear, branched, or cyclic alkyl units include the followini non-limiting examples: methyl (Ci), ethyl (C2), n-propyl (C3), z'so-propyl (C3), cyclopropyl (Ci), n-butyl (C4), sec-butyl (C4), iso-buty\ (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 (Ci), 1 -chloroethyl (C2), 2 -hydroxy ethyl (C2), 1,2-difluoroethyl (C2), 2,2,2- trifluoroethyl (C3), 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-methyl ethenyl) (C3), isopropenyl (also 2-methylethen-2-yl) (C3), buten-4-yl (C4), and the like; substituted linear or branched alkenyl, non-limiting example: of which include, 2-chloroethenyl (also 2-chlorovinyl) (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 (Cs), 5-hydroxy-5-ethylhept-3-ynyl (C9), and the like. Substituted and unsubstituted "alkoxy" are used herein denotes a unit having the general formula -OR100 wherein R100 is an alkyl, alkylenyl, or alkynyl unit as defined herein above, for example, methoxy, methoxymethyl, methoxy methyl.
Substituted and unsubstituted "haloalkyl" are used herein denotes an alkyl unit having a hydrogen atom substituted by one or more halogen atoms, for example, trifluoromethyl, 1 ,2- dicloroethyl, and 3,3,3-trifluoropropyl.
The term "aryl" as used herein denotes cyclic organic units that comprise at least one benzene ring having a conjugated and aromatic six-membered ring, non-limiting examples of which include phenyl (C6), naphthylen-1-yl (C 10), naphthylen-2-yl (C 10). 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 (Ce), 3- methylphenyl (Ce), 2-amino-4-fluorophenyl (Cβ), 2-(iV,A/-diethylamino)phenyl (Ce), 2- cyanophenyl (C6), 2,6-di-/erf-butylphenyl (C6), 3-methoxyphenyl (C6), 8-hydroxynaphthylen-2- yl (Cio), 4,5-dimethoxynaphthylen-l-yl (C10), and 6-cyanonaphthylen-l-yl (C10).
The term "heteroaryl" denotes an organic unit comprising a five or six membered conjugated and aromatic ring wherein at least one of the ring atoms is a heteroatom selected from nitrogen, oxygen, or sulfur.. The heteroaryl rings can comprise 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, such as a pyridine ring, a furan ring, or thiofuran ring.. A "heteroaryl" can also be a fused multicyclic and heteroaromatic ring system having wherein at least one of the rings is an aromatic ring and at least one atom of the aromatic ring is a heteroatom including nitrogen, oxygen, or sulfur
The following are non-limiting examples of heteroaryl rings according to the present disclosure:
Figure imgf000006_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 imgf000007_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 imgf000007_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 following are non-limiting examples of units which can substitute for hydrogen atoms on a hydrocarbyl or other unit: i) linear, branched, or cyclic alkyl, alkenyl, and alkynyl; for example, methyl (Ci), ethyl (C2), n-propyl (C3), /sø-propyl (C3), cyclopropyl (C3), propylen-2-yl (C3), propargyl (C3), n-butyl (C4), ώo-butyl (C4), sec-butyl (C4), tert-butyl (C4), cyclobutyl (C4), n-pentyl (C5), cyclopentyl (C5), n-hexyl (C6), and cyclohexyl (C6); ii) substituted or unsubstituted aryl; for example, phenyl, 2-fluorophenyl, 3- chlorophenyl, 4-methylphenyl, 2-ammophenyl,.3-hydroxyphenyl, A- 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) -(CR12aRl2b)qORn; for example, -OH, -CH2OH, -OCH3, -CH2OCH3, -
OCH2CH3, -CH2OCH2CH3, -OCH2CH2CH3, and -CH2OCH2CH2CH3; vi) -(CR12aR' 2b)qC(O)R' ' ; for example, -COCH3, -CH2COCH3, -OCH2CH3, -CH2COCH2CH3, -COCH2CH2CH3, and -CH2COCH2CH2CH3; vii) -(CR128R12^qC(O)OR1 ' ; for example, -CO2CH3, -CH2CO2CH3, CO2CH2CH3, -CH2CO2CH2CH3, -CO2CH2CH2CH3, and CH2CO2CH2CH2CH3; viii) -(CRI2aR12b)qC(O)N(R")2; for example, -CONH2, -CH2CONH2,
CONHCH3, -CH2CONHCH3, -CON(CH3)2, and -CH2CON(CH3)2; ix) -(CRl2aR12b)qOC(O)N(Rl ')2; for example, -OC(O)NH2, -CH2OC(O)NH2, -OC(O)NHCH3, -CH2OC(O)NHCH3, -OC(O)N(CH3)2, and CH2OC(O)N(CHa)2; x) -(CR12aRI2b)qN(R' ')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, m is from O to 2, m+n =3; for example, -
CH2F, -CHF2, -CF3, -CCl3, or -CBr3; xiii) -(CR12aR12b)qCN; for example; -CN, -CH2CN, and -CH2CH2CN; xiv) -(CR12aRl2b)qNO2; for example; -NO2, -CH2NO2, and -CH2CH2NO2; xv) -(CRI2aRl2b)qSO2R' '; for example, -SO2H, -CH2SO2H, -SO2CH3,
CH2SO2CH3, -SO2C6H5, and -CH2SO2C6H5; and xvi) -(CR12aRI2b)qSO3R' ' ; for example, -SO3H, -CH2SO3H, -SO3CH3, CH2SO3CH3, -SO3C6H5, and -CH2SO3C6H5; xvii) hydroxyl groups or thiol groups, xviii) amino groups, mono substituted amino, or disubstituted amino, wherein each R1 ' is independently hydrogen, substituted or unsubstituted C1-C4 linear, branched, or cyclic alkyl; or two R1 ' units can be taken together to form a ring comprising 3-7 atoms; RI2a and Rl2b are each independently hydrogen or C1-C4 linear or branched alkyl; the index q is from O to 4.
The compounds and compositions recited herein can have a number of utilities, and address several unmet medical needs, inter alia;
1) Providing compositions effective as inhibitors of human protein prolyl hydroxylase, thereby stimulating an angiogenic response in human tissue, thereby providing a method for increasing blood flow, oxygen delivery and energy utilization in ischemic tissues;
2) Providing compositions effective as human protein HIF- lα prolyl hydroxylase inhibitors, and thereby increasing the concentration of HIF-I α leading to greater activation and sustaining the of various biological pathways that are the normal response to cellular hypoxia;
3) Providing compositions effective in stimulating an erythropoietic (EPO) response in cell; and thereby enhancing the maintenance of red blood cells by controlling the proliferation and differentiation of erythroid progenitor cells into red blood cells;
4) Providing compositions effective in stimulating an angiogenic response and thereby increasing the number and density of blood vessels and thus alleviating the adverse consequences of hypertension and diabetes, inter alia, claudication, ischemic ulcers, accelerated hypertension, and renal failure; 5) Providing compositions that activate Vascular Endothelial Growth Factor (VEGF) gene transcription in hypoxic cells thus increasing stimulus of important biological responses, inter alia, vasodilation, vascular permeability, and endothelial cell migration and proliferation.
Therefore, these and other unmet medical needs are resolved by the HIF- lα prolyl hydroxylase inhibitors of the present disclosure, which are capable of regulating blood flow, oxygen delivery and energy utilization in ischemic tissues that are caused by insufficient regulation of HIF-I α prolyl hydroxylase. Those of skill in the art will also recognize that inhibition of HIF-I α prolyl hydroxylase enzymes will have other positive medical effects on human tissue and the alleviation of symptoms and disease states other than those symptoms or diseases states that are specifically pointed out in the present disclosure. However, as greater details arise concerning disease states and conditions related to the angiogenic process, these yel undisclosed or yet unknown conditions will be positively affected by compositions which stimulate the body own response to hypoxia and other low blood oxygen conditions.
For the purposes of the present disclosure the terms "compound," "analog," and "composition of matter" stand equally well for the HIF- lα prolyl hydroxylase enzyme inhibitors described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms "compound," "analog," and "composition of matter" are used interchangeably throughout the present specification.
The compounds disclosed herein include all salt forms, for example, salts of both basic groups, inter alia, amines, as well as salts of acidic groups, inter alia, carboxylic acids. The following are non-limiting examples of anions that can form pharmaceutically acceptable salts with basic groups: chloride, bromide, iodide, sulfate, bisuifate, 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 pharmaceutically acceptable salts of the anionic form of acidic substituent groups on the compounds described herein: sodium, lithium, potassium, calcium, magnesium, zinc, bismuth, and the like.
The HIF- lα prolyl hydroxylase inhibitor compounds described herein are substituted aryl or heteroaryl amides, having the core structure shown in Formula (I) below.
Figure imgf000010_0001
(D
wherein X can be N or CH; L is an organic linking unit as further described, below, and Y, R, R1 and R2 can be any of the units further described below.
When X is a nitrogen atom the compounds of the present disclosure are 2- arnidopyri dines and when X is CH the compounds of the present disclosure are arylamides, as shown below:
Figure imgf000010_0002
aryl amide 2-amidopyridines
R and R1 are optional substituent groups that can be independently chosen from a wide variety of inorganic (hydrogen, hydroxyl, amino, halogen or the like) or organic substituent units, such as alkyls, cycloalkyls, heterocyclic, heteroaryl s, and the like, wherein such substituent units can optionally have from 1 to 12 carbon atoms, or 1 to 10 carbon atoms, or 1 to six carbon atoms. In many aspects of the invention, R and R1 can each be independently a chosen from: i) hydrogen; ii) substituted or unsubstituted phenyl; and iii) substituted or unsubstituted heteroaryl. wherein the optional substitutent units for the phenyl and heteroaryl rings can be chosen from a wide variety of inorganic and Ci-C4 organic radicals, and there are typically zero, one, two, or three of such substituent groups. In many such aspects, one, two, or three substituentsfor the above-mentioned phenyl and heteroaryl rings can be independently selected from: i) C1-C4 linear, branched, or cyclic alkyl; ii) C1-C4 linear, branched, or cyclic alkoxy; iii) C1-C4 linear, branched, or cyclic haloalkyl; iv) halogen; v) -CN; vi) -NHC(O)R4 vii) -C(O)NR5aR≤b; viii) heteroaryl; or ix) two substitutions can be taken together to form a fused ring having from 5 to 7 atoms; wherein the above-mentioned R4 unit can be hydrogen or a C1-C4 linear, branched, or cyclic alkyl; and wherein the R5a andR5b units can be independently selected from: i) hydrogen; ii) C1-C4 linear, branched, or cyclic alkyl; or iii) R5a and R5b can be taken together to form a ring having from 3 to 7 atoms.
In some aspects of the compounds of Formula (I)5 the R units can be chosen from substituted or unsubstituted phenyl; or substituted or unsubstituted heteroaryls; and the R1 units are hydrogen.
In other aspects of the compounds of Formula (I), R can be a substituted or unsubstituted phenyl, having one, two, or three optional inorganic or organic substitutents, which in some embodiments are chosen from: i) C1-C4 linear, branched, or cyclic alkyl; ii) Ci-C4 linear, branched, or cyclic alkoxy; iii) C 1 -C4 linear, branched, or cyclic haloalkyl; iv) halogen; or v) -CN.
Non-limiting examples of R units include 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-iso- propylphenyl, 3-z'sø-propylphenyl, 4-wo-propylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4- cyanophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3- ethoxyphenyl, 4-ethoxyphenyl, 2-∑.sø-propoxyphenyl, 3-2so-propoxyphenyl, 4-iso- propoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3- trifluoromethylphenyl, and 4-trifluoromethylphenyl.
In additional aspects of the compounds of Formula (I) the R units can have the formula -NH(C(O)R4 wherein R4 is C1-C4 linear, branched, or cyclic alkyl. Non limiting examples of such R units include: i) -NH(C(O)CH3; ii) -NH(C(O)CH2CH3; ii) -NH(C(O)CH2CH2CH3; ii) -NH(C(O)CH(CH3)2; ii) -NH(C(O)(cyclopropyl); and ii) -NH(C(O)CH2CH2CH2CH3.
In additional aspects of the compounds of Formula (I), the R units can have the formula:
Figure imgf000012_0001
wherein R10 has the formula -C(O)NR5aR5b; wherein R5a and R5b can be independently selected from hydrogen, Ci-C4 linear or branched alkyls, or R5a and R5b are taken together to from a ring having 5 or 6 atoms. In some such aspects, the R10 units can have the formula: — C(O)NR5aR5b wherein R5a and R5b are each independently selected from hydrogen, methyl, ethyl, n-propyl, /so-propyl, and cyclopropyl. Non-limiting examples of such R10 units include: i) -C(O)NH2; ii) -C(O)NHCH3; iii) -C(O)N(CH3)2; iv) -C(O)NH(CH2CH3); v) -C(O)N(CH2CH3)2; vi) -C(O)N(CH3)(CH2CH3). vii) -C(O)NH(CH2CH2CH3); viii) -C(O)N(CH2CH2CH3)2; ix) -C(O)NH[CH(CH3)2]; x) -C(O)N[CH(CH3)2]2; xi) -C(O)N(CH2CH2CH3)[CH(CH3)2]; and xii) -C(O)NH(cyclopropyl). In additional aspects of the compounds of Formula (I), R5a and R5b together to form a ring having 5 or 6 ring atoms, non-limiting examples of R10 units are heteroaryl units chosen from pyrrol idin-1-yl, piperidin-1-yl, piperazin-1-yl, and morpholin-4-yl.
In additional aspects of the compounds of Formula (I), the R10 units can be heteroaryl units, non limiting examples of which are thiazol-2-yl, thiazol-4-yl, l,2,3,4-tetrazol-5-yl, [l,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, 1,2,3,4- tetrazol-5-yl, [l,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, and isoquinolin-4-yl.
In additional aspects of the compounds of Formula (I), the R units can include substituted phenyl units wherein two substitutions can be taken together to form a fused ring having from 5 to 7 ring atoms, for example a 2,3-dihydro-benzo[l,4]dioxin-6-yl ring which would provide a compound having the formula:
Figure imgf000013_0001
Other examples of R include units wherein R is hydrogen and R1 is hydrogen.
Figure imgf000013_0002
wherein R2, X, Y, L, and R9 can be independently chosen in any manner as otherwise taught herein with respect to the compounds of Formula (I).
As described previously above, the R1 substituents for compounds of Formula (I) can be chosen from a wide variety of inorganic and organic units. In some embodiments, R1 is a phenyl ring, which can optionally be substituted with 1, 2, or 3 substituent units, independently selected from inorganic or Ci -C4 organic units. In some are chosen from: i) Ci -C4 linear, branched, or cyclic alkyl; ii) Ci-C4 linear, branched, or cyclic alkoxy; iii) C1-C4 linear, branched, or cyclic haloalkyl; iv) halogen; or v) -CN.
Non-limiting examples of R1 include 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-iso-propylphenyl, 3-iso- propylphenyl, 4-ύopropylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4- ethoxyphenyl, 2-/so-propoxyphenyl, 3-isopropoxyphenyl, 4-wo-propoxyphenyl, 2- cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, and 4-trifluoromethylphenyl.
Another example of R1 units includes compounds wherein R is hydrogen and R1 units are hydrogen.
In some aspects of the compounds of Formula (I), R is hydrogen and R1 is a substituted or unsubstituted phenyl, wherein the substitutions are chosen from: i) C1-C4 linear, branched, or cyclic alkyl; ii) C1-C4 linear, branched, or cyclic alkoxy; iii) C1-C4 linear, branched, or cyclic haloalkyl; iv) halogen; and v) -CN.
In connection with the compounds of Formula (I), Y is a unit that can be chosen from a wide variety of inorganic units, such as H, —OH, -NH2, or a halogen, and C1-C4 organic units. For example, Y can be chosen from: i) hydrogen; ii) —OR3, wherein R3 is hydrogen, or a lower alkyl, such as methyl, or ethyl.
In connection with the compounds of Formula (I), the R2 units can be chosen from a wide variety of inorganic units, such as -OH, or -NH2 units, or a variety of organic units.
In some aspects fo the compounds of the invention, R2 is chosen from: i) -OR6; or ii) -NR7aR7b; wherein R6 is hydrogen or C1-C4 linear, branched, or cyclic alkyl; and R7a andR7b are each independently chosen from: i) hydrogen; ii) C1-C4 linear, branched, or cyclic alkyl; or iii) R7a and R7b can be taken together to form a ring having from 3 to 7 atoms.
In certain favored aspects of the invention the R2 units are hydroxyl (—OH) wherein the compounds are carboxylic acids, or may also be present in the form of a salt as the corresponding hydroxyl/carboxylate anion, i.e. R2 can bea -O" unit, so as to form a compound having a carboxylate group, as shown below.
Figure imgf000015_0001
wherein R, R1, R2, X, Y, L, and R9 can be independently chosen in any manner as otherwise taught herein with respect to the compounds of Formula (I).
Another example of R2 includes compounds wherein R6 is Ct-C4 linear, branched, or cyclic alkyl providing R2 units which are alkoxy wherein the compounds formed are organic esters having C1-C4 linear, branched, or cyclic alkyl groups. Non-limiting examples of R2 units are: i) -OCH3; ii) -OCH2CH3; and iii) -OCH2CH2CH3.
Yet further examples of R2 units include compounds wherein R2 has the formula — NR7aR7b; and R7a and R7b are each independently chosen from: i) hydrogen; and ii) C1-C4 linear, branched, or cyclic alkyl. Non-limiting examples of R2 units include: i) -NH2; ii) -NHCH3; iii) -N(CH3)2; iv) -NH(CH2CH3); v) -N(CH2CH3)2; vi) -N(CH3)(CH2CH3). vii) -NH(CH2CH2CH3);
Figure imgf000015_0002
ix) -NH[CH(CH3)2]; x) -N[CH(CH3)2]2; xi) -N(CH2CH2CH3)[CH(CH3);!]; and xii) -NH(cyclopropyl).
A yet further example of R2 units includes compounds wherein R2 has the formula — NR7aR7b; and R7a and R7b are taken together to form a ring having from 3 to 7 atoms, wherein the non- limiting examples of R2 units include aziridin-1-yl, axetidin-l-yl, pyrolidin-1-yl, piperidin- 1-yl, piperazin-1-yl, and morpholin-4-yl.
In connection with the compounds of Formula (I), L is a unit that links the nitrogen atom of the carboxyamide group to the neighboring carbonyl group. L is typically a Ci-C6 or Ci-C4 organic linking unit. In some embodiments, L comprises a one or more optionally substituted methylene units having the formula:
-[C(R8aR8b)]y-; wherein R8a and R8b are each independently hydrogen, Ci-C6 linear or branched alkyl, or phenyl: and the index y is from 1 to 4.
An example of L units includes units wherein R8a and R8b are both hydrogen and the index n is equal to 1 , the L unit has the formula:
-CH2- and are referred to herein as methylene linking units, so as to form compounds having the structure shown below:
Figure imgf000016_0001
wherein R, R , R , X, Y, and R can be independently chosen in any manner as otherwise taught herein with respect to the compounds of Formula (I).
Another example of L units includes units wherein R8a and R8b are each hydrogen or methyl and the index n is equal to 1 , these units having the formula:
-CH(CH3)- or -C(CH3)2-. A further example of L units includes units wherein all R8a and R8b units are hydrogen and the index n is equal to 2, these units having the formula:
-CH2CH2- and are referred to herein as ethylene linking units. In connection with the compounds of Formula I, the R9 substituent for the amide nitrogen atom can be hydrogen or a C1-C4 organic substituent, such as a C1-C4 alkyl group, such as methyl, or a Ci-C4 haloalkyl, such as a trifluoromethyl group.
The compounds of Formula (I) can be organized into several categories for the strictly non-limiting purpose of describing alternatives for synthetic strategies for the preparation of subgenera of compounds within the scope of Formula (I) that are not expressly exemplified herein. This mental organization into categories does not imply anything with respect to increased or decreased biological efficacy with respect to any of the compounds or compositions of matter described herein.
One such subgenus of the compounds of Formula (I) relates to compounds having the formula:
Figure imgf000017_0001
which can be more specifically described by methyl ester compounds having the formula:
Figure imgf000017_0002
wherein R units can be substituted or unsubstituted phenyl, non-limiting examples of which are described in Table I herein below.
TABLE I
Figure imgf000017_0003
Figure imgf000018_0003
Such compounds can be prepared by the procedure outlined in Scheme I and further described in Example 1 herein below.
Scheme I
Figure imgf000018_0001
Reagents and conditions: (a) C6H5OH, NaH, THF; microwave 190 0C, 5 hr.
Figure imgf000018_0002
1 2
Reagents and conditions: (b) NaOH, H2O, MeOH; reflux, 16 hr.
Figure imgf000019_0001
2 3
Reagents and conditions: (c) GlyOMe.HCl, EDCI, HOBt, DMF; 0 0C to rt, 3 days.
Figure imgf000019_0002
3 4
Reagents and conditions: (d) H2: Pd/C, MeOH, rt, 16 hr.
Figure imgf000019_0003
4 5
Reagents and conditions: (e) (CF3SO2O2NC6H5, MeOH, rt, 16 hr.
Figure imgf000019_0004
5 6
Reagents and conditions: (f) 3-chlorophenylboronic acid, Pd(dppf)Cl2, K3PO4, dioxane; 85 0C, 16 hr.
EXAMPLE 1
{ [5 -(3-Chloro-phenyl)-3-hydroxy-pyτidine-2-carbonyl]-amino } acetic acid methyl ester (6)
Preparation of 3,5-bis-benzyloxy-pyridine-2-carbonitrile (1): To an 80 mL microwave pressure vessel is charged dry THF (30 mL) and benzyl alcohol (6.32 mL, 61.1 mmol). The solution is cooled to 00C and sodium hydride (2.44 g of a 60% dispersion in mineral oil, 61.1 mmol) is added in portions. The reaction mixture is gradually allowed to warm to room temperature with efficient stirring until the evolution of hydrogen gas ceases. The solution is re- cooled to 0 0C and 3,5-dichloro-2-cyanopyridine (5.00 g, 29.1 mmol) is added, and the solution is transferred to an unfocussed Mars 5 CEM microwave reactor to 1900C, 300 W and held for 5 hours. The reaction mixture is quenched with H2O, concentrated under reduced pressure, diluted with EtOAc and washed with 2M Na2CCh, H2O and saturated aqueous NaCl. The organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to give a brown solid. The crude solid is purified over silica (EtOAc:heptane, gradient 1 :1 to 1:0) to afford 8.6 g (94% yield) of the desired compound as an orange solid. 1H NMR (400 MHz,
CDCl3) δ ppm 7.96 (1 H, d, J= 2.2 Hz), 7.25 - 7.37 (10 H, m), 6.78 (1 H, d, J= 2.2 Hz), 5.10 (2 H, s), 5.03 (2 H, s). HPLC-MS: m/z 317 [M+H]+.
Preparation of 3,5-'bis-benzyloxy-pyridine-2-carboxylic acid (2): To a solution of 3,5- bis-benzyloxy-pyridine-2-carbonitrile, I3 (26.0 g, 82.3 mmol) in MeOH (217 mL) is added 30% w/v sodium hydroxide (320 mL) and the reaction mixture is refluxed for 16 hours. The solvent is removed under reduced pressure and the resulting suspension is acidified with cone. HCl until the pH is between 1 and 2. The precipitate that results is collected by filtration, washed with H2O (10 mL) and dried overnight in a vacuum oven to afford 30 g (quantitative) of the desired product as the hydrochloride salt. 1H NMR (250 MHz, DMSO-^6) δ ppm 8.02 (1 H5 d, J= 2.4 Hz), 7.29 - 7.53 (11 H, m), 5.96 (1 H, br s), 5.28 (4 H, s). HPLC-MS: m/z 336 [M+H]+.
Preparation of [(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-acetic acid methyl ester (3): To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid HCl , 2, (8.06 g, 21.7 mmol) in DMF (10O mL) at 0 0C under N2 is added diisopropylethylamine (11.35 mL, 65.1 mmol), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (6.23 g, 32.6 mmol) and 1- hydroxybenzotriazole (HOBt) (0.294 g, 2.2 mmol). The solution is stirred for 5 minutes and glycine methyl ester hydrochloride (4.09 g, 32.6 mmol) is added. The reaction is allowed to warm slowly to room temperature and stirred 3 days. The reaction volume is partially concentrated under reduced pressure then diluted with EtOAc and washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer is dried (MgSO4), filtered am concentrated under reduced pressure to afford a yellow oil that is purified over silica (EtOAc :heptane gradient 1:1 to 1:0) to afford 3.5 g (40% yield) of the desired product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (1 H, t, J= 4.9 Hz), 7.95 (1 H3 d, J= 1.8 Hz), 7.38 - 7.44 (2 H3 m), 7.22 - 7.35 (8 H, m), 6.85 (1 H3 d, J= 2.6 Hz), 5.14 (2 H, s), 5.03 (2 H, s), 4.18 (2 H3 d, J= 5.5 Hz), 3.69 (3 H3 s). HPLC-MS: m/z 407 [M+H]+.
Preparation of [(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid methyl ester (4):
To a solution [(SjS-bis-benzyloxy-pyridine^-carbonyO-aminoJ-acetic acid methyl ester (3.50 g, 8.62 mmol) in MeOH (100 mL) is added 10% Pd/C (0.350 g3 0.862mmol) and the reaction mixture stirred under an atmosphere OfH2 at room temperature for 16 hours. The suspension is filtered through Celite™ and the filtrate concentrated under reduced pressure. The crude material is purified over silica (MeOHrCH2Cl2 gradient 1% to 5%) to afford 1.95 g (quantitative yield) of the desired compound as an off-white solid. 1H NMR (250 MHz, MeOD) δ ppm 7.62 (1 H, d, J= 2.4 Hz)3 6.53 (1 H3 d3 J= 2.4 Hz), 4.04 (2 H3 s), 3.64 (3 H, s). HPLC-MS: m/z 227 [M+H]+.
Preparation of [(3-hydroxy-5-trifluoromethanesulfonyloxy-pyridine-2-carbonyl)-amino]- acetic acid methyl ester (5): To a solution of [(3,5-dihydroxy-pyridine-2-carbonyl)-amino]- acetic acid methyl ester, 4, (1.95 g, 8.62 mmol) in MeOH (60 mL) is added diisopropylethylamine (DIPEA) (1.62 mL, 9.3 mmol). The mixture is cooled to 0 0C and N- phenyl trifluoromethansulfonimide (3.32 g, 9.3 mmol) is added. The resulting solution is slowly warmed to room temperature and stirred for an additional 16 hours. The solvent is removed under reduced pressure and the crude material is purified over silica (EtOAc:hexane 1:4) to afford 2.27 g (73% yield) of the desired product as an off-white solid. !H NMR (400 MHz3 CDCl3) δ ppm 12.17 (1 H, s), 8.27 (1 H, t, J= 5.5 Hz)3 8.08 (1 H3 d, J= 2.2 Hz), 7.28 (1 H3 d, J = 2.2 Hz)3 4.24 (2 H3 d, J= 5.5 Hz), 3.82 (3 H, s). HPLC-MS: m/z 359 [M+H]+.
Preparation of {[5-(3-chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic aci( methyl ester (6): To a degassed solution of [(3-hydroxy-5-trifluoromethane-sulfonyloxy- pyridine-2-carbonyl)-amino]-acetic acid methyl ester, 5, (0.30 g, 0.84 mmol) in 1,4-dioxane (10 mL) at room temperature under N2 is added 3-chlorophenylboronic acid (0.196 g, 1.26 mmol), Pd(dppf)Cl2 (0.068 g3 0.0084 mmol) and K3PO4 (0.195 g, 0.92 mmol). The resulting suspensior is heated in a sealed tube at 85 0C for 16 hours. After this time, the mixture is cooled to room temperature and concentrated under reduced pressure. The residue is then treated with IM HCl (1 mL) and diluted with EtOAc. The organic layer is separated, washed with H2O, saturated aqueous NaCl and concentrated under reduced pressure. The crude material is purified over silica (EtOAc: heptane 3:7). The resulting solid can be crystallized from EtOAc/heptane to afforc 0.143g (53% yield) of the desired compound as a colorless solid. 1H NMR (400 MHz, CDCl3) δ ppm 1 1.77 (1 H, s), 8.36 (1 H5 t, J= 5.7 Hz), 8.24 (1 H, d, J= 1.8 Hz), 7.50 - 7.53 (1 H, m), 7.39 - 7.42 (2 H, m), 7.34 - 7.37 (2 H, m), 4.20 (2 H, d, J= 5.9 Hz)5 3.76 (3 H5 s). HPLC-MS: m/z.
The procedure outlined in Scheme I can be modified by substituting in step (f) other reagents for 3-chlorophenylboronic acid. Non-limiting examples include 4-chlorophenylboronic acid, 2-chlorophenylboronic acid, 2-fluorophenylboronic acid, 3-fluorophenylboronic acid, 4- fluorophenylboronic acid, 2-rnethylphenylboronic acid, 3-methylphenylboronic acid, and 4- methylphenylboronic acid.
The following are further non-limiting examples of compounds encompassed within first aspect of Category I of the present disclosure.
Figure imgf000022_0001
{[5-(4-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino} -acetic acid methyl ester: 1H NMR (400 MHz5 CDCl3) δ ppm 11.77 (1 H5 s), 8.36 (1 H5 1, J = 5.5 Hz), 8.23 (1 H, d, J - 1.8 Hz), 7.44 - 7.49 (2 H, m), 7.38 - 7.42 (3 H5 m), 4.20 (2 H, d, J = 5.9 Hz), 3.76 (3 H5 s). HPLC- MS: m/z 321 [M+H]+.
Figure imgf000022_0002
{[5-(2-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino} -acetic acid methyl ester: 1H NMR (400 MHz5 MeOD) δ ppm 8.10 (1 H, d, J = 1.8 Hz), 7.46 (1 H, dd, J = 7.5, 2.4 Hz), 7.30 - 7.35 (4 H5 m), 4.11 (2 H5 s), 3.68 (3 H, s). HPLC-MS: m/z 321 [M+H]+.
Figure imgf000023_0001
{[5-(4-Fluorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino} -acetic acid methyl ester: 1H NMR (250 MHz, CDCl3) δ ppm 1 1.88 (1 H, s), 8.48 (1 H, t, J = 5.6 Hz), 8.33 (1 H, d, J = 2.1 Hz), 7.55 - 7.65 (2 H3 m), 7.49 (1 H, d, J = 2.1 Hz), 7.17 - 7.27 (2 H, m), 4.28 - 4.32 (2 H, m), 3.86 (3 H5 s). HPLC-MS: m/z 305 [M+H]+.
Figure imgf000023_0002
[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-acetic acid methyl ester: 1H NMR (400 MHz, CDCl3) δ ppm 11.72 (1 H, s), 8.36 (1 H, t, J = 5.1 Hz), 8.26 (1 H, d, J = 1.8 Hz), 7.43 (2 H, d, J = 8.0 Hz), 7.40 (1 H, d, J = 1.8 Hz), 7.23 (2 H, d, J = 8.1 Hz), 4.19 (2 H, d, J = 5.9 Hz), 3.75 (3 H, s), 2.35 (3 H, s). HPLC-MS: m/z 301 [M+H]+.
Figure imgf000023_0003
{[3-Hydroxy-5-(4-isopropylphenyl)-pyridine-2-carbonyl]-amino}-acetic acid methyl ester: 1H NMR (250 MHz, CDCl3) δ ppm 11.88 (1 H, s), 8.54 (1 H, t, J = 5.6 Hz), 8.38 (1 H, d, J = 1.8 Hz), 7.55 - 7.60 (2 H, m), 7.54 (1 H, d, J = 2.1 Hz), 7.36 - 7.42 (2 H, m), 4.30 (2 H, d, J = 5.8 Hz), 3.85 (3 H, s), 2.93 - 3.07 (1 H, m), 1.33 (6 H, d, J = 7.0 Hz). HPLC-MS: m/z 329 [M+H]+.
Figure imgf000023_0004
{[5-(4-Ethylphenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester: 1H NMR (250 MHz, CDCl3) δ ppm 11.86 (1 H, s), 8.51 (1 H, t, J = 5.8 Hz), 8.37 (1 H, d, J = 1.8 Hz), 7.56 (2 H, d, J - 8.2 Hz), 7.53 (1 H, d, J = 1.8 Hz), 7.36 (2 H, d, J = 8.5 Hz), 4.30 (2 H, d, J = 5.8 Hz), 3.85 (3 H, s), 2.75 (2 H, q, J = 7.6 Hz), 1.31 (3 H5 1, J = 7.6 Hz). HPLC-MS: m/z 315
Figure imgf000024_0001
{[3-Hydroxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-amino}-acetic acid methyl ester: 1H NMR (250 MHz, CDCl3) δ ppm 11.91 (1 H, s), 8.48 (1 H, t, J = 6.1 Hz), 8.37 (1 H, d, J = 1.8 Hz), 7.60 - 7.92 (4 H, m), 7.54 (1 H, d, J = 2.1 Hz), 4.31 (2 H, d, J = 5.8 Hz), 3.86 (3 H, s). HPLC-MS: m/z 355 [MH-H]+.
Figure imgf000024_0002
{[5-(4-Cyanophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester: 1H NMR (400 MHz, CDCl3) δ ppm 11.83 (1 H, s), 8.36 (1 H, t, J = 5.12 Hz), 8.26 (1 H, d, J = 1.83 Hz), 7.70 - 7.75 (2 H, m), 7.62 - 7.66 (2 H, m), 7.43 (1 H, d, J = 1.83 Hz), 4.21 (2 H, d, J = 5.49 Hz), 3.76 (3 H, s). HPLC-MS: m/z 312 [M+H]+.
Figure imgf000024_0003
{[5-(3-Cyanophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino} -acetic acid methyl ester: 1H NMR (250 MHz, DMSO-d6) δ ppm 12.30 (1 H, s), 9.51 (1 H, t, J = 5.8 Hz), 8.55 (1 H, d, J = 1.8 Hz), 8.32 (1 H, s), 8.14 (1 H, d, J = 8.5 Hz), 7.89 (1 H3 d, J = 7.8 Hz), 7.81 (1 H, d, J = 1.9 Hz), 7.68 (1 H, t, J = 7.8 Hz), 4.06 (2 H, d, J = 6.1 Hz), 3.63 (3 H, s). HPLC-MS: m/z 312 [M+H]+.
Figure imgf000024_0004
{[5-(3-Carbamoylphenyl)-3-hydroxy-pyridine-2-carbonyl]-amino} -acetic acid methyl ester: 1H NMR (250 MHz, DMSOd6) δ ppm 12.30 (1 H3 s), 9.54 (1 H, t, J = 6.0 Hz), 8.61 (1 H, d3 J = 1.8 Hz), 8.29 (1 H, s), 8.18 (1 H3 br s), 7.98 (2 H3 1, J = 8.1 Hz), 7.84 (1 H3 d, J = 1.7 Hz), 7.62 (1 H, t, J = 7.8 Hz), 7.53 (1 H, br s), 4.12 (2 H3 d, J = 6.0 Hz)3 3.69 (3 H, s). HPLC-MS: m/. 330 [M+H]+.
Figure imgf000025_0001
( {3 -Hydroxy-5 -[3 -(pyrrolidine- 1 -carbonyl)-phenyl]-pyridine-2-carbonyl } -amino)-acetic acid methyl ester: 1H NMR (250 MHz, CDCl3) δ ppm 11.80 (1 H3 s), 8.44 (1 H, t, J = 5.3 Hz), 8.35 (1 H, s), 7.77 (1 H, s), 7.47 - 7.70 (4 H, m), 4.28 (2 H, d, J = 5.7 Hz), 3.83 (3 H, s), 3.64 - 3.76 (2 H3 m), 3.42 - 3.55 (2 H, m), 1.84 - 2.07 (4 H, m). HPLC-MS: m/z 384 [M+H]+.
Figure imgf000025_0002
({5-[3-(Cyclopropanecarbonyl-amino)-phenyl]-3-hydroxy-pyridine-2-carbonyl}-amino)- acetic acid methyl ester: 1H NMR (250 MHz3 CDCl3) δ ppm 1 1.80 (1 H3 s), 8.45 (1 H, br s),
8.29 (1 H3 s), 7.65 - 7.88 (2 H, m), 7.29 - 7.60 (4 H3 m), 4.18 - 4.31 (3 H3 m), 3.83 (3 H, s), 1.05 - 1.17 (2 H3 m), 0.81 - 0.98 (2 H, m). HPLC-MS: m/z 370 [M+H]+.
The following heteroaryl substituted phenyl compound can be prepared from {[5-(3- • cyano-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino} acetic acid methyl ester by treatment with trimethylsilyl azide and di-butyl tin oxide in DME and heating the mixture to 140 0C, 150 W3 200 psi in a microwave reactor.
Figure imgf000025_0003
( {3-Hydroxy-5-[3-(2H-tetrazol-5-yl)-phenyl]-pyridine-2-carbonyl}-amino)-acetic acid methyl ester: 1H NMR (400 MHz3 DMSOd6) δ ppm 12.33 (1 H3 s), 9.55 (1 H, t, J = 6.1 Hz)3 8.62 (1 H, d, J = 1.8 Hz), 8.43 (1 H, s), 8.14 (1 H, d, J = 7.9 Hz)3 8.05 (1 H, d, J = 8.1 Hz), 7.83 (1 H, d, J = 1.9 Hz), 7.76 (1 H, t, J = 7.8 Hz), 4.12 (2 H3 d, J = 6.1 Hz), 3.69 (3 H, s). HPLC-MS: m/z 355 [M+H]+.
For the purposes of describing synthetic methods, another mental subgenus of the compounds of Formula (I) have the formula:
Figure imgf000026_0001
wherein R units which are substituted or unsubstituted heteroaryl, non-limiting examples of which are described in Table II herein below.
TABLE II
Figure imgf000026_0002
The compounds encompassed within the compounds described immediately above can be prepared by the procedure outlined in Scheme I and described in Example 1 herein above.
The procedure outlined in Scheme I can be modified by substituting in step (f) other reagents for 3-chlorophenylboronic acid. Non-limiting examples of substitutes include 3- (thiazol-2-yl)phenylboronic acid, 3-(thiazol-4-yl)phenylboronic acid, 4-(thiazol-2- yl)phenylboronic acid, 4-(thiazol-4-yl)phenylboronic acid, 3-(imidazol-2-yl)phenylboronic acid. 4-(imidazol-2-yl)phenylboronic acid, 3-(furan-2-yl)phenylboronic acid, 3-(furan-3- yl)phenylboronic acid, and 3-(thiophene-2-yl)phenylboronic acid.
The following are non-limiting examples of such compounds.
Figure imgf000027_0001
[(S-Hydroxy-P^^bipyridinyi-ό-carbonyty-aminoJ-acetic acid methyl ester 1H NMR (250 MHz, CDCl3) δ ppm 11.80 (1 H, s), 8.87 (1 H, d, J = 1.7 Hz), 8.70 (1 H, dd, J = 4.8, 1.6 Hz), 8.45 (1 H, t, J = 5.8 Hz), 8.33 (1 H, d, J = 1.9 Hz), 7.91 (1 H, ddd, J = 8.0, 2.3, 1.7 Hz), 7.51 (1 H, d, J = 1.9 Hz), 7.45 (1 H3 ddd, J = 7.9, 4.8, 0.7 Hz), 4.28 (2 H, d, J = 5.8 Hz), 3.83 (3 H, s). HPLC-MS: m/z 288 [M+H]+.
Figure imgf000027_0002
[(5'-Hydroxy-[2,3']bipyridinyl-6'-carbonyl)-amino]-acetic acid methyl ester: 1H NMR
(250 MHz, CDCl3) δ ppm 8.70 - 8.79 (2 H, m), 8.49 (1 H, t, J = 5.8 Hz), 7.72 - 7.92 (3 H, m), 7.31 - 7.39 (1 H, m), 4.28 (2 H, d, J = 5.8 Hz), 3.83 (3 H, s). HPLC-MS: m/z 288 [M+H]+.
Figure imgf000027_0003
[(3-Hydroxy-5-pyrimidin-5-yl-pyridine-2-carbonyl)-ammo]-acetic acid methyl ester: 1H
NMR (250 MHz, CDCl3) δ ppm 11.90 (1 H, s), 9.32 (1 H, s), 9.00 (2 H, s), 8.45 (1 H, br s), 8.34 (1 H, d, J = 1.8 Hz), 7.53 (1 H, d, J = 1.8 Hz), 4.29 (2 H, d, J = 5.7 Hz), 3.84 (3 H, s). HPLC- MS: m/z 289 [M+H]+.
Figure imgf000027_0004
[(S-Hydroxy-S-isoquinolin^-yl-pyridine^-carbonyO-aminoJ-acetic acid methyl ester: 1H NMR (250 MHz, CDCl3) δ ppm 11.80 (1 H5 s), 9.38 (1 H, br s), 8.51 (2 H, t, J = 5.7 Hz), 8.27 (1 H, s), 8-13 (1 H, d, J = 7.2 Hz), 7.67 - 7.93 (3 H, m), 7.51 (1 H, s), 4.31 (2 H, d, J = 5.7 Hz), 3.85 (3 H, s). HPLC-MS: m/z 338 [M+H]+.
Figure imgf000028_0001
[(3-Hydroxy-5-thiazol-2-yl-pyridine-2-carbonyl)-amino]-acetic acid methyl ester: 1H NMR (250 MHz, CDCl3) δ ppm 11.80 (1 H, s), 8.67 (1 H, d, J = 1.8 Hz)3 8.39 (1 H, br s), 7.93 (1 H, d, J = 3.3 Hz), 7.78 (1 H, d, J = 1.7 Hz), 7.43 (1 H, d, J = 3.2 Hz), 4.22 (2 H, d, J = 5.8 Hz)3 3.78 (3 H, s). HPLC-MS: m/z 294 [M+H]+.
Another mental subgenus of the compounds of Formula (I) encompasses compounds having the formula:
Figure imgf000028_0002
wherein R units which are substituted or unsubstituted phenyl, non-limiting examples of which are described in Table III herein below.
TABLE III
Figure imgf000028_0003
Figure imgf000029_0002
The compounds described immediately above can be prepared by the procedure outlined in Scheme II and described in Example 2.
Scheme II
Figure imgf000029_0001
6 7
Reagents and conditions: (a) NaOH, H2O/THF; rt, 1 hr.
EXAMPLE 2 {[S-ζS-ChlorophenyO-S-hydroxypyridine^-carbonylJamino} -acetic acid (7)
Preparation of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid (7): To a solution of {[5-(3-chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino} -acetic acid methyl ester, 6, (0.163 g, 0.509 mmol) in THF (5 mL) is added IM NaOH (1.5 ml, 1.27 mmol) and the reaction mixture stirred at room temperature for 1 hour. The solution is acidified using 1 M HCl (3 mL), the solvent removed under reduced pressure and the resulting solid suspended in CHCl3: iso-propanol (1:1), filtered and the filtrate dried (MgSO4), filtered and re-concentrated under reduced pressure. The crude material is triturated with a small amount of MeOH to afford 0.10 g (64% yield) of the desired product as a colorless solid. 1H NMR (400 MHz, MeOD) δ ppm 8.31 (IH, d, J= 1.8 Hz), 7.47 (2 H, d, J = 1.8 Hz), 7.30-7.65 (4H, m), 4.07 (2H, s). HPLC- MS: m/z 307 [M+H]+.
The following are further non-limiting examples.
Figure imgf000030_0001
{[5-(4-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid: 1H NMR (400 MHz, MeOD) δ ppm 8.33 (1 H, d, J= 1.5 Hz), 7.61 (2 H, d, J= 8.4 Hz), 7.48 (1 H, d, J= 1.8 Hz), 7.42 (2 H, d, J = 8.4 Hz), 4.06 (2 H, s). HPLC-MS: m/z 307 [M+H]+.
Figure imgf000030_0002
{[5-(2-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid: 1H NMR (400 MHz, MeOD) δ ppm 8.10 (1 H, d, J= 1.8 Hz)5 7.40-7.56 (1 H, m), 7.09-7.40 (4 H, m), 4.07 (2H s). HPLC-MS: m/z 307 [M+H]+.
Figure imgf000030_0003
{[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid: 1H NMR (250 MHz, DMSO-^6) δ ppm 12.39 (1 H, br s), 9.38 (1 H, t, J= 6.2 Hz), 8.53 (1 H, d, J= 2.1 Hz), 7.91 (2 H, dd, J= 8.8, 5.5 Hz), 7.74 (1 H, d, J= 2.1 Hz), 7.38 (2 H, t, J= 8.8 Hz)5 4.02 (2 H, d, . = 6.4 Hz). HPLC-MS: m/z 291 [M-HH]+.
Figure imgf000030_0004
[(3-Hydroxy-5-(4-methylphenyl)pyridine-2-carbonyl)amino]-acetic acid: I1 H NMR (400 MHz3 MeOD) δ ppm 8.40 (1 H, s), 7.68 (1 H, s), 7.53 (2 H, d, J= 8.42 Hz)5 7.26 (2H, d, J= 8.05 Hz), 4.10 (2 H, s), 2.31 (3 H, s). HPLC-MS: m/z 287 [M+H]+.
Figure imgf000031_0001
{[5-(4-Ethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid: 1H NMR (250 MHz, DMSO-^6) δ ppm 12.40 (1 H, s), 9.35 (1 H, t, J= 6.1 Hz), 8.52 (1 H, d, J= 2.1 Hz), 7.76 (2 H, d, J = 8.2 Hz)5 7.71 (1 H, d, J = 1.8 Hz)5 7.38 (2 H, d, J= 8.2 Hz)5 4.02 (2 H, d, J= 6.1 Hz), 2.68 (2 H, q, J= 7.6 Hz)5 1.22 (3 H5 1, J= 7.5 Hz). HPLC-MS: m/z 301 [M+H]+.
Figure imgf000031_0002
{[3-Hydroxy-5-(4-isopropylphenyl)pyridine-2-carbonyl]amino}-acetic acid: 1H NMR (250 MHz, DMSO-4) δ ppm 12.40 (1 H, s), 9.36 (1 H5 t, J= 6.2 Hz), 8.52 (1 H, d, J= 1.8 Hz), 7.70 (2 H, d, J= 1.8 Hz), 7.76 (2 H, d, J= 8.2 Hz), 7.41 (2 H5 d5 J= 8.2 Hz), 4.02 (2 H, d, J = 6.1 Hz), 2.97 (1 H, m, J= 7.0 Hz), 1.25 (6 H, d, J= 7.0 Hz). HPLC-MS: m/z [M-HH]+ 315.
Figure imgf000031_0003
{[3-Hydroxy-5-(3-trifluoromethylphenyl)pyridine-2-carbonyl]amino}-acetic acid: 1H NMR (250 MHz, DMSO-J6) δ ppm 12.42 (1 H, br s), 9.41 (1 H5 t, J= 6.4 Hz), 8.61 (1 H, d, J = 1.8 Hz), 8.10 - 8.22 (2 H5 m), 7.88 (1 H5 d, J= 1.8 Hz)5 7.73 - 7.86 (2 H5 m), 4.03 (2 H, d, J= 6.1 Hz). HPLC-MS: m/z 341 [M+H]+.
Figure imgf000031_0004
{[5-(4-CyanophenyI)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid: 1H NMR (400 MHz5 MeOD) δ ppm 8.38 (1 H, d5 J = 1.8 Hz), 7.75-7.83 (4 H, m), 7.56 (1 H, d, J = 1.8 Hz), 4.06 (2 H, s). HPLC-MS: m/z 298 [M+H]+.
Figure imgf000032_0001
{[5-(3-Cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid: 1H NMR (250 MHz, DMSO- d6) δ ppm 12.40 (1 H, s), 9.40 (1 H, t, J= 6.17 Hz), 8.59 (1 H, d, J= 1.71 Hz), 8.37 (1 H, s), 8.19 (1 H, d, J= 7.77 Hz), 7.93 (1 H, d, J= 7.88 Hz), 7.86 (1 H, d, J= 1.94 Hz), 7.73 (1 H, t, J= 7.77 Hz), 4.00 (2 H, d, J= 6.17 Hz). HPLC-MS: m/z 298 [M+H]+.
Figure imgf000032_0002
{[5-(5-Chloro-2-methylphenyl)-3-hydroxypyridine-2-carbonyl]amino} -acetic acid: 1H NMR (250 MHz, DMSO-cfe) δ ppm 12.35 (1 H, br s), 9.34 (1 H5 1, J= 6.0 Hz), 8.17 (1 H, d, J= 1.8 Hz), 7.47 (1 H3 d, J= 1.8 Hz), 7.33 - 7.45 (3 H, m), 3.95 (2 H, d, J= 5.9 Hz), 2.22 (3 H5 s). HPLC-MS: m/z 321 [M+H]+.
Figure imgf000032_0003
{ [3-Hydroxy-5-(4-isopropoxyphenyl)pyridine-2-carbonyl]amino } -acetic acid: 1H NMR (250 MHz, OMSO-d6) δ ppm 12.36 (1 H, br s), 9.35 (1 H, t, J= 5.9 Hz), 8.50 (1 H5 d, J= 1.8 Hz), 7.71 (1 H, d, J= 1.8 Hz), 7.27 - 7.46 (3 H, m), 7.02 (1 H, d, J= 8.5 Hz)5 4.70 - 4.85 (1 H, m), 4.01 (2 H5 d, J= 6.1 Hz), 1.29 (6 H5 d, J= 5.9 Hz). HPLC-MS: m/z 331 [M+H]+.
Figure imgf000032_0004
({5-[3-(Cyclopropanecarbonylamino)phenyl]-3-hydroxy-pyridine-2-carbonyl}-amino)- acetic acid: 1H NMR (250 MHz, DMSO-<4) δ ppm 12.40 (1 H, br s), 10.39 (1 H, s), 9.37 (1 H, t, J = 6.1 Hz), 8.43 (1 H, d, J = 1.9 Hz), 7.97 (1 H, s), 7.64 - 7.71 (1 H, m), 7.60 (1 H, d, J= 1.8 Hz), 7.41 - 7.49 (2 H, m), 3.99 (2 H, d, J= 6.1 Hz), 1.73 - 1.86 (1 H3 m), 0.74 - 0.84 (4 H, m). HPLC-MS: m/z 356 [M+H]+.
Figure imgf000033_0001
({3-Hydroxy-5-[3-(pyrrolidine-l-carbonyl)phenyl]-pyridine-2-carbonyl}amino)-acetic acid: 1H NMR (250 MHz, DMSO-^6) δ ppm 12.40 (1 H, s), 9.38 (1 H, t, J= 6.3 Hz), 8.55 (1 H, d, J= 1.8 Hz), 7.88-7.94 (2H, m), 7.77 (IH, d, J= 1.8 Hz), 7.56-7.63 (2 H, m), 4.01 (2 H, d, J = 6.0 Hz), 3.41-3.54 (4 H, m), 1.76-1.96 (4 H, m). HPLC-MS: m/z 370 [M+H]+.
Figure imgf000033_0002
( {3-Hydroxy-5-[3-(2/J-tetrazol-5-yl)phenyl]-pyridine-2-carbonyl } -amino)-acetic acid: 1H NMR (250 MHz, DMSO-Ci6) δ ppm 12.40 (1 H, s), 9.51 (1 H, br s), 8.50 (1 H, s), 8.20 (1 H, s), 7.94 (1 H, d, J= 1.5 Hz), 7.88 - 7.99 (1 H, m), 7.72 (1 H, d, J= 1.9 Hz), 7.34 - 7.53 (1 H, m), 7.48 (2 H, d, J= 2.2 Hz), 7.00 (1 H, d, J = 1.8 Hz), 6.38 (1 H, br s), 3.54 (2 H, br s). HPLC-MS: m/z 341 [M+H]+.
The fourth aspect of Category I of the present disclosure encompasses compounds having the formula:
Figure imgf000033_0003
wherein R units are substituted or unsubstituted heteroaryl. Non-limiting examples of these R units are described in Table IV herein below. TABLE IV
Figure imgf000034_0003
The compounds which encompass the fourth aspect of Category I of the present disclosure can be prepared by the procedure outlined in Scheme II and described in Example 2 herein beginning with compounds which are members of the first and second aspect of Category I. The following are non-limiting examples of compound encompassed by the fourth aspect of Category I.
Figure imgf000034_0001
[(5l-Hydroxy-[2,3']bipyridinyl-6'-carbonyl)-amino]-acetic acid: 1H NMR (250 MHz5 DMSO-^6) δ ppm 12.45 (1 H, s), 9.45 (1 H, t, J= 6.1 Hz), 8.91 (1 H, d, J= 1.8 Hz), 8.73-8.79 (1 H, m) 8.20 (1 H5 d, J= 8.0 Hz), 8.07 (1 H, d, J= 1.8 Hz)5 8.01 (1 H5 dt, J= 7.8, 1.8 Hz), 7.52 (1 H, ddd, J= 7.5, 4.8, 0.9 Hz)5 4.01 (2 H, d, J = 6.1 Hz). HPLC-MS: m/z 274 [M+H]+.
Figure imgf000034_0002
[(5-Hydroxy-[3,3']bipyridinyl-6-carbonyl)-amino]-acetic acid: 1H NMR (250 MHz5 DMSO-^6) δ ppm 12.44 (1 H5 br s), 9.46 (1 H5 1, J= 6.1 Hz)5 9.30 (1 H, s), 8.86 (1 H5 d, J= 5.3 Hz), 8.76 (1 H, d, J= 8.2 Hz), 8.67 (1 H, d, J= 1.9 Hz)5 7.92 - 8.00 (2 H, m), 4.02 (2 H, d, J= 6.1 Hz). HPLC-MS: m/z 21 A [M+H]+.
Figure imgf000035_0001
[(3-Hydroxy-5-pyrimidin-5-yl-pyridine-2-carbonyl)-amino]-acetic acid: 1H NMR (250 MHz, DMSO-^6) δ ppm 12.45 (1 H, br s), 9.45 (1 H, t, J= 5.9 Hz), 9.27 - 9.33 (3 H, m), 8.67 (1 H, d, J= 1.8 Hz), 7.97 (1 H, d, J= 1.9 Hz), 4.02 (2 H, d, J= 6.2 Hz). HPLC-MS: m/z 275
[M+H]+.
Figure imgf000035_0002
[(3-Hydroxy-5-isoquinolin-4-yl-pyridine-2-carbonyl)-amino]-acetic acid: 1H NMR (250 MHz, DMSO-J6) δ ppm 12.53 (1 H, br s), 9.83 (1 H, s), 9.52 (1 H, t, J = 6.1 Hz), 8.71 (1 H, s), 8.54 (1 H, d, J= 8.1 Hz), 8.38 (1 H, d, J= 1.7 Hz), 7.92 - 8.13 (3 H, m), 7.73 (1 H, d, J= 1.7 Hz), 4.04 (2 H, d, J= 6.1 Hz). HPLC-MS: m/z 324 [M+Hf.
Figure imgf000035_0003
[(3-Hydroxy-5-thiazol-2-yl-pyridine-2-carbonyl)-amino]-acetic acid: 1H NMR (250 MHz, DMSO-ife) δ ppm 12.50 (1 H, s), 9.46 (1 H, t, J = 6.1 Hz), 8.76 (1 H, d, J= 1.8 Hz), 8.07 (1 H, d, J= 3.2 Hz), 8.00 (1 H, d, J= 3.2 Hz), 7.90 (1 H5 d, J= 1.8 Hz), 4.00 (2 H, d, J= 6.1 Hz). HPLC-MS: m/z 280 [M+H]+.
Figure imgf000035_0004
{[5-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-3-hydroxy-pyridine-2-carbonyl]-amino}-aceti< acid: 1H NMR (250 MHz, DMSO-cfe) δ ppm 12.83 (1 H, br s), 12.32 (1 H, s), 9.31 (1 H, t, J = 6.1 Hz), 8.46 (1 H, d, J= 1.9 Hz), 7.64 (1 H, d, J= 1.9 Hz), 7.37 (1 H, d, J = 2.2 Hz), 7.28 - 7.34 (1 H, m), 6.98 (1 H, d, J= 8.5 Hz), 4.29 (4 H, s), 3.99 (2 H, d, J= 6.1 Hz). HPLC-MS: m/z 331 [M+H]+.
S
Category II of the present disclosure relates to compounds having the formula:
Figure imgf000036_0001
wherein the first aspect encompasses compounds having the formula:
Figure imgf000036_0002
R units are substituted or unsubstituted phenyl. Non-limiting examples of these R units are described in Table V herein below.
TABLE V
Figure imgf000036_0003
Figure imgf000037_0003
The compounds that encompass the first aspect of Category II of the present disclosure can be prepared by the procedure outlined in Scheme V and described in Example 3 herein below.
Figure imgf000037_0001
8
Reagents and conditions: (a) 4-chlorophenyl boronic acid, Pd(dppf)Cl2,K3PO4, dioxane/MeOH;
80 0C, 3 hr.
Figure imgf000037_0002
8 9
Reagents and conditions: (b) 4-chlorophenyl boronic acid, Pd(dppf)Cl2,K3Pθ4,
Figure imgf000038_0001
9 10
Reagents and conditions: (c) glycine ethyl ester HCl, EDCI, HOBt, DIPEA, DMF, CH2Cl2; rt,
16 hr.
EXAMPLE 3 [(4'-Chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester (10)
Preparation of 4'-chloro-3-methoxy-biphenyl-4-carboxylic acid methyl ester (8): To a degassed solution of methyl 4-bromo-2-methoxybenzoate (0.70 g, 2.86 mmol) in 1,4- dioxane (10 mL) and MeOH (2.5 rtiL) at room temperature under nitrogen blanketing is added 4-chlorophenyl boronic acid (0.536 g, 3.43 mmol), Pd(dppf)Cl2 (0.233 g, 0.286 mmol) and K3PO4 (0.728 g, 3.43 mmol). The resulting suspension is heated to 800C and stirred for 3 hours after which the reaction is cooled to room temperature and filtered through Celite™. The collected solids are washed with additional MeOH and the filtrate concentrated under reduced pressure. The crude material is purified over silica (hexanes:EtOAc gradient 6: 1 to 4:1) to afforc 0.614 g (78% yield) of the desired product as orange crystals. 1H NMR (400 MHz, CDCl3) δ ppm 7.89 (1 H, d, J= 8.0 Hz), 7.52 - 7.56 (2 H, m), 7.44 (2 H, d, J= 8.7 Hz), 7.17 (1 H, d, J= 8.0 Hz), 7.12 (1 H, d, J= 1.6 Hz), 3.99 (3 H, s), 3.92 (3 H, s). HPLC-MS: m/z 277 [M+H]+.
Preparation of 4'-chloro-3-methoxy-biphenyl-4-carboxylic acid (9): To a solution of 4'- chloro-3-methoxy-biphenyl-4-carboxylic acid methyl ester, 8, (0.615 g, 2.22 mmol) in THF (20 mL) and H2O (5 mL) at room temperature is added LiOH (0.932 g, 22.2 mmol). The resulting suspension is heated to reflux for 2 hours. The reaction is cooled and concentrated under reduced pressure. The crude product is acidified using cone. HCl and the resulting solid is collected by filtration washed with H2O and dried to afford 0.532 g (91%) of the desired produc as a grey solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.69 (1 H, br s), 8.26 (1 H, d, J= 8.1 Hz), 7.53 - 7.58 (2 H, m), 7.44 - 7.50 (2 H, m), 7.33 (1 H, dd, J= 8.1, 1.6 Hz), 7.20 (1 H, d, J= 1.3 Hz), 4.17 (3 H, s). HPLC-MS: m/z 263 [M+H]+. Preparation of [(4'-chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester (10): To a solution of 4'-chloro-3-methoxy-biphenyl-4-carboxylic acid, 9, (0.325 g, 1.24 mmol) in CH2Cl2 (5 mL) and DMF (1.5 mL) at room temperature under N2 is added glycine ethyl ester hydrochloride (0.19 g, 1.36 mmol), l-(3-dimethylamino-propyl)-3-ethylcarbodiimide (EDCI) (0.261 g, 1.36 mmol), 1-hydroxybenzotriazole (HOBt) (0.033 g, 0.248 mmol) and diisopropylethylamine (DIPEA) (0.432 ml, 2.28 mmol). The resulting suspension is stirred for 16 hours after which the reaction mixture is diluted with EtOAc and washed with IM HCl, IM NaOH and saturated aqueous NaCl. The organic phase is separated, dried (MgSO4), filtered and concentrated under reduced pressure. The crude material is purified over silica (hexanes:EtOAc 1 : 1) to afford 0.364 g (85% yield) of the desired product as a colorless solid. 1H NMR (400
MHz, CDCl3) δ ppm 8.51 (1 H, br s), 8.28 (1 H, d, J= 8.1 Hz), 7.53 - 7.57 (2 H, m), 7.42 - 7.46 (2 H, m), 7.27 (1 H, dd, J= 8.1, 1.6 Hz), 7.14 (1 H, d, J = 1.5 Hz), 4.29 (2 H, d, J= 4.8 Hz), 4.28 (2 H, q, J= 7.1 Hz), 4.09 (3 H, s), 1.34 (3 H, t, J= 7.2 Hz). HPLC-MS: m/z 348 [MH-H]+.
A further non-limiting example includes the following.
Figure imgf000039_0001
[(S-Methoxy-^-methyl-biphenyM-carbonyO-aminol-acetic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ ppm 8.52 (br s, 1 H), 8.26 (d, J= 8.14 Hz, 1 H), 7.53 (d, J = 8.05 Hz, 2 H), 7.28 - 7.33 (m, 3 H), 7.17 (d, J= 1.37 Hz, 1 H), 4.13 - 4.45 (m, 4 H), 4.08 (s, 3 H), 2.42 (s, 3 H), 1.33 (t, J = 7.18 Hz, 3 H). HPLC-MS: m/z 328 [M+H]+.
The compounds of Formula (I) also encompasse compounds having the formula:
Figure imgf000039_0002
wherein R units are substituted or unsubstituted phenyl. Non-limiting examples of these R units are described in Table VI herein below. TABLE VI
Figure imgf000040_0001
The compounds disclosed immediately above can be prepared by the procedure outlined Scheme VI and described in Example 4 herein below. Scheme VI
Figure imgf000041_0001
10 11
Reagents and conditions: (a) BBr3, CH2Cl2; rt, 3 days.
EXAMPLE 4 [(4'-Chloro-3-hydroxy-biphenyl-4-carbonyl)-amino]-acetic acid (11)
Preparation of [(4'-chloro-3-hydroxy-biphenyl-4-carbonyl)-amino]-acetic acid (11): To i solution of [(4'-chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester (0.053 g, 0.152 mmol) in CH2Cl2 (2 mL) at room temperature under nitrogen is added BBr3 (1.52 ml of a IM solution in CH2Cl2, 1.52 mmol) dropwise. The resulting mixture is stirred for 3 days after which time the reaction is quenched with H2O (0.5 mL) then acidified to pH 1 with cone. HCl. The mixture is extracted with EtOAc (x 2), the organic phase separated, dried (MgSO4), filtered and concentrated under reduced pressure. The crude material is purified by preparative HPLC to afford 0.019 g (41% yield) of the desired product as a white solid. 1H NMR (400 MHz, DMSO- βfe) δ Ppm 12.41 (1 H, s), 9.19 (1 H, s), 7.96 (1 H, d, J= 8.3 Hz), 7.74 (2 H, d, J= 8.7 Hz), 7.54 (2 H, d, J= 8.7 Hz), 7.21 (1 H, d, J= 1.7 Hz), 7.26 (1 H, dd, J= 8.3, 1.8 Hz), 3.99 (2 H, d, J = 5.5 Hz). HPLC-MS: m/z 306 [M+H]+.
The following is a non-limiting example of the second aspect of Category II of the present disclosure.
Figure imgf000041_0002
[(3-Hydroxy-4'-methyl-biphenyl-4-carbonyl)-amino]-acetic acid: 1H NMR (400 MHz, DMSO-^6) δ ppm 12.37 (1 H, s), 9.17 (1 H, s), 7.94 (1 H, d, J= 8.32 Hz), 7.60 (2 H5 d, J = 8.14 Hz)3 7.29 (2 H, d, J= 7.96 Hz), 7.22 (1 H, dd, J= 8.32, 1.83 Hz)5 7.18 (1 H5 d, J= 1.74 Hz)5 4.00 (2 H3 d, J= 5.67 Hz)3 2.35 (3 H3 s). HPLC-MS: m/z 286 [M+H]+.
Category III of the present disclosure relates to compounds having the formula:
Figure imgf000042_0001
wherein non-limiting examples of R3 R >6a a «_nd j R r>6b are further described herein below in Table VII.
TABLE VII
Figure imgf000042_0002
Figure imgf000043_0002
The compounds which are encompassed within Category III of the present disclosure cat be prepared by the procedures outlined herein below in Schemes VII and VIII and described in Examples 5 and 6.
Scheme VII
Figure imgf000043_0001
7 12
Reagents and conditions: (a)
EXAMPLE 5 5-(3-Chlorophenyl)-iV-[2-(dimethylamino)-2-oxoethyl]-3-hydroxypicolinamide (12) Preparation of 5-(3-chlorophenyl)-N-[2-(dimethylamino)-2-oxoethyl]-3- hydroxypicolinamide (12): To a solution of {[5-(3-chlorophenyl)-3-hydroxy-pyridine-2- carbonyl]-amino} -acetic acid, 7, (0.043 g, 0.139 mmol) in DMF (2 mL) at 00C under N2 is added diisopropylethylamine (0.072 ml, 0.42 mmol), l-(3-dimethylamino-propyl)-3- ethylcarbodiimide (EDCI) (0.040 g, 0.21 mmol) and 1-hydroxybenzotriazole (HOBt) (0.002 g, 0.014 mmol). The resulting mixture is stirred for 5 minutes before dimethylamine (0.10 mL of a 2M solution in THF, 0.21 mmol) is added. The reaction is warmed slowly to room temperature and stirred for 3 days. The reaction is diluted with EtOAc, washed with H2O, and saturated aqueous NaCl. The organic phase is dried (MgSO4), filtered, concentrated under reduced ■ pressure and the crude material is purified over silica (EtOAc) to afford 0.20 g (43% yield) of the desired product as a colorless solid. 1H NMR (250 MHz, CDCl3) δ ppm 11.90 (1 H, s), 8.83 (1 H, t, J= 4.6 Hz), 8.25 (1 H, d, J= 1.8 Hz), 7.51 (1 H, m), 7.31 - 7.44 (4 H, m), 4.19 (2 H, d, J = 4.6 Hz), 2.99 (3 H, s), 2.98 (3 H, s). HPLC-MS: m/z 334 [M+H]+.
Scheme VIII
Figure imgf000044_0001
Reagents and conditions: (a) 2-aminoacetamide HCl, EDCI, HOBt, DMF;
0 0C to rt, 3 days.
Figure imgf000044_0002
13 14
Reagents and conditions: (b) H2: PdVC, MeOH, rt, 22 hr.
Figure imgf000044_0003
Reagents and conditions: (c) (CF3SO2)2NC6H5, MeOH; rt, 24 hr.
Figure imgf000045_0001
15 16
Reagents and conditions: (d) 3-chlorophenylboronic acid, Pd(dppf)Cl2, K3PO4, dioxane; 85 °C, 48 hr.
EXAMPLE 6 5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carboxylic acid carbamoylmethyl-amide (16)
Preparation of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid carbamoylmethyl-amide
(13): To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid, 2, (1.00 g, 2.99 mmol) in DMF (20 mL) at room temperature under N2 is added l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDCI) (0.925 g, 5.97 mmol) and 1-hydroxybenzotriazole (HOBt) (0.806 g, 5.97 mmol). The resulting solution is stirred for 15 minutes then 2-aminoacetamide hydrochloride (0.66 g, 5.97 mmol) and diisopropylethylamine (1.56 ml, 8.96 mmol) are added. After 3 days the reaction mixture is concentrated under reduced pressure and H2O added. The solid which forms is collected by filtration and is washed with water to afford 0.598 g (51% yield) of the desired product as a white solid. 1H NMR (250 MHz, DMSO-J6) δ ppm 8.39 (1 H, t, J= 5.6 Hz), 8.01 (1 H, d, J= 2.2 Hz), 7.28 - 7.56 (12 H, m), 7.11 (1 H, br s), 5.26 (2 H5 s), 5.25 (2 H, s), 3.81 (2 H, d, J= 5.6 Hz). HPLC-MS: m/z 392 [M+H]+.
Preparation of 3,5-dihydroxy-pyridine-2-carboxylic acid carbamoylmethyl-amide (14): A solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid carbamoylmethyl-amide, 13, (0.598 g, 1.53 mmol) in EtOH (100 mL) containing 10% Pd/C (0.120 g) is stirred under an atmosphere ofH2 for 22 hours. The reaction solution is filtered through Celite™ and the collected solids are washed with hot MeOH. The combined filtrate and washings are concentrated under reduced pressure to afford 0.32 g (99% yield) of the desired product cream-colored solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 12.42 (1 H, s), 10.84 (1 H, br s), 8.75 (1 H, t, J= 5.8 Hz), 7.75 (1 H, d, J= 2.3 Hz)5 7.47 (1 H5 br s), 7.13 (1 H, br s), 6.67 (1 H, d, J= 2.3 Hz), 3.85 (2 H5 d, J= 5.9 Hz). HPLC-MS: m/z 212 [M+H]+.
Preparation of trifluoromethaπesulfonic acid 6-(carbamoylmethyl-carbarnoyl)-5- hydroxy-pyridin-3-yl ester (15): To a solution of 3,5-dihydroxypyridine-2-carboxylic acid carbamoylmethyl-amide, 14, (0.30 g, 1.42 mmol) in MeOH (10 mL) and DMF (5 mL) at 0 0C under N2 is added diisopropylethylamine (0.247 ml, 1.42 mmol) followed by N- phenyltrifluoromethanesulfonamide (0.508 g, 1.42 mmol). The resulting mixture is warmed slowly to room temperature and stirring is continued for 24 hours. The solvent is then removed under reduced pressure and the crude material is purified over silica (2% MeOH:CH2Cl2) to afford 0.404 g (83% yield) of the desired product as a pale yellow solid. 1H NMR (250 MHz, DMSO-cfe) δ ppm 12.85 (1 H5 br s), 9.28 (1 H5 X, J = 5.9 Hz)5 8.41 (1 H, d, J = 2.3 Hz), 7.85 (1 H, d, J= 2.4 Hz), 7.52 (1 H5 br s), 7.18 (1 H5 br s), 3.88 (2 H, d, J= 6.1 Hz). HPLC-MS: m/z 344 [M+H]+.
Preparation of 5-(3-chlorophenyl)-3-hydroxy-pyridine-2-carboxylic acid carbamoylmethyl-amide (16): To a degassed solution of trifiuoromethanesulfonic acid 6- (carbamoylmethyl-carbamoyl)-5-hydroxy-pyridin-3-yl ester, 15, (0.20 g, 0.58 mmol) in 1,4- dioxane (3.5 mL) at room temperature under N2 is added 3-chlorophenyl boronic acid (0.109 g, 0.70 mmol), K3PO4 (0.148 g, 0.70 mmol) and Pd(dppf)Cl2 (0.048 g5 0.06 mmol). The resulting suspension is heated to 900C in a sealed rube for 22 hours. The reaction is cooled to room temperature and additional 3-chlorophenyl boronic acid (0.055 g, 0.35 mmol) and Pd(dppf)Cl2 (0.048 g, 0.06 mmol) is added and the reaction reheated to 90 0C for an additional 22 hours. After cooling, the reaction solution is filtered through Celite™ and the collected solids are washed with additional MeOH. The filtrate and washings are concentrated under reduced pressure and the residue dissolved in CH2Cl2 and washed with 10% citric acid. The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product is purified over silica (2% MeOHrCH2Cl2) to afford 0.033 g (18% yield) of the desired product as a colourless solid. 1H NMR (250 MHz5 DMSO-^6) δ ppm 12.46 (1 H, s), 9.17 (1 H5 1, J= 5.9 Hz)5 8.55 (1 H, d, J= 2.0 Hz), 7.93 (1 H5 d, J= 0.9 Hz)5 7.75 - 7.84 (2 H5 m), 7.49 - 7.60 (3 H5 m), 7.18 (1 H5 s), 3.91 (2 H5 d, J= 5.9 Hz). HPLC-MS: m/z 306 [M+H]+. The following are non-limiting examples of compounds encompassed within Category III of the present disclosure.
Figure imgf000047_0001
5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carboxylic acid (isopropylcarbamoyl-m ethyl)- amide: 1H NMR (250 MHz, CDCl3) δ ppm 8.60 (1 H, t, J= 6.4 Hz), 8.25 (1 H, d, J= 2.0 Hz), 7.50 - 7.53 (1 H, m), 7.44 (1 H, d, J= 2.0 Hz), 7.35 - 7.43 (3 H, m), 5.69 (1 H, br s), 4.04 (2 H, d, J= 5.9 Hz), 3.41 (1 H, q, J= 7.0 Hz), 1.13 (6 H, d, J= 6.6 Hz). HPLC-MS: m/z 348 [M+H]+.
Figure imgf000047_0002
3-Hydroxy-5-(4-memylphenyl)-pyridine-2-carboxylic acid (methylcarbamoyl-methyl)- amide: 1H NMR (250 MHz, CDCl3) δ ppm 11.90 (1 H, s), 8.47 (1 H, t, J= 5.9 Hz), 8.25 (1 H, d, J= 1.8 Hz), 7.33 - 7.56 (3 H, m), 7.12 - 7.31 (2 H, m), 6.07 (1 H, br s), 3.90 - 4.24 (2 H, m), 2.66 - 2.98 (3 H, m), 2.35 (3 H, s). HPLC-MS: m/z 300 [M+H]+.
Figure imgf000047_0003
5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carboxylic acid (methylcarbamoyl-methyl)- amide: 1H NMR (250 MHz, CDCl3) δ ppm 1 1.79 (1 H, br s), 8.55 (1 H, br s), 8.31 (1 H, s), 7.6C (1 H, s), 7.41 - 7.53 (4 H, m), 6.01 (1 H, br s), 4.15 (2 H, d, J= 5.8 Hz), 2.90 (3 H, d, J= 4.7 Hz). HPLC-MS: m/z 320 [M+Hf.
Category IV of the present disclosure relates to compounds having the formula:
Figure imgf000047_0004
wherein the first aspect relates to compounds having the formula:
Figure imgf000048_0001
non-limiting examples of R, R5, and L units are further described herein below in Table VIII.
TABLE VIII
Figure imgf000048_0002
Figure imgf000049_0001
Figure imgf000050_0002
The compounds described immediately abover wherein R5 is C1-C4 linear, branched, or cyclic alkyl can be prepared by the procedures outlined herein below in Scheme IX and described in Example 7.
Scheme IX
Figure imgf000050_0001
17 Reagents and conditions: (a) 2-amino-2-methylpropionic acid methyl ester, EDCI, HOBt, DMF;
0 0C to rt, 3 days.
Figure imgf000051_0001
17 18
Reagents and conditions: (b) H2: Pd/C, MeOH, rt, 22 hr.
Figure imgf000051_0002
18 • 19
Reagents and conditions: (c) (CF3SO2)INC6H5, MeOH; rt, 24 hr.
Figure imgf000051_0003
19 20
Reagents and conditions: (d) 3-chlorophenylboronic acid, Pd(dppf)Cl2, K3PO4, dioxane; 85 0C, 48 hr.
EXAMPLE 7
2- { [5-(3-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino} -2-methyl-propionic acid methyl ester (20)
Preparation of 2-[(3,5-bis-benzyloxy-pyτidine-2-carbonyl)-arnino]-2-methyl-propionic acid methyl ester (17): To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid, 2, (1.0 g, 2.99 mmol) in DMF (20 mL) at room temperature under N2 is added l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.925 g, 5.97 mmol) and 1- hydroxybenzotriazole (HOBt) (0.806 g, 5.97 mmol). The mixture is stirred for 15 minutes after which α-aminoisobutyric acid (0.917 g, 5.97 mmol) and diisopropylethyl-amine (DIPEA) (1.56 mL, 8.96 mmol) are added. The resulting solution is stirred at room temperature for 16 hours then concentrated under reduced pressure. The resulting brown oil is purified over silica (EtOAc: heptane 1:1) to afford 0.58 g (45% yield) of the desired compound as a colorless solid. 1H NMR (250 MHz, CDCl3) δ ppm 8.13 (1 H, s), 8.02 (1 H, d, J = 2.3 Hz), 7.31 - 7.48 (10 H, m), 6.90 (1 H, d, J= 2.3 Hz), 5.19 (2 H, s), 5.10 (2 H, s), 3.74 (3 H, s), 1.58 (6 H, s). HPLC-MS: m/z 435 [M+H]+.
Preparation of 2-[(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester (18): A solution of 2-[(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-2- methylpropionic acid methyl ester, 17, (0.58 g, 1.34 mmol) in MeOH (100 mL) containing 10% Pd/C (0.116 g) is stirred under an atmosphere of H2 for 22 hours. The reaction solution is filtered through CeI ite™ and the collected solids are washed with hot MeOH. The combined filtrate and washings are concentrated under reduced pressure to afford 0.321 g (94% yield) of the desired compound as a grey solid. 1H NMR (250 MHz, MeOD) δ ppm 7.67 (1 H, d, J= 2.4 Hz), 6.58 (1 H5 d, J= 2.4 Hz), 3.69 (3 H, s), 1.56 (6 H, s). HPLC-MS: m/z 255 [M+H]+ .
Preparation of 2-[(3-hydroxy-5-trifIuoromethanesulfonyloxy-pyridine-2-carbonyl)- amino]-2-methyl-propionic acid methyl ester (19): To a solution in 2-[(3,5-dihydroxy-pyridine- 2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, 18, (0.312 g, 1.23 mmol) in MeOH (10 mL) containing diisopropylethylamine (0.214 mL, 1.23 mmol) at 0 0C under N2 is added N- phenyltrifluoromethanesulfonamide (0.439 g, 1.23 mmol). The reaction is warmed slowly to room temperature and stirred for 40 hours. The solvent is removed under reduced pressure and the crude oil which remains is purified over silica (EtOAc±eptane 1:9) to afford 0.17O g (36% yield) of the desired compound as a yellow oil. 1H NMR (250 MHz, MeOD) δ ppm 8.85 (1 H, b s), 8.19 (1 H, d, J= 2.4 Hz), 7.46 (1 H, d, J= 2.3 Hz), 3.74 (3 H, s), 1.63 (6 H5 s). HPLC-MS: m/z 387 [M+H]+.
Preparation of 2-{[5-(3-chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2- methyl-propionic acid methyl ester (20): To a degassed solution of 2-[(3-hydroxy-5- trifluoromethanesulfonyloxy-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl este (0.17 g, 0.44 mmol) in 1,4-dioxane (3 mL) at room temperature under N2 is added 3- chlorophenyl boronic acid (0.082 g, 0.53 mmol), K3PO4 (0.112 g, 0.53 mmol) and Pd(dppf)Cl2 (0.036 g, 0.04 mmol). The resulting suspension is heated to 85 0C in a sealed tube for 20 hours. After cooling, the reaction solution is filtered through Celite™ and the collected solids are washed with additional MeOH. The filtrate and washings are concentrated under reduced pressure and the residue dissolved in CH2Cl2 and washed with 10% citric acid. The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product is purified over silica (EtOAc:heptane 1:4) to afford 0.112 g (73% yield) of the desired compound as a colorless oil. 1H NMR (250 MHz, CDCl3) δ ppm 11.83 (1 H, br s), 8.29 (1 H, br s), 8.10 (1 H, d, J= 2.0 Hz), 7.40 (1 H, m), 7.08 - 7.34 (4 H, m), 3.65 (3 H, s), 1.55 (6 H, s). HPLC-MS: m/z 349 [M+H]+.
The compounds of Formula (I) wherein R5 is hydrogen can be prepared by the procedures outlined herein below in Scheme X and described in Example 8
Scheme X
Figure imgf000053_0001
20 21
Reagents and conditions: (a) LiOH, THF/H2O; rt, 3 days.
EXAMPLE 8
2-{[5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}- 2-methyl-propionic acid (21)
Preparation of 2-{[5-(3-chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2- methyl-propionic acid (21): To a solution of 2-{[5-(3-chlorophenyl)-3-hydroxy-pyridine-2- carbonyl]-amino}-2-methyl-propionic acid methyl ester, 20, (0.082 g, 0.24 mmol) in THF (4 mL) is added LiOH (0.024 g, 0.98 mmol) and H2O (1 mL) and the resulting solution stirred for days at room temperature. The solvent is removed under reduced pressure and the pale yellow solid that remains is then acidified with IM HCl to until the pH is approximately 1 and the solution extracted twice with EtOAc. The combined organic layers are combined, dried (Na2SC<4), filtered and concentrated under reduced pressure to afford 0.064 g (81% yield) of the desired compound as a white solid. 1H NMR (250 MHz, DMSO-J6) δ ppm 12.99 (1 H, br s), 12.25 (1 H3 S), 9.05 (1 H, s), 8.53 (1 H, d, J= 2.0 Hz), 7.91 (1 H, s), 7.74 - 7.83 (2 H, m), 7.51 - 7.58 (2 H, m), 1.58 (6 H, s). HPLC-MS: m/z 335 [M+H]+.
Further non-limiting examples include the following.
Figure imgf000054_0001
3-[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-propionic acid ethyl ester: 1H NMR (250 MHz, CDCl3) δ ppm 12.12 (1 H, s), 8.44 (1 H, t, J = 5.9 Hz)5 8.31 (1 H, d, . = 1.8 Hz), 7.44 - 7.55 (3 H, m), 7.30 (2 H, d, J= 7.9 Hz), 4.21 (2 H, q, J= 7.2 Hz), 3.76 (2 H, q, J= 6.4 Hz), 2.68 (2 H, t, J= 6.2 Hz), 2.43 (3 H, s), 1.30 (3 H, t, J= 7.2 Hz). HPLC-MS: m/z 32S [MH-H]+.
Figure imgf000054_0002
3-[(3-Hydroxy-5-(3-chlorophenyl)-pyridine-2-carbonyl)-amino]-propionic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ ppm 12.16 (1 H, s), 8.45 (1 H, t, J= 5.7 Hz), 8.25 (1 H, d, J= 1.6 Hz), 7.55 (1 H, s), 7.37 - 7.47 (4 H, m), 4.20 (2 H, q, J= 7.1 Hz), 3.75 (2 H, q, J= 6.3 Hz), 2.68 (2 H, t, J= 6.2 Hz), 1.28 (3 H, t, J= 7.1 Hz). HPLC-MS: m/z 349 [M+H]+.
Figure imgf000054_0003
3-{[5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-propionic acid: 1H NMR (250 MHz, DMSO-^6) δ ppm 12.63 (1 H, br s), 12.37 (1 H, br s), 9.20 (1 H, t, J= 5.6 Hz), 8.50 (1 H, d, J= 1.8 Hz), 7.91 (1 H, s), 7.72 - 7.84 (2 H, m), 7.54 (2 H, m), 3.54 (2 H, q, J = 6.8 Hz), 2.58 (2 H, t, J= 6.9 Hz). HPLC-MS: m/z 321 [M+H]+.
Figure imgf000055_0001
3-[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-propionic acid: h 1H NMR (250 MHz, DMSO-J6) δ ppm 12.59 (1 H5 br s), 9.15 (1 H, t, J= 5.9 Hz), 8.46 (1 H, d, J= 1.8 Hz)5 7.70 (2 H, d, J= 8.2 Hz), 7.66 (1 H, d, J= 2.0 Hz)3 7.33 (2 H, d, J= 8.1 Hz), 3.54 (2 H, q, J= 6.7 Hz), 2.57 (2 H, t, J= 7.0 Hz)5 2.36 (3 H, s). HPLC-MS: m/z 301 [M+H]+.
Figure imgf000055_0002
2-{[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}-2-methyl-propionic acid: 1H NMR (250 MHz, DMSO-d6) δ ppm 12.99 (1 H, br s), 12.25 (1 H, s), 9.05 (1 H, s), 8.53 (1 H, d, J = 2.0 Hz), 7.91 (1 H, s), 7.74 - 7.83 (2 H, m), 7.51 - 7.58 (2 H, m), 1.58 (6 H, s). HPLC-MS: m/z 335 [M+H]+.
The second aspect of Category IV relates to compounds having the formula:
wherein non-limiting
Figure imgf000055_0003
described herein below in Table IX.
TABLE IX
Figure imgf000055_0004
Figure imgf000056_0001
Figure imgf000057_0002
Another subgenus of the Compounds of Formula (I) can be prepared by the procedures outlined herein below in Scheme XI and described in Example 9.
Scheme XI
Figure imgf000057_0001
21 22
Reagents and conditions: (a) CH3NH2 HCl, EDCI, HOBt, DMF; 0 0C to rt, 2 days.
EXAMPLE 9
5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carboxylic acid (1-methyl-l - methylcarbamoyl-ethyl)-amide (22)
Preparation of 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid (1 -methyl- 1- methylcarbamoyl-ethyl)-amide (22): To a solution of 2-{[5-(3-chlorophenyl)-3- hydroxypyridine-2-carbonyl]-amino}-2-methyl-propionic acid, 21, (0.030 g, 0.09 mmol) in DMF (2 mL) at room temperature under N2 is added l-(3-dimethylamino-propyl)-3- ethylcarbodiimide (EDCI) (0.021 g, 0.13 mmol), 1-hydroxybenzotriazole (HOBt) (0.012 g, 0.09 mmol) and diisopropylethylamine (DIPEA) (0.047 ml, 0.27 mmol). The reaction is stirred for 5 minutes then methylamine hydrochloride (0.09 g, 0.13 mmol) is added. After stirring for 2 days the solvent is removed under reduced pressure and the residue partitioned between CH2Cl2 and H2O. The organic layer is separated, washed with sat. NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product is purified over silica (MeOH:CH2Cl2 1 :99) to afford 0.025 g (80% yield) of the desired compound as a colorless oil. 1H NMR (250 MHz, CDCl3) δ ppm 11.93 (1 H, br s), 8.50 (1 H, s), 8.26 (1 H, d, J = 1.8 Hz), 7.56 (1 H, d, J = 1.4 Hz), 7.38 - 7.50 (4 H, m), 6.50 (1 H, br s), 2.87 (3 H, d, J = 4.7 Hz), 1.71 (6 H, s). HPLC- MS: m/z 348 [M+H]+.
Another subgenus of the compounds of Formula (I) relates to compounds having the formula:
Figure imgf000058_0001
which can be exemplified by compounds having the formula:
Figure imgf000058_0002
wherein the R1 units are substituted or unsubstituted phenyl. Non-limiting examples of these units are described in Table X herein below.
TABLE X
Figure imgf000058_0003
Figure imgf000059_0003
Another subgenus of the compounds of Formula (I) can be prepared by the procedure outlined in Scheme XII and described in Example 10 herein below.
Scheme XII
Figure imgf000059_0001
23 Reagents and conditions: (a) GlyOMe.HCl, EDCI, HOBt, CH2Cl2; rt, 16 hr.
Figure imgf000059_0002
23 24
Reagents and conditions: (b) 4-methylphenyl boronic acid, Pd(dppf)Cl2, K3PO4, dioxane/H2O;
700C, 16 hr.
EXAMPLE 10 [(4-(4-Methylphenyl)pyridine-2-carbonyl)amino]-acetic acid methyl ester (24)
Preparation of [(4-iodo-ρyridine-2-carbonyl)-amino]-acetic acid methyl ester (23): To a solution of 4-iodo-picolinic acid (1.41 g, 5.66 mmol) in CH2Cb (35 mL) at room temperature under N2 is added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.62 g, 8.49 mmol) and 1-hydroxybenzotriazole (HOBt) (0.077 g, 0.57 mmol). The solution is stirred for 5 minutes and glycine methyl ester hydrochloride (1.07 g, 8.49 mmol) is added and the reaction is stirred 16 hours. The reaction volume is concentrated under reduced pressure and the crude material was partitioned between EtOAc and IM K2CO3. The aqueous phase is removed and the organic phase washed with H2O, sat. NaCl, dried (MgSO4), filtered and concentrated under reduced pressure to afford a brown oil which is purified over silica (EtOAc:heptane gradient 1:4) to afford 0.805 g (44% yield) of the desired product as a colorless solid. HPLC- MS: m/z 321 [MH-H]+.
Preparation of [(4-(4-methylphenyl)pyridine-2-carbonyl)amino]-acetic acid methyl ester (24): To a degassed solution of [(4-iodo-pyridine-2-carbonyl)-amino]-acetic acid methyl ester, 23, (0.150, 0.47 mmol) in 1,4-dioxane (4 mL) and MeOH (2 mL) is added K3PO4 (0.109 mg, 0.52 mmol), Pd(dppf)CI2 (0.038 g, 0.047 mmol) and 4-methylphenyl boronic acid (0.064 g, 0.47 mmol). The reaction is heated to 70 0C in a sealed tube under N2 for 16 hours. The solvents are then removed under reduced pressure and the solid which remains is partitioned between CH2Cl2 and IM K2CO3. The aqueous phase is removed and the organic phase washed with H2O. sat. NaCl, dried (MgSO4), filtered and concentrated under reduced pressure. The crude material is purified over silica (EtOAc :heptane gradient 1 :4 to 3:7) to afford 0.113 g (85% yield) of the desired compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.60 (1 H, dd, J = 5.1, 0.7 Hz), 8.55 (1 H, t, J = 4.8 Hz), 8.43 - 8.44 (1 H, m), 8.43 (1 H, s), 7.66 (1 H, dd, J = 5.1, 1.8 Hz), 7.63 (2 H, d. J = 8.4 Hz), 7.32 (2 H, d, J = 8.1 Hz)54.31 (1 H, d, J = 5.9 Hz), 3.81 (2 H, s), 2.43 (3 H, s). HPLC-MS: m/z 285 [M+H]+.
The following are non-limiting examples of compounds described immediately above.
Figure imgf000060_0001
{[4-(4-Cyanophenyl)pyridine-2-carbonyl] amino} -acetic acid methyl ester: I1 Η. NMR (400 MHz, CDCl3) δ ppm 8.63 (1 H, d, J = 5.1 Hz), 8.45 (1 H, t, J = 5.3 Hz), 8.36 (1 H, d, J = 1.8 Hz), 7.74 (4 H, s), 7.59 (1 H, dd, J = 5.1, 1.8 Hz), 4.24 (2 H, d, J = 5.9 Hz), 3.74 (3 H, s). HPLC-MS: m/z 296 [M+H]+.
Figure imgf000061_0001
{[4-(4-Chlorophenyl)pyridine-2-carbonyl]amino}-acetic acid methyl ester: 1H NMR (400 MHz, CDCl3) δ ppm 8.56 (1 H, dd, J = 4.9, 0.9 Hz), 8.47 (I H, t, J = 5.1 Hz), 8.33 (I H, dd; J = 2.0, 0.9 Hz), 7.51 - 7.61 (3 H, m), 7.41 (2 H, m), 4.23 (2 H, d, J = 5.5 Hz)5 3.74 (3 H, s). HPLC-MS: m/z 305 [M+H]+.
Figure imgf000061_0002
{[4-(3-Chlorophenyl)pyridine-2-carbonyl]amino}acetic acid methyl ester: 1H NMR (400 MHz, CDCl3) δ ppm 8.57 (1 H, dd, J = 5.1, 0.7 Hz), 8.47 (1 H, t, J = 5.1 Hz), 8.33 (1 H, m), 7.62 (1 H, m), 7.57 (1 H, dd, J = 5.1, 1.8 Hz), 7.47 - 7.54 (1 H, m), 7.31 - 7.42 (2 H, m), 4.24 (2 H, d, J = 5.9 Hz), 3.74 (3 H, s). HPLC-MS: m/z 305 [M+H]+.
Figure imgf000061_0003
{[4-(2-Chlorophenyl)pyridine-2-carbonyl]-amino}-acetic acid methyl ester: 1H NMR (400 MHz, CDCl3) δ ppm 8.57 (1 H, dd, J = 5.1, 0.7 Hz), 8.46 (1 H, t, J = 4.6 Hz), 8.20 (1 H, dd J = 1.8, 0.7 Hz), 7.50 (1 H, dd, J = 5.1, 1.8 Hz), 7.42 - 7.46 (1 H, m), 7.30 (1 H, d, J = 1.8 Hz), 7.28 - 7.32 (2 H, m), 4.23 (2 H, d, J = 5.5 Hz), 3.74 (3 H, s). HPLC-MS: m/z 305 [M+H]+.
The second aspect of Category V encompasses compounds having the formula:
Figure imgf000061_0004
wherein R1 units are substituted or unsubstituted phenyl, non-limiting examples of which are described in Table XI herein below.
TABLE XI
Figure imgf000061_0005
Figure imgf000062_0002
The compounds of the second aspect can be prepared by the procedure outlined in Scheme XIII and described in Example 11 herein below.
Scheme XIII
Figure imgf000062_0001
24 25
Reagents and conditions: (a) LiOH, THF, H2O; rt, 16 hr. EXAMPLE 1 1 [(4-(4-Methyl-phenyl)pyridine-2-carbonyl)-amino]-acetic acid (25)
Preparation of [(4-(4-Methyl-phenyl)pyridine-2-carbonyl)-amino]-acetic acid (25): To a solution of [(4-(4-methyl-phenyl)pyridine-2-carbonyl)-amino]-acetic acid methyl ester, 24, (0.092 g, 0.32 mmol) in THF (2 nϊL) at room temperature is added H2O (1 mL) and LiOH.H2O (0.027 g, 0.64 mmol). The reaction is stirred for 16 hours after which time the solution is acidified using IM HCl. The solvents are removed under reduced pressure and the solid that remains is suspended in a mixture of THF: MeOH and filtered. The filtrate is concentrated under reduced pressure and the resulting solid is triturated with MeOH and collected by filtration to provide 0.012 g (12% yield) of the desired compound as a colorless solid. 1H NMR (250 MHz, MeOD) δ ppm 8.69 (1 H, d, J = 4.8 Hz), 8.38 (1 H, s), 7.86 (1 H, d, J = 6.2 Hz)5 7.72 (2 H, d, J = 8.1 Hz), 7.38 (1 H, d, J = 7.9 Hz), 4.21 (1 H, s), 2.44 (2 H, s). HPLC-MS: m/z 271 [M+H]+.
The following are non- limiting examples of compounds compounds of Formula (I).
Figure imgf000063_0001
{[4-(4-Cyanophenyl)pyridine-2-carbonyl]amino} -acetic acid: 1H NMR (250 MHz,
MeOD) δ ppm 8.69 (1 H, d, J = 6.0 Hz), 8.38 (1 H, br s), 7.71 - 8.01 (2 H, m), 4.10 (2 H, s). HPLC-MS: m/z 282 [M+H]+.
Figure imgf000063_0002
{[4-(4-Chlorophenyl)pyridine-2-carbonyl]-amino} -acetic acid: I1 H NMR (250 MHz,
MeOD) δ ppm 8.75 (1 H, s), 8.44 (1 H, br s), 7.85 (3 H, m), 7.57 (2 H, d, J = 7.8 Hz), 4.23 (2 H s). HPLC-MS: m/z 291 [M+H]+.
Figure imgf000064_0001
{[4-(3-Chlorophenyl)pyridine-2-carbonyl] amino} -acetic acid: 1H NMR (400 MHz, MeOD) δ ppm 8.63 (1 H, d, J = 5.5 Hz), 8.27 (1 H, br s), 7.73 (1 H, s), 7.77 (1 H, d, J = 4.0 Hz), 7.64 (1 H, d, J = 7.0 Hz), 7.36 - 7.49 (3 H, m), 4.09 (2 H, s). HPLC-MS: m/z 291 [M+H]+.
Figure imgf000064_0002
{[4-(2-Chlorophenyl)pyridine-2-carbonyl]amino}-acetic acid: 1H NMR (250 MHz, MeOD) δ ppm 8.63 (1 H, d, J = 4.9 Hz), 8.05 - 8.10 (1 H, m), 7.55 (1 H, dd, J = 4.9, 1.6 Hz), 7.46 (1 H, dt, J = 3.9, 2.1 Hz), 7.35 (4 H, d, J = 2.7 Hz), 4.08 (2 H, s). HPLC-MS: m/z 291 [M+H]+.
Another subgenus of the compounds of Formula (I) havethe formula:
Figure imgf000064_0003
wherein non-limiting examples of R and R > 6 are further described herein below in Table XII.
TABLE XII
Figure imgf000064_0004
Figure imgf000065_0003
The compounds described above can be prepared by the procedures outlined in Schemes XIV-XVI and described in Examples 12 -14 herein below.
Scheme XIV
Figure imgf000065_0001
2 26
Reagents and conditions: (a) glycine tert-buty\ ester HCl, EDCI, HOBt,
DIPEA, DMF; rt, 48 hr.
Figure imgf000065_0002
26 27
Reagents and conditions: (b) H2: Pd/C, EtOH, rt, 22 hr.
EXAMPLE 12 [(3,5-Dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid tert-b\xty\ ester (27)
Preparation of [(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-acetic acid tert-buty\ ester (26): To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid, 2, (2.36 g, 6.36 mmol) in DMF (20 mL) at room temperature under N2 is added l-(3-dimethyl-aminopropyl)-3- ethylcarbodiimide (EDCI) (1.83 g, 9.54 mmol) and 1-hydroxybenzo-triazole (HOBt) (0.086 g, 0.64 mmol). The mixture is stirred for 15 minutes after which time glycine tert-butyl ester hydrochloride (1.60 g, 9.54 mmol) and dϋsopropylethylamine (DIPEA) (3.32 ml, 19.08 mmol) are added. The resulting solution is stirred at room temperature for 48 hours then concentrated under reduced pressure. The resulting brown oil is purified over silica (EtOAc) to afford 3.04 g (99% yield) of the desired compound as a yellow solid. 1H NMR (250 MHz, CDCl3) δ ppm 8.19 (1 H5 1, J = 5.2 Hz)5 8.01 - 8.08 (2 H, m), 7.27-7.54 (9 H, m), 6.97 (1 H, d, J = 2.4 Hz), 5.24 (2 H5 s), 5.13 (2 H, s), 4.17 (2 H, d, J = 5.2 Hz), 1.51 (9 H, s). HPLC-MS: m/z 449 [M+H]+.
Preparation of [(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butyl ester (27): A solution of [(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butyl ester 26, (3.04 g, 6.79 mmol) in EtOH (100 mL) containing 10% Pd/C (0.300 g) is stirred under an atmosphere of H∑ for 22 hours. The suspension is then filtered through Celite™, concentrated under reduced pressure, and the crude product purified over silica (2.5% MeOH/CH2Cl2) to afford 1.20 g (66% yield) of the desired compound as a colorless oil. 1H NMR (250 MHz, CDCl3) δ ppm 11.90 (1 H, br s), 8.94 (1 H, br s), 8.20 (1 H, t, J = 5.6 Hz), 7.76 (1 H, d, J = 2.4 Hz), 6.77 (1 H, d, J = 2.1 Hz), 4.13 (2 H, d, J = 5.5 Hz), 1.53 (9 H, s). HPLC-MS: m/z 269 [M+H]+.
Scheme XV
Figure imgf000066_0001
27 28
Reagents and conditions: (a) TFA, CH2Cl2; rt, 16 hr.
EXAMPLE 13 [(3,5-Dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid (29)
Preparation of [(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid (29): To a solution of [(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butyl ester, 28, (0.10 g, 0.37 mmol) in CH2Cl2 (4 mL) at room temperature is added trifluoroacetic acid (1 mL). The reaction is stirred for 16 hours at room temperature and then concentrated under reduced pressure. The solid that remains is collected by filtration, washed with Et2O to afford 0.070 g (89% yield) of the desired compound as a colorless solid. 1H NMR (250 MHz5 DMSO-d6) δ ppm 10.86 (1 H, br s), 9.00 (1 H5 1, J = 6.1 Hz)5 7.77 (1 H, d, J = 2.4 Hz)5 6.69 (1 H5 d, J = 2.4 Hz), 3.95 (1 H5 d5 J = 6.2 Hz). HPLC-MS: m/z 213 [M-HH]+. Scheme XVI
Figure imgf000067_0001
29
Reagents and conditions: (a) glycine ter/-butyl ester HCl, EDCI, HOBt,
DIPEA, DMF; rt, 3 days.
Figure imgf000067_0002
29 30
Reagents and conditions: (b) TFA, CH2Cl2; rt, 5 hr.
EXAMPLE 14 [(3-Hydroxy-pyridine-2-carbonyl)-amino]-acetic acid (30)
Preparation of [(3-hydroxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butyl ester (29):
To a solution of 3-hydroxypicolinic acid (0.20 g, 1.44 mmol) in DMF (5 mL) at 00C under N2 is added diisopropylethylamine (DIPEA) (0.75 ml, 4.3 mmol), l-(3-dimethyl-aminopropyl)-3- ethylcarbodiimide (EDCI) (0.412 g, 2.9 mmol) and 1-hydroxybenzo-triazole (HOBt) (0.019 g, 0.14 mmol). The resulting mixture is stirred for 5 min before glycine tert-butyl ester HCl (0.36 g, 2.9 mmol) is introduced. The resulting solution is stirred at room temperature for 3 days then concentrated under reduced pressure. The reaction mixture is diluted with EtOAc then washed with IM HCl, sat. NaCl, and the organic layer is dried (MgSθ4), filtered and concentrated under reduced pressure to a crude oil that is purified over silica (EtOAc/heptane 1 :4) to afford 0.078 g (22% yield) of the desired compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1 1.80 (1 H, s), 8.39 (1 H, br s), 8.02 (1 H, dd, J = 4.4, 1.5 Hz), 7.27 (1 H, dd, J= 8.8, 4.4 Hz), 7.25 (1 H, dd, J= 8.4, 1.5 Hz), 4.06 (2 H, d, J= 5.5 Hz), 1.44 (9 H, s). HPLC-MS: m/z 197 [M- IBu]+. 4832
67
Preparation of [(3-Hydroxy-pyridine-2-carbonyl)-amino]-acetic acid (30): To a solution of [(3-hydroxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butyl ester, 29, (0.070 g, 0.277 rnmol) in CH2Cl2 (4 mL) is added TFA (1 mL). The resulting solution is stirred for 5 hours then concentrated under reduced pressure to afford 0.054 g (99% yield) of the desired compound as a colorless solid. 1H NMR (400 MHz, MeOD) δ ppm 8.09 (1 H, d, J- 3.3 Hz)3 7.36 - 7.59 (2 H, m), 4.08 (2 H, s). HPLC-MS: m/z 197 [M+Hf.
Category VII of the present disclosure relates to compounds having the formula:
Figure imgf000068_0001
wherein non-limiting examples of R and R6 are further described herein below in Table XIII.
TABLE XIII
Figure imgf000068_0002
Figure imgf000069_0004
The compounds which encompass Category VII of the present disclosure can be prepared by the procedures outlined in Schemes XVII and XVIII and described in Examples 15 and 16 herein below.
Scheme XVII
Figure imgf000069_0001
28
Reagents and conditions: (a) (4-ClC6H4)B(OH)2, Pd(dppf)Cl2, K3PO4, 1,4-dioxane, MeOH; 80 0C, 3 hr.
Figure imgf000069_0002
28 29
Reagents and conditions: (b) LiOH, THF, H2O; reflux,
Figure imgf000069_0003
29 30
Reagents and conditions: (c) GlyOEt.HCl, EDCI5 HOBt, DIPEA, DMF, CH2Cl2; rt, EXAMPLE 15 3-Methoxy-4'-methyl-biphenyl-4-carboxylic acid methyl ester (30)
Preparation of 4'-chloro-3-methoxy-biphenyl-4-carboxylic acid methyl ester (28): To a degassed solution of methyl 4-bromo-2-methoxybenzoate (0.70 g, 2.86 mmol) in 1,4- dioxane (10 mL) and MeOH (2.5 raL) is added 4-chlorophenyl boronic acid (0.536 g, 3.43 mmol), Pd(dppf)Cl2 (0.233 g, 0.286 mmol) and K3PO4 (0.728 g, 3.43 mmol). The resulting suspension is heated to 80 0C and stirred for 3 hours. After this time, the reaction is cooled to room temperature and filtered through Celite™. The solids that form are collected and washed with additional MeOH before the filtrate 1 s concentrated under reduced pressure. The crude material is purified over silica (hexanes:EtOAc; 6:1 to 4:1) to provide 0.615 g (78% yield) of the desired compound as orange crystals. 1H NMR (400 MHz3 CDCl3) δ ppm 7.89 (1 H, d, J= 8.0 Hz), 7.52 - 7.56 (2 H, m), 7.44 (2 H, d, J= 8.7 Hz), 7.17 (1 H5 d, J = 8.0 Hz), 7.12 (1 H, d, J = 1.6 Hz), 3.99 (3 H, s), 3.92 (3 H, s). HPLC-MS: m/z 211 [M+H]+.
Scheme XVIII
Figure imgf000070_0001
30 31
Reagents and conditions: (a) LiOH, THF, H2O; reflux, 2 hr.
EXAMPLE 16 4'-Chloro-3-τnethoxy-biphenyl-4-carboxylic acid
Preparation of 4'-chloro-3-methoxy-biphenyl-4-carboxylic acid (31): To a solution of 4'-chloro-3-methoxy-biphenyl-4-carboxylic acid methyl ester, 30, (0.615 g, 2.22 mmol) in THF (20 mL) and H2O (5 mL) is added LiOH (0.932 g, 22.2 mmol). The resulting suspension is heated to reflux for 2 hours. The reaction is cooled and concentrated under reduced pressure. The crude product is acidified using cone. HCl and the resulting solid is collected by filtration, washed with H2O to afford 0.532 g (91% yield) of the desired compound as a grey solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.69 (1 H, br s), 8.26 (1 H, d, J- 8.1 Hz), 7.53 - 7.58 (2 H, m), 7.44 - 7.50 (2 H, m), 7.33 (1 H, dd, J= 8.1, 1.6 Hz), 7.20 (1 H, d, J= 1.3 Hz)5 4.17 (3 H, s). HPLC-MS: m/z 263 [M+H]+.
The following are non-limiting examples of additional compounds of Formula (I)..
Figure imgf000071_0001
3-Methoxy-4'-methyl-biphenyl-4-carboxylic acid methyl ester: 1H NMR (250 MHz, CDCl3) δ ppm 7.89 (1 H, d, J= 7.9 Hz), 7.52 (2 H, d, J= 8.2 Hz)5 7.25 - 7.32 (2 H3 m), 7.15 7.24 (2 H5 m)s 3.99 (3 H, s), 3.92 (3 H, s), 2.42 (3 H5 s). HPLC-MS: m/z 257 [M+H]+.
Figure imgf000071_0002
3-Methoxy-4'-methyl-biphenyl-4-carboxylic acid: 1H NMR (400 MHz, CDCl3) δ ppm 10.74 (1 H, br s), 8.24 (1 H5 d, J= 8.1 Hz), 7.52 (2 H, d, J= 8.1 Hz), 7.36 (1 H, dd, J= 8.1, 1.5 Hz)5 7.30 (2 H, d, J= 7.9 Hz)5 7.23 (1 H, d, J= 1.4 Hz), 4.16 (3 H5 s), 2.43 (3 H5 s). HPLC-MS: m/z 243 [M+H]+.
Additional compounds of Formula (I) the formula:
Figure imgf000071_0003
wherein non-limiting examples of R8a, R8b, R9 and R6 are further described herein below in
Table .
TABLE XΓV
Figure imgf000071_0004
Figure imgf000072_0002
The compounds described above can be prepared by the procedures outlined herein below in Schemes XIX and XX and described in Examples 17 and 18 herein below.
Scheme XIX
Figure imgf000072_0001
32
Reagents and conditions: (a) 2-(iV-methylamino)acetic acid ester HCl, EDCI, HOBt, DIPEA,
DMF; rt, 32 hr.
EXAMPLE 17 [(3-Hydroxy-pyridine-2-carbonyl)-methyl-amino]-acetic acid ethyl ester (32)
Preparation of [(3-hydroxy-pyridine-2-carbonyl)methylamino]acetic acid ethyl ester (31): To a solution of 3-hydroxy picolinic acid (0.40 g, 2.88 mmol) in DMF (5 mL) is added diisopropylethylamine (DIPEA) (1.50 ml, 8.63 mmol), l-(3-dimethylamino-propyl)-3- ethylcarbodiimide (EDCI) (0.825 g, 4.31 mmol) and 1-hydroxybenzotriazole (HOBt) (0.039 g, 0.29 mmol). The reaction mixture is stirred for 5 minutes then methylamino-acetic acid ester hydrochloride (0.663 g, 4.31 mmol) is added. The reaction is stirred at room temperature for 32 hours after which the solvent is removed under reduced pressure. The residue is partitioned between EtOAc and IM HCl and the organic layer separated, dried (MgSO4), filtered and concentrated under reduced pressure. The crude material is purified over silica (EtOAc :hexanes 1:1) to afford 0.10 g (15% yield) of the desired compound as a colourless solid. HPLC-MS: m/z 240 [M+H]+.
Scheme XX
Figure imgf000073_0001
Reagents and conditions: (a) NaOH, THF, H2O; reflux, 3 hr.
EXAMPLE 18
[(3-Hydroxy-pyridine-2-carbonyl)-methyl-amino]-acetic acid (33)
Preparation of [(3-hydroxy-pyridine-2-carbonyl)-methyl-amino]-acetic acid (33): To a solution of [(3-hydroxy-pyridine-2-carbonyl)methylamino]acetic acid ethyl ester, 32, (0.10 g, 0.42 mmol) in THF (4 mL) is added H2O (1 mL) and NaOH (0.90 g, 2.25 mmol). The reaction is stirred for 3 hours then concentrated under reduced pressure. The remaining oil is acidified to pH ~1 with IM HCl and the solution is concentrated under reduced pressure to give an off-white solid. The solid is suspended in CHCl3:isopropanol (1:1) then collected by filtration. The solid is washed with additional CHClaήsopropanol (1:1) then transferred to a flask and triturated with Et2O to afford 0.075 g (85% yield) of the desired compound as a pale yellow solid. 1H NMR (250 MHz, MeOD) δ ppm (rotamers) 8.26 (1 H, br s), 7.63 - 7.74 (1 H, m), 7.56 - 7.63 (1 H3 m), 4.38 (1 H, s), 4.32 (1 H, s), 3.20 (1.5 H, s), 3.12 (1.5 H, s). HPLC-MS: m/z IW [M+H]+.
The following are non-limiting examples of the compounds described above.
Figure imgf000074_0001
2-(S)-[(3-Hydroxy-pyridine-2-carbonyl)-amino]-propionic acid methyl ester: 1H NMR (250 MHz, CDCl3) δ ppm 11.86 (1 H, s), 8.47 (1 H, br s), 8.10 (1 H5 dd, J= 4.1, 1.7 Hz), 7.28 - 7.43 (2 H, m), 4.63 - 4.84 (1 H, m), 3.81 (3 H, s), 1.57 (3 H, d, J = 7.3 Hz). HPLC-MS: m/z 225 [M+H]+.
Figure imgf000074_0002
l-(3-Hydroxy-pyridine-2-carbonyl)-pyrrolidine-2-carboxylic acid methyl ester: 1H NMR (250 MHz, CDCl3) δ ppm (rotamers) 12.86 (0.67 H, br s), 12.44 (0.33 H, br s), 8.14 (0.33 H, t, J= 2.9 Hz), 7.98 (0.67 H, dd, J= 3.7, 2.1 Hz), 7.24 - 7.31 (2 H, m), 5.38 (0.67 H, dd, J= 8.5, 3.4 Hz), 4.63 - 4.75 (0.33 H, m), 4.37 (0.67 H, t, J= 6.7 Hz), 3.80 - 4.01 (1.33 H, m), 3.79 (1 H, s), 3.70 (2 H, s), 1.87 - 2.44 (4 H, m). HPLC-MS: m/z 251 [M+H]+.
Figure imgf000074_0003
2S-[(3-Hydroxy-pyridine-2-carbonyl)-amino]-propionic acid: 1H NMR (250 MHz, DMSO-J6) δ ppm 12.87 (1 H, br s), 12.28 (1 H, s), 9.19 (1 H, d, J= 7.5 Hz), 8.19 (1 H, dd, J = 4.3, 1.4 Hz), 7.50 - 7.65 (1 H, m), 7.37 - 7.49 (1 H, m), 3.95 - 4.95 (1 H, m), 1.45 (3 H, d, J= 7. Hz). HPLC-MS: m/z 211 [M+H]+.
Administration of one or more of the compounds of Formula (I), alone in the form of pharmaceutical compositions, optionally in combination with other pharmaceutically active compounds or compositions, can be effective in treatment of the following disease states or conditions: i) as human protein HIF- lα prolyl hydroxylase inhibitors; and thereby providing a means for regulating blood flow, oxygen delivery and energy utilization in ischemic tissues; ii) the compounds of the present disclosure are efficacious in regulating blood flow, oxygen delivery and energy utilization in ischemic tissues; and iii) the compounds of the present disclosure provide stabilized HIF-lα by blocking a degradation pathway mediated by HIF prolyl hydroxylase.
Each of the disease states or conditions which the formulator desires to treat may require differing levels or amounts of the compounds described herein to obtain a therapeutic level. The formulator can determine this amount by any of the testing procedures known to the artisan or ordinary skil in the art.
The compounds of the present disclosure can be HIF- lα prolyl hydroxylase inhibitors when administered in pharmaceutically effective amounts, and thereby provide increased angiogenic response or cellular responses which are activated by transcription factors that are directly or indirectly affected by an increase in cellular HIF- lα concentration. Non-limiting examples of these diseases or disease states are listed herein below, inter alia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, and anemia. The compounds disclosed herein are especially effective in the treatment of anemia. Stimulation of EPO production: anemia HIF-I is a transcription factor that also regulates the hypoxia-inducible EPO gene. HIF-
1 binding is required for EPO transcriptional activation in response to hypoxia (Semenza, G.L.,"Regulation of erythropoietin production: New insights into molecular mechanisms of oxygen homeostasis", Hematol. Oncol CUh. North Am., Vol. 8, pp. 863-884 (1994)). In particular, HIF- lα binds to the 31 hypoxia-response element of the EPO gene which results in the marked enhancement of EPO transcription (Semenza, G. L., et al. "Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1", J. Biol. Chem. Vol. 269, pp. 23757-63 (1994)). EPO, in turn, is essential for maintenance of red blood cells by controlling the proliferation and differentiation of erythroid progenitor cells into red blood cells (Krantz, S. B., "Erythropoietin," Blood, Vol. 77, pp 419-434 (1991)). During fetal development, the liver serves as the primary source of EPO. Shortly before birth, production of EPO in the liver decreases and the kidney becomes the primary source of EPO. However, in adults other organs such as the liver and brain produce small but significant amounts of EPO. A erythropoietin deficiency is associated with anemia. In humans, the most prevalent form of anemia is associated with kidney failure. EPO has been described in the treatment of anemia: associated with chemotherapy; that occurs as a consequence of AIDS; and due to prematurity and autologous blood donation. EPO has even been suggested as a general use agent in pre-operative elective surgery. 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, LX. ei al, 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. In 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 vesse maturation.
Angiogenesis is regulated by a balance of naturally occurring pro- and anti-angiogenic factors. Vascular endothelial growth factor, fibroblast growth factor, and angiopoeitin represen 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 identifiec 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 of Cancer 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, NewEng. 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 el 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)). Peripheral Vascular Disease
Peripheral vascular disease (PVD) is the term used to describe the clinical syndrome of vascular insufficiency outside of the coronary circulation and typically involving the circulation to the lower extremities. There are an estimated 8-12 million patients in the US with peripheral vascular disease; another 16.5 million undiagnosed. Atherosclerosis is by far the leading cause of peripheral vascular disease (PVD), although a number of discrete disease processes can contribute to its development and progression (i.e. diabetes, immune vasculitis and trauma). Atherosclerotic PVD can present in three ways:
1) Asymptomatic PVD diagnosed on the basis of noninvasive testing (usually physical exam); 2) Intermittent claudication with symptoms of leg pain with exercise; and
3) Critical limb ischemia with leg pain at rest and limb-threatening ischemic changes (usually non-healing or infected cutaneous ulcerations). The age- adjusted (average age 66 years) prevalence of PVD in the US population is approximately 12%. Of those patients with claudication, 20-30% will have progressive symptoms and 10% will require amputation for critical limb ischemia. Although patients with symptomatic PVD suffer significant decreases in mobility, muscle mass, bone density and quality of life, there are currently no effective medical therapies available.
The present disclosure provides compounds which when administered in vivo inhibit HIF- lα prolyl hydroxylase thereby leading to increased expression of HIF-regulated genes, inter alia, angiogenic factors, erythropoietin, and glycolytic enzymes thereby resulting in improvement in blood flow, oxygen delivery and energy utilization in ischemic tissues. 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.
Wounds 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
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.
Diabetes/Hypertension
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. The present disclosure further relates to forms of the present compounds, which under normal human or higher mammalian physiological conditions, release the compounds described herein. One iteration of this aspect includes the pharmaceutically acceptable salts of the analogs described herein. The formulator, for the purposes of compatibility with delivery mode, excipients, and the like, can select one salt form of the present analogs over another since the compounds themselves are the active species which mitigate the disease processes described herein.
FORMULATIONS The present disclosure also relates to compositions or formulations which comprise the human protein HIF- lα prolyl hydroxylase inhibitors according to the present disclosure. In general, the compositions of the present disclosure comprise: a) an effective amount of one or more human protein HIF- lα prolyl hydroxylase inhibitor according to the present disclosure which are effective for treating PVD CAD, heart failure, ischemia, and anemia; 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 compositions according to the present disclosure include: a) from about 0.001 mg to about 1000 mg of one or more human protein HIF-lα prolyl hydroxylase inhibitor according to the present disclosure; and b) one or more excipients. Another example according to the present disclosure relates to the following compositions: a) from about 0.01 mg to about 100 mg of one or more human protein prolyl HIF-
1 α prolyl hydroxylase inhibitor according to the present disclosure; and b) one or more excipients.
A further example according to the present disclosure relates to the following compositions: a) from about 0.1 mg to about 10 mg of one or more human protein HIF- lα prolyl hydroxylase inhibitor 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 HIF- lα prolyl hydroxylase inhibitors, 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. 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.
The present disclosure further relates to the use of one or more of the HIF-I α prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating anemia.
The present disclosure further relates to the use of one or more of the HIF- lα prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating angiogenesis. The present disclosure further relates to the use of one or more of the HIF- lα prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating peripheral vascular disease.
The present disclosure further relates to the use of one or more of the HIF- lα prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating wounds. The present disclosure further relates to the use of one or more of the HIF- lα prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating atherosclerotic lesions. The present disclosure further relates to the use of one or more of the HIF- lα prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating diabetes.
The present disclosure further relates to the use of one or more of the HIF-I α prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating hypertension. The present disclosure further relates to the use of one or more of the HIF- lα prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating a disease affected by the level of VEGF, GAPDH and erythropoietin.
The present disclosure further relates to the use of one or more of the HIF- lα prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating a disorder 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.
The present disclosure further relates to the use of one or more of the HIF- lα prolyl hydroxylase inhibitors disclosed herein for making a medicament for treating a disorder 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, 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.
METHOD OF USE By increasing the transcription of these HIF-I target genes, the HIF-lα prolyl hydroxylase inhibitors of the present disclosure provide a method for increasing the vascularization of tissue in a subject. As used herein, "vascularization of tissue" means a pro- angiogenic response whereby blood vessels or other vessels or ducts develop at or around the afflicted tissue. The afflicted tissue need not be hypoxic or ischemic per se, but rather the HIF- lα prolyl hydroxylase inhibitors help to sustain or further stimulate the body's pro-angiogenic response to hypoxia. A non-limiting example of "vascularization" includes capillary proliferation in a non-healing wound or along the border of ischemic tissue. Thus, these compounds enhance the ability of the body to revascularize damaged tissues or increase vasculature (e.g. to prevent hypoxic damage). Non-limiting examples of "tissue" include: cardiac tissue, such as myocardium and cardiac ventricles; skeletal muscle; neurological tissue, such as from the cerebellum; internal organs, such as the stomach, intestine, pancreas, liver, spleen, and lung; and distal appendages such as fingers and toes. • Stimulated by a build up of the cellular concentration of HIF-I α is the production of
Vascular Endothelial Growth Factor (VEGF) which is known for its ability to induce vascular leakage. Oxygen tension has been shown to be a key regulator of VEGF gene expression, both in vitro and in vivo. During VEGF induction it is demonstrated that VEGF induces the formation of functional neo-vessels in the mouse cornea and enhanced blood flow in a dog model of coronary artery disease. The HIF- lα prolyl hydroxylase inhibitors of the present disclosure provide enhancement in the expression of multiple hypoxia inducible genes including VEGF, GAPDH and erythropoietin (EPO). Additionally, the HIF- lα prolyl hydroxylase inhibitors of the present disclosure provide enhanced the accumulation of HIFl -α in the cytoplasm and nucleus. Transgenic mice expressing a constitutively active HIF- lα in the skin have increased dermal vascularity and had a 13-fold increase in VEGF levels
The present disclosure also relates to a method for controlling human protein HIF- lα prolyl hydroxylase. The present method comprises the step of administering to a human or higher mammal an effective amount of a composition comprising one or more human protein HIF- lα prolyl hydroxylase inhibitors according to the present disclosure. The present disclosure also relates to the use of the human protein HIF- lα prolyl hydroxylase inhibitors according to the present disclosure in the manufacture of a medicament for the treatment of atrial arrhythmias and related disorders.
The present disclosure also relates to hypoxia inducible factor HIF-I α prolyl hydroxylase inhibition in myocardial remodeling and function, thereby providing means for inducing angiogenesis in a patient experiencing ischemia.
The present disclosure relates to a method for treating anemia comprising administering to a human or mammal in need of treatment an effective amount of one or more human protein HIF- lα prolyl hydroxylase inhibitors according to the present disclosure.
The present disclosure relates to a method for regulating anemia comprising administering to a human or mammal in need of treatment an effective amount of one or more human protein HIF- lα prolyl hydroxylase inhibitors according to the present disclosure. The present disclosure relates to a method for preventing anemia comprising administering to a human or mammal in need of treatment an effective amount of one or more human protein HIF- lα prolyl hydroxylase inhibitors according to the present disclosure.
PROCEDURES
EGLN-I activity assay
The EGLN-I (or EGLN-3) enzyme activity is determined using mass spectrometry (matrix-assisted laser desorption ionization, time-of-flight MS, MALDI-TOF MS - for assay details, see reference (Greis et al., 2006). Recombinant human EGLN-1-179/426 is prepared as described above and in the Supplemental Data. Full-length recombinant human EGLN-3 is prepared in a similar way, however it is necessary to use the His-MBP-TVMV-EGLN-3 fusion for the assay due to the instability of the cleaved protein. For both enzymes, the HIF- lα peptide corresponding to residues 556-574 (DLDLEALAPYIP ADDDFQL) is used as substrate. The reaction is conducted in a total volume of 50 uL containing TrisCl (5 mM, pH 7.5), ascorbate (120 μM), 2-oxoglutarate (3.2 μM), HIF-lα (8.6 μM), and bovine serum albumin (0.01%). The enzyme, quantity predetermined to hydroxylate 20% of substrate in 20 minutes, is added to start the reaction. Where inhibitors are used, compounds are prepared in dimethyl sulfoxide at 10- fold final assay concentration. After 20 minutes at room temperature, the reaction is stopped by transferring 10 μL of reaction mixture to 50 μL of a mass spectrometry matrix solution (α- cyano-4-hydroxycinnamic acid, 5 mg/mL in 50% acetonitrile/0.1% TFA, 5 mM NH4PO4). Two microliters of the mixture is spotted onto a MALDI-TOF MS target plate for analysis with an Applied Biosystems (Foster City, CA) 4700 Proteomics Analyzer MALDI-TOF MS equipped with a Nd: YAG laser (355 nm, 3 ns pulse width, 200 Hz repetition rate). Hydroxylated peptide product is identified from substrate by the gain of 16 Da. Data defined as percent conversion of substrate to product is analyzed in GraphPad Prism 4 to calculate IC50 values.
VEGF ELISA assay
HEK293 cells are seeded in 96-well poly-lysine coated plates at 20,000 cells per well in DMEM (10% FBS, 1% NEAA, 0.1% glutamine). Following overnight incubation, the cells are washed with 100 uL of Opti-MEM (Gibco, Carlsbad, CA) to remove serum. Compound in DMSO is serially diluted (beginning with 100 μM) in Opti-MEM and added to the cells. The conditioned media is analyzed for VEGF with a Quantikine human VEGF immunoassay kit (R&D Systems, Minneapolis, MN). Optical density measurements at 450nm are recorded using the Spectra Max 250 (Molecular Devices, Sunnyvale, CA). Data defined as % of DFO stimulation is used to calculate EC50 values with GraphPad Prism 4 software (San Diego, CA).
Mouse ischemic hindlimb study
All animal work is conducted in accordance with the Guide for the Care and Use of Laboratory Animals (National Academy of Sciences; Copyright ©1996) and the Institutional Animal Care and Use Committee guidelines at Procter and Gamble Pharmaceuticals. We studiec 9-10 week old male C57B1/6 mice from Charles River Laboratory (Portage, MI). The mice are orally dosed with vehicle (aqueous carbonate buffer, 50 mM; pH 9.0) or compound 1 in vehicle at 50 mg/kg or 100 mg/kg. The animals are dosed three times: day 1 at 8am and 5 pm, day 2 at 8am. One hour after the first dose, unilateral arterial ligation is performed under anesthesia using isoflurane. The femoral artery is ligated proximal to the origin of the popliteal artery. The contralateral limb underwent a sham surgical procedure. Ligation is performed in an alternating fashion between right and left hindlimbs. Two hours after 8am dosing on day 2, we obtained blood by ventricular stick while the mice are anesthetized with isoflurane. Serum samples for EPO analysis are obtained using gel clot serum separation tubes. Heart, liver, and gastrocnemius muscles are harvested, snap-frozen in liquid nitrogen, and stored in -8O0C until use.
Mouse Serum EPO assay The mouse serum EPO is detected using Mouse Quantikine Erythropoietin ELISA kit from R&D Systems according to manufacturer's instructions.
Mouse tissue HIF Western blot analysis
Tissues from mice stored at -8O0C are powdered with mortar and pestle chilled with liquid nitrogen. Nuclear extracts are prepared using an NE-PER kit (Pierce Biotechnology). For immunoprecipitation, nuclear extract is added to monoclonal antibody to HIF- let (Novus, Littleton, CO) at a tissue to antibody ratio of 200:1. The suspension is incubated in a conical micro centrifuge tube for 4 hours at 4°C. Protein A/G-coupled agarose beads (40 ul of a 50% suspension) are then added to the tube. Following overnight tumbling at 4°C, the beads are washed 3 times with ice-cold phosphate buffered saline. The beads are then prepared for SDS- PAGE with 40 ul of Laemmli sample buffer. Proteins separated on SDS-PAGE are transferred onto nitrocellulose sheets with XCeIl-II Blot Module system (Invitrogen, Carlsbad, CA). The blots are blocked with 5% BSA prior to incubation with a rabbit antibody to HIF- lα at 1 :100 dilution (Novus). The blots are then washed with Tris-buffered saline/Tween-20 buffer and incubated with horseradish peroxidase-conjugated goat anti-rabbit secondary antibody (Pierce, Rockford, IL). Blots are developed with the ECL reagent (Amersham, Piscataway, NJ). Images of blots are captured with an Epson Expression 1600 scanner.
Table XV below provides non-limiting examples of the in vivo response for compounds according to the present disclosure.
TABLE XV
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
* ND = not determined.
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 mear
"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 ar admission that it is prior art with respect to the present invention. To the extent that an) 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 tha 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

CLAIMS What is claimed is 1. A compound having the formula:
Figure imgf000091_0001
wherein X is N or CH;
R and R1 are each independently a unit chosen from: i) hydrogen; ii) substituted or unsubstituted phenyl; and iii) substituted or unsubstituted heteroaryl; said substitutions chosen from: i) C1-C4 linear, branched, or cyclic alkyl; ii) C1-C4 linear, branched, or cyclic alkoxy; iii) C1-C4 linear, branched, or cyclic haloalkyl; iv) halogen; v) -CN; vi) -NHC(O)R4 vii) -C(O)NR5aR5b; viii) heteroaryl; or ix) two substitutions can be taken together to form a fused ring having from 5 to 7 atoms;
R4 is Ci-C4 linear, branched, or cyclic alkyl; R5a and R5b are each independently: i) hydrogen; ii) C1-C4 linear, branched, or cyclic alkyl; or iii) R5a and R5b can be taken together to form a ring having from 3 to 7 atoms; R2 is chosen from: i) -OR6; or ii) -NR7aR7b; R6 is hydrogen or C1-C4 linear, branched, or cyclic alkyl;
R7a andR7b are each independently: i) hydrogen; ii) C1-C4 linear, branched, or cyclic alkyl; or iii) R7a and R7b can be taken together to form a ring having from 3 to 7 ring atoms;
Y is chosen from: i) hydrogen; ii) -OR3;
R3 is hydrogen, methyl, or ethyl;
L is a linking unit having the formula:
-[C(R8aR8b)]n-
R8a andR8b are each independently hydrogen, methyl, or ethyl; the index n is from 1 to 3; R9 is hydrogen or methyl.
2. A compound according to Claim 1 wherein X is N.
3. A compound according to Claim 2 wherein R is substituted or unsubstituted phenyl.
4. A compound according to Claim 3 wherein R is chosen from 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, and 4-chlorophenyl.
5. A compound according to Claim 3 wherein R is chosen from 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2- jsσ-propoxyphenyl, 3-/so-propoxyphenyl, 4-zso-propoxyphenyl, 2-cyanophenyl, 3- cyanophenyl, and 4-cyanophenyl.
6. A compound according to Claim 3 wherein R is chosen from 2-methoxyρhenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2- /so-propoxyphenyl, 3-/so-propoxyphenyl, 4-/so-propoxyphenyl, 2-cyanophenyl, 3- cyanophenyl, and 4-cyanophenyl.
7. A compound according to Claim 3 wherein R is a unit having the formula:
Figure imgf000093_0001
wherein R10 has the formula -C(O)NR5aR5b; R5a and R5b are each hydrogen or RSa and R5b are taken together to from a ring having 5 or 6 atoms.
8. A compound according to Claim 7 wherein R5a and R5b are taken together to form a pyrrolidin-1-yl ring.
9. A compound according to Claim 3 wherein R is a unit having the formula:
Figure imgf000093_0002
wherein R10 has the formula -NHC(O)R4; R4 is a unit chosen from methyl, ethyl, n- propyl, zso-propyl, and cyclopropyl.
10. A compound according to Claim 3 wherein R is a unit having the formula:
Figure imgf000093_0003
wherein R19 is a heteroaryl unit chosen from l,2,3,4-tetrazol-5-yl, [l,254]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, and thiophene-3-yl.
11. A compound according to Claim 2 wherein R is substituted or unsubstituted heteroaryl.
12. A compound according to Claim 11 wherein R is a unit chosen from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, isoquinolin-1 yl, isoquinolin-3-yl, and isoquinolin-4-yl.
13. A compound according to Claim 11 wherein R is a unit chosen from thiazol-2-yl, thiazol-4-yl, l,2,3,4-tetrazol-5-yl, [l,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3- yl, thiophene-2-yl, and thiophene-3-yl.
14. A compound according to Claim 2 wherein R2 is —OR6; R6 is hydrogen or methyl.
15. A compound according to Claim 14 wherein R6 is hydrogen.
16. A compound according to Claim 14 wherein R6 is methyl.
17. A compound according to Claim 2 wherein R2 is -NR7aR7b; R7a and R7b are each independently hydrogen, methyl, or ethyl.
18. A compound according to Claim 17 wherein R2 is chosen from: i) -NH2; ii) -NHCH3; or iii) -N(CH3)2.
19. A compound according to Claim 2 wherein R3 is hydrogen or methyl.
20. A compound according to Claim 19 wherein R3 is hydrogen.
21. A compound according to Claim 2 wherein L has the formula chosen from: i) -CH2-; ii) -CH2CH2-; or iii) -C(CH3)2-.
22. A compound according to Claim 21 wherein L has the formula -CH2--
23. A compound having the formula:
Figure imgf000095_0001
wherein R is substituted or unsubstituted phenyl; said substitutions are chosen from: i) C1-C4 linear, branched, or cyclic alkyl; ii) C1-C4 linear, branched, or cyclic alkoxy; iii) C1-C4 linear, branched, or cyclic haloalkyl; iv) halogen; v) -CN; vi) -NHC(O)R4 vii) -C(O)NR5aR5b; viii) heteroaryl; or ix) two substitutions can be taken together to form a fused ring having from 5 to 7 atoms;
R4 is C1-C4 linear, branched, or cyclic alkyl; R5a and R5b are each independently: i) hydrogen; ii) C1-C4 linear, branched, or cyclic alkyl; or iii) R5a andR5b can be taken together to form a ring having from 3 to 7 atoms.
24. A compound having the formula:
Figure imgf000095_0002
wherein R is a heteroaryl unit chosen from thiazol-2-yl, thiazol-4-yl, l,2,3,4-tetrazol-5- yl, [l,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3- yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5- yl, isoquinolin-1-yl, isoquinolin-3-yl, and isoquinolin-4-yl.
25. A compound having the formula:
Figure imgf000096_0001
wherein R is substituted or unsubstiruted phenyl; said substitutions are chosen from: i) C1-C4 linear, branched, or cyclic alkyl; ii) C1-C4 linear, branched, or cyclic alkoxy; iii) C1-C4 linear, branched, or cyclic haloalkyl; iv) halogen; v) -CN; vi) -NHC(O)R4 vii) -C(O)NR5aR5b; viii) heteroaryl; or ix) two substitutions can be taken together to form a fused ring having from 5 to 7 atoms;
R4 is C1-C4 linear, branched, or cyclic alkyl; R5a andR5b are each independently: i) hydrogen; ii) C1-C4 linear, branched, or cyclic alkyl; or iii) R5a and R5b can be taken together to form a ring having from 3 to 7 atoms.
26. A compound having the formula:
Figure imgf000096_0002
wherein R is a heteroaryl unit chosen from thiazol-2-yl, thiazol-4-yl, l,2,3,4-tetrazol-5- yl, [l,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3- yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5- yl, isoquinolin-1-yl, isoquinolin-3-yl, and isoquinolin-4-yl.
27. A compound chosen from:
{[5-(3-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;
{[5-(4-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;
{[5-(2-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino} -acetic acid methyl ester;
{[5-(4-Fluoro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester; [(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;
{[3-Hydroxy-5-(4-isopropyl-phenyl)-pyridine-2-carbonyl]-amino} -acetic acid methyl ester;
{[5-(4-Ethyl-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;
{[3-Hydroxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carbonyI]-amino}-acetic acid methyl ester;
{[5-(4-Cyano-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;
{[5-(3-Cyano-phenyl)-3-hydroxy-pyridine-2-carbonyl]-arnino} -acetic acid methyl ester;
{[5-(3-Carbamoyl-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester; ({3-Hydroxy-5-[3-(pyrrolidine- 1 -carbonyl)-phenyl]-pyridine-2-carbonyl } -amino)-acetic acid methyl ester;
({5-[3-(Cyclopropanecarbonyl-amino)-phenyl]-3-hydroxy-pyridine-2-carbonyl}-amino)- acetic acid methyl ester;
({3-Hydroxy-5-[3-(2iy-tetrazol-5-yl)-phenyl]-pyridine-2-carbonyl}-amino)-acetic acid methyl ester;
[(5-Hydroxy-[3,3']bipyridinyl-6-carbonyl)-amino]-acetic acid methyl ester
[(5'-Hydroxy-[2,3']bipyridinyl-6'-carbonyl)-amino]-acetic acid methyl ester;
[(3-Hydroxy-5-pyrimidin-5-yl-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;
[(3-Hydroxy-5-isoquinolin-4-yl-pyridine-2-carbonyl)-amino]-acetic acid methyl ester; [(3-Hydroxy-5-thiazol-2-yl-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;
{[5-(3-Chlorophenyl)-3-hydroxypyridme-2-carbonyl]ammo}-acetic acid;
{[5-(4-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;
{[5-(2-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;
{[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid; [(3-Hydroxy-5-(4-methylphenyl)pyridine-2-carbonyl)amino]-acetic acid;
{[5-(4-Ethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid; {[3-Hydroxy-5-(4-isopropylphenyl)pyridine-2-carbonyl]amino}-acetic acid;
{[3-Hydroxy-5-(3-trifluoromethylphenyl)pyridine-2-carbonyl]amino}-acetic acid;
{[5-(4-Cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino} -acetic acid;
{[5-(3-Cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino} -acetic acid; {[5-(5-Chloro-2-methylphenyl)-3-hydroxypyridine-2-carbonyl]amino} -acetic acid;
{[3-Hydroxy-5-(4-isopropoxyphenyl)pyridine-2-carbonyl]amino} -acetic acid;
({5-[3-(Cyclopropanecarbonylamino)phenyl]-3-hydroxy-pyridine-2-carbonyl}-amino)- acetic acid;
( {3-Hydroxy-5-[3-(pyrrolidine- 1 -carbonyl)phenyl]-pyridine-2-carbonyl} amino)-acetic acid;
({3-Hydroxy-5-[3-(2H-tetrazol-5-yl)phenyl]-pyridine-2-carbonyl}-amino)-acetic acid;
[(5'-Hydroxy-[2,3']bipyridinyl-6'-carbonyl)-amino]-acetic acid;
[(S-Hydroxy-PjS'jbipyridinyl-θ-carbonyrj-aminoJ-acetic acid;
[(3-Hydroxy-5-pyrimidin-5-yl-pyridine-2-carbonyl)-amino]-acetic acid; [(3-Hydroxy-5-isoquinolin-4-yl-pyridine-2-carbonyl)-amino]-acetic acid;
[(3-Hydroxy-5-thiazol-2-yl-pyridine-2-carbonyl)-amino]-acetic acid;
{[5-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid;
[(4'-Chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester; [(3-Methoxy-4'-methyl-biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester;
[(4'-Chloro-3-hydroxy-biphenyl-4-carbonyl)-amino]-acetic acid;
[(3-Hydroxy-4'-methyl-biphenyl-4-carbonyl)-amino]-acetic acid;
5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carboxylic acid dimethylcarbamoylmethyl- amide 5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carboxylic acid carbamoylmethyl-amide;
5-(3-Chloro-phenyl)-3-hydroxy-pyridine-2-carboxylic acid carbamoylmethyl-amide;
5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carboxylic acid (isopropylcarbamoyl-methyl) amide;
3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carboxylic acid methylcarbamoyl-methyl- amide;
5 -(3 -Chloro-phenyl)-3-hydroxy-pyridine-2-carboxylic acid methylcarbamoyl-methy 1- amide; 2-{[5-(3-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester; 2-{[5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid 3-[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-propionic acid ethyl ester; 3-[(3-Hydroxy-5-(3-chlorophenyl)-pyridine-2-carbonyl)-amino]-propionic acid ethyl ester;
3-{[5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-propionic acid; 3-[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-propionic acid;
2-{[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}-2-methyl-propionic acid; 5-(3-Chlorophenyl)-3-hydroxypyridine-2-carboxylic acid (1 -methyl- 1-methylcarbamoyl ethyl)-amide; [(4-(4-Methylphenyl)pyridine-2-carbonyl)amino]-acetic acid methyl ester;
{[4-(4-Cyanophenyl)pyridine-2-carbonyl] amino} -acetic acid methyl ester; {[4-(4-Chlorophenyl)pyridine-2-carbonyl]amino}-acetic acid methyl ester; {[4-(3-Chlorophenyl)pyridine-2-carbonyl]amino}acetic acid methyl ester; {[4-(2-Chlorophenyl)pyridine-2-carbonyl]-amino}-acetic acid methyl ester; [(4-(4-Methyl-phenyl)pyridine-2-carbonyl)-amino]-acetic acid
{[4-(4-Cyanophenyl)pyridine-2-carbonyl]amino}-acetic acid; {[4-(4-Chlorophenyl)pyridine-2-carbonyl]-amino} -acetic acid; { [4-(3-Chlorophenyl)pyridine-2-carbonyl]amino} -acetic acid; {[4-(2-Chlorophenyl)pyridine-2-carbonyl]amino}-acetic acid; • [(3,5-Dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butyϊ ester
[(3,5-Dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid; [(3-Hydroxy-pyridine-2-carbonyl)-arnino]-acetic acid tert-butyl ester; [(3-Hydroxy-pyridine-2-carbonyl)-amino]-acetic acid (30); To a solution of [(3-hydroxj pyridine-2-carbonyl)-amino]-acetic acid tert-butyl ester; 3-Methoxy-4'-methyl-biphenyl-4-carboxylic acid methyl ester;
4 ' -Chloro-3 -methoxy-bipheny 1-4-carboxy lie acid; 3-Methoxy-4'-methyl-biphenyl-4-carboxylic acid methyl ester; 3-Methoxy-4'-methyl-biphenyl-4-carboxylic acid; [(3-Hydroxy-pyridine-2-carbonyl)-methyl-amino]-acetic acid; 2-(S)-[(3-Hydroxy-pyridine-2-carbonyl)-amino]-propionic acid methyl ester; l-(3-Hydroxy-pyridine-2-carbonyl)-pyrrolidine-2-carboxylic acid methyl ester; and 2S-[(3-Hydroxy-pyridine-2-carbonyl)-amino]-propionic acid.
28. A composition comprising:
A) one or more compounds according to Claim 1 ; and
B) one or more excipients or carriers.
29. A method for treating a disease chosen from a disorder 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, 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 comprising administering to a human a compound according to Claim 1.
30. A method for treating a disease chosen from a 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 comprising administering to a human a compound according to Claim 1.
31. A method for treating a disease chosen from a disorder chosen from skeletal muscle and myocardial ischemia, stroke, coronary artery disease, peripheral vascular disease, coronary artery disease comprising administering to a human a compound according to Claim 1.
32. A method for regulating angiogenesis in a human comprising administering to a human compound according to Claim 1.
33. A method for vascularizing ischemic tissue in a human comprising administering to a human a compound according to Claim 1.
34. A method for promoting the growth of skin graft replacements comprising administering to a human a compound according to Claim 1.
35. 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.
36. A method for treating anemia in a human or a mammal comprising administering to a human or a mammal an effective amount of one or more compounds according to any of Claims 1 and 23-27.
37. A method for regulating anemia in a human or a mammal comprising administering to a human or a mammal an effective amount of one or more compounds according to any of Claims 1 and 23-27.
38. A method for preventing anemia in a human or a mammal comprising administering to a human or a mammal an effective amount of one or more compounds according to any of Claims 1 and 23-27.
39. A compound according to any of Claims 1 and 23-27, wherein the compound is a pharmaceutically acceptable of either basic groups or acid groups.
40. A compound according to Claim 36 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.
41. A compound according to Claim 36 wherein the compounds are salts comprising cation chosen from sodium, lithium, potassium, calcium, magnesium, and bismuth.
42. A compound according to Claim 1 , having the formula:
Figure imgf000102_0001
wherein R is substituted or unsubstituted phenyl; said substitutions are chosen from: i) C1-C4 linear, branched, or cyclic alkyl; ii) C1-C4 linear, branched, or cyclic alkόxy; iii) C1-C4 linear, branched, or cyclic haloalkyl; iv) halogen; v) -CN; vi) -NHC(O)R4 vii) -C(O)NR5aR5b; viii) heteroaryl; or ix) two substitutions can be taken together to form a fused ring having from 5 to 7 atoms;
R4 is C1-C4 linear, branched, or cyclic alkyl; R5a andR5b are each independently: i) hydrogen; ii) • C 1-C4 linear, branched, or cyclic alkyl; or iii) R5a and R5b can be taken together to form a ring having from 3 to 7 atoms.
43. A compound according to Claim 1, having the formula:
Figure imgf000102_0002
wherein R is a heteroaryl unit chosen from thiazol-2-yl, thiazol-4-yl, l,2,3,4-tetrazol-5- yl, [l,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, fiιran-3-yl, thiophene-2-yl, thiophene-3 yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5- yl, isoquinolin-1-yl, isoquinolin-3-yl, and isoquinolin-4-yl.
44. A pharmaceutically acceptable salt of any of the compounds of claims 1-27, 42, or 43.
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