NZ618570B2 - Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides - Google Patents

Abstract

Disclosed are processes for preparing [(3-hydroxypyridine-2-carbonyl)amino]-alkanoic acids, derivatives, inter alia, 5-aryl substituted and 5-heteroaryl substituted [(3-hydroxypyridine-2-carbonyl]amino} acetic acids. Further disclosed are methods for making prodrugs of [(3-hydroxypyridine-2-carbonyl)-amino]acetic acids, for example, [(3-hydroxypyridine-2-carbonyl]amino}acetic acid esters and {[3-hydroxypyridine-2-carbonyl]amino} acetic acid amides. The disclosed compounds are useful as prolyl hydroxylase inhibitors or for treating conditions wherein prolyl hydroxylase inhibition is desired. )-amino]acetic acids, for example, [(3-hydroxypyridine-2-carbonyl]amino}acetic acid esters and {[3-hydroxypyridine-2-carbonyl]amino} acetic acid amides. The disclosed compounds are useful as prolyl hydroxylase inhibitors or for treating conditions wherein prolyl hydroxylase inhibition is desired.

Description

PROCESS FOR PREPARING [(3-HYDROXYPYRIDINECARBONYL)AMINO]ALKANOIC ACIDS, ESTERS AND AMIDES PRIORITY This Application claims priority from US. Provisional Application Serial No. 61/493,536, filed June 6, 2011, the entirety of which is included herein by reference.

FIELD Disclosed are processes for preparing droxypyridine—2-carbonyl)amino]- alkanoic acids, derivatives, inter alia, 5—aryl substituted and 5— aryl substituted [(3— hydroxypyridine—2-carbonyl]amino}acetic acids. Further sed are methods for making prodrugs of [(3 —hydroxypyridinecarbonyl)-amino]acetic acids, for example, [(3- hydroxypyridinecarbonyl]amino}acetic acid esters and {[3-hydroxypyridine-2— carbonyl]amino}acetic acid amides. The disclosed compounds are useful as prolyl hydroxylase tors or for treating conditions wherein prolyl hydroxylase inhibition is desired.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 depicts an outline of one embodiment for preparing the disclosed prolyl hydroxylase inhibitors.

Figure 2 depicts an outline of one ment for preparing the disclosed prolyl hydroxylase inhibitor ester prodrugs.

Figure 3 depicts an outline of one embodiment for preparing the disclosed prolyl hydroxylase inhibitor amide gs.

DETAILED SURE The materials, nds, itions, articles, and methods described herein may be understood more readily by reference to the following detailed description of specific aspects of the disclosed subject matter and the Examples included therein.

Before the present materials, compounds, compositions, articles, devices, and methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific synthetic methods or specific reagents, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

Also, throughout this specification, various ations are referenced. The sures of these publications in their entireties are hereby orated by reference into this application in order to more fully describe the state of the art to which the disclosed matter pertains. The nces sed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the nce is relied upon.

General Definitions In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings: All percentages, ratios and proportions herein are by weight, unless otherwise ied. All temperatures are in degrees Celsius (0C) unless ise specified.

By "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the relevant active compound without causing clinically unacceptable biological s or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

A weight percent of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

“Admixture” or “blend” is generally used herein means a physical ation of two or more different components.

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 d 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 es otherwise. Thus, for example, reference to “[(3 -hydroxypyridinecarbonyl)amino]alkanoic acid” es mixtures of two or more such [(3 -hydroxypyridinecarbonyl)amino]alkanoic acids, reference to “the compound” includes mixtures of two or more such compounds, which can include mixtures of l isomers (racemic mixtures), and the like.

“Optional” or “optionally” means that the subsequently bed 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 tood 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 . 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 riately understood by the skilled artisan. For example, if the value “10” is disclosed, then “less than or equal to 10” as well as er than or equal to 10” is also disclosed. It is also understood that throughout the application data are provided in a number of different formats and that this data represent endpoints and starting points and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also sed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

The ing chemical hierarchy is used throughout the specification to describe and enable the scope of the present disclosure and to particularly point out and distinctly claim the units which comprise the compounds of the present disclosure, however, unless ise ically defined, the terms used herein are the same as those of the artisan of ry skill. The term “hydrocarbyl” stands for any carbon atom-based unit (organic molecule), said units optionally ning one or more organic functional group, including nic atom comprising salts, inter alia, carboxylate salts, quaternary ammonium salts.

Within the broad meaning of the term “hydrocarbyl” are the s “acyclic hydrocarbyl” and “cyclic hydrocarbyl” which terms are used to divide hydrocarbyl units into cyclic and non—cyclic classes.

As it relates to the following definitions, “cyclic hydrocarbyl” units can comprise only carbon atoms in the ring (i.e., carbocyclic and aryl rings) or these units can comprise one or more heteroatoms in the ring (i.e., heterocyclic and heteroaryl rings). For “carbocyclic” rings the lowest number of carbon atoms in a ring is 3 carbon atoms; cyclopropyl. For “aryl” rings the lowest number of carbon atoms in a ring are 6 carbon atoms; phenyl. For “heterocyclic” rings the lowest number of carbon atoms in a ring is l carbon atom; diazirinyl, a C1 heterocyclic ring. Ethylene oxide comprises 2 carbon atoms and is a C2 heterocyclic ring. For “heteroaryl” rings the lowest number of carbon atoms in a ring is 1 carbon atom; l,2,3,4-tetrazolyl, a C1 heteroaryl ring. The terms “heterocycle” and “heterocyclic ring” can also include “heteroaryl rings.” The ing is a non-limiting description of the units encompassed by the terms “acyclic arbyl” and “cyclic hydrocarbyl” as used herein.

A. Substituted and unsubstituted c hydrocarbyl: For the purposes of the present disclosure the term “substituted and unsubstituted acyclic hydrocarbyl” encompasses 3 categories of units: 1) linear or branched alkyl, non-limiting examples of which e, methyl (C1), ethyl (C2), yl (C3), opyl (C3), n—butyl (C4), sec—butyl (C4), iso—butyl (C4), tert— butyl (C4), and the like; substituted linear or branched alkyl, non-limiting examples of which includes, hydroxymethyl (C1), chloromethyl (C1), trifluoromethyl (C1), aminomethyl (C1), l-chloroethyl (C2), 2-hydroxyethyl (C2), fluoroethyl (C2), 3—carboxypropyl (C3), and the like. 2) linear or branched alkenyl, non-limiting examples of which include, ethenyl (C2), 3— yl (C3), l-propenyl (also 2-methylethenyl) (C3), penyl (also 2— methylethenyl) (C3), butenyl (C4), and the like; substituted linear or branched alkenyl, non-limiting examples of which include, 2-chloroethenyl (also 2— chlorovinyl) (C2), 4-hydroxybuten-l-yl (C4), 7-hydroxymethylocten-2—yl (C9), 7—hydroxymethyloct-3,5-dienyl (C9), and the like. 3) linear or branched alkynyl, non-limiting es of which include, ethynyl (C2), prop—2—ynyl (also propargyl) (C3), -l-yl (C3), and 2—methyl-hexyn-l-yl (C7); substituted linear or branched alkynyl, non-limiting examples of which include, oxymethylhexynyl (C7), 6-hydroxymethylhept-3 -ynyl (Cg), 5—hydroxy—5—ethylhept-3 -ynyl (C9), and the like.

B. Substituted and unsubstituted cyclic hydrocarbyl: For the purposes of the present disclosure the term “substituted and unsubstituted cyclic hydrocarbyl” encompasses 5 categories of units: 2012/040833 l) The term “carbocyclic” is defined herein as “encompassing rings comprising from 3 to 20 carbon atoms, in one embodiment from 3 to 10 carbon atoms, in another embodiment from 3 to 7 carbon atoms, in a still further embodiment 5 or 6 carbon atoms, wherein the atoms which comprise said rings are limited to carbon atoms, and further each ring can be independently substituted with one or more moieties capable of replacing one or more hydrogen atoms.” The following are non-limiting es of “substituted and unsubstituted carbocyclic rings” which encompass the following ries of units: i) carbocyclic rings having a single substituted or unsubstituted hydrocarbon ring, non-limiting examples of which e, cyclopropyl (C3), 2—methyl— cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), 2,3—dihydroxycyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclopentadienyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cycloheptyl (C7), cyclooctanyl (Cg), 2,5— dimethylcyclopentyl (C5), 3,5—dichlorocyclohexyl (C6), 4—hydroxycyclohexyl (C6), and 3 ,3 ,5 thylcyclohex- l -yl (C6). ii) carbocyclic rings having two or more substituted or unsubstituted fused arbon rings, non-limiting examples of which include, octahydropentalenyl (Cg), octahydro- enyl (C9), 3a,4,5,6,7,7a-hexahydro-3H—indenyl (C9), decahydroazulenyl (C10). iii) carbocyclic rings which are substituted or unsubstituted bicyclic hydrocarbon rings, non-limiting examples of which include, o-[2. l. l]hexanyl, bicyclo[2.2. l]heptanyl, bicyclo[3. l. l]heptanyl, l,3 -dimethyl[2.2. l ]heptan-2—yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl. 2) The term “aryl” is defined herein as “units encompassing at least one phenyl or naphthyl ring and wherein there are no heteroaryl or heterocyclic rings fused to the phenyl or naphthyl ring and further each ring can be independently tuted with one or more moieties capable of replacing one or more hydrogen atoms.” The following are non-limiting examples of “substituted and unsubstituted aryl rings” which encompass the ing categories of units: i) C6 or C10 substituted or unsubstituted aryl rings; phenyl and naphthyl rings whether substituted or unsubstituted, non-limiting es of which include, phenyl (C6), naphthylen-l-yl (C10), naphthylenyl (C10), 4-fluorophenyl (C6), 2- hydroxyphenyl (C6), 3-methylphenyl (C6), 2-aminofluorophenyl (C6), 2-(N,N— diethylamino)phenyl (C6), 2—cyanophenyl (C6), 2,6—di—tert—butylphenyl (C6), 3— methoxyphenyl (C6), 8-hydroxynaphthylen-2—yl (C10), 4,5-dimethoxynaphthylen-l- yl (C10), and 6-cyano-naphthylen-l-yl (C10). ii) C6 or C10 aryl rings fused with l or 2 saturated rings to afford C8-C20 ring systems, non-limiting examples of which include, o[4.2.0]octa-l,3,5-trienyl (Cg), and indanyl (C9). 3) The terms “heterocyclic” and/or “heterocycle” are defined herein as “units comprising one or more rings having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (0), or sulfur (S), or mixtures of N, O, and S, and wherein further the ring which contains the heteroatom is also not an aromatic ring.” The following are non-limiting examples of “substituted and unsubstituted heterocyclic rings” which ass the following categories of units: i) heterocyclic units haVing a single ring containing one or more heteroatoms, non-limiting es of which include, diazirinyl (C1), inyl (C2), urazolyl (C2), azetidinyl (C3), pyrazolidinyl (C3), imidazolidinyl (C3), oxazolidinyl (C3), isoxazolinyl (C3), thiazolidinyl (C3), isothiazolinyl (C3), azolidinonyl (C3), oxazolidinonyl (C3), hydantoinyl (C3), tetrahydrofuranyl (C4), idinyl (C4), morpholinyl (C4), zinyl (C4), dinyl (C4), dihydropyranyl (C5), tetrahydropyranyl (C5), piperidinonyl (valerolactam) (C5), 2,3,4,5-tetrahydro-1H- azepinyl (C6), 2,3-dihydro-lH—indole (Cg), and l,2,3,4-tetrahydroquinoline (C9). ii) heterocyclic units haVing 2 or more rings one of which is a heterocyclic ring, non-limiting examples of which e hexahydro- 1H-pyrrolizinyl (C7), 3 a,4,5,6,7,7a-hexahydro- lH—benzo[d]imidazolyl (C7), 3a,4,5,6,7,7a—hexahydro- 1H- indolyl (Cg), l,2,3,4-tetrahydroquinolinyl (C9), and decahydro-lH— cycloocta[b]pyrrolyl (C10). 4) The term “heteroaryl” is defined herein as “encompassing one or more rings comprising from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (0), or sulfur (S), or mixtures of N, O, and S, and wherein further at least one of the rings which comprises a atom is an aromatic ring.” Heteroaryl rings can comprise from 1 to 19 carbon atoms, in another embodiment heteroaryl rings can comprise from 1 to 9 carbon atoms. The following are non—limiting examples of “substituted and unsubstituted cyclic rings” which ass the following ries of units: i) aryl rings containing a single ring, non-limiting examples of which include, l,2,3,4-tetrazolyl (C1), [1,2,3]triazolyl (C2), [1,2,4]triazolyl (C2), triazinyl (C3), thiazolyl (C3), lH—imidazolyl (C3), yl (C3), isoxazolyl (C3), isothiazolyl (C3), furanyl (C4), thiophenyl (C4), pyrimidinyl (C4), 2-phenylpyrimidinyl (C4), pyridinyl (C5), 3-methylpyridinyl (C5), and 4-dimethylaminopyridinyl (C5) ii) heteroaryl rings containing 2 or more fused rings one of which is a heteroaryl ring, non-limiting examples of which e: 7H—purinyl (C5), 9H—purinyl (C5), 6— amino-9H—purinyl (C5), 5H—pyrrolo[3,2—d]pyrimidinyl (C6), 7H—pyrrolo[2,3- d]pyrimidinyl (C6), pyrido[2,3-d]pyrimidinyl (C7), ylbenzo[d]thiazolyl (C7), lH—indolyl (Cg), 4,5,6,7-tetrahydro-l-H—indolyl (Cg), quinoxalinyl (Cg), 5- uinoxalinyl (Cg), quinazolinyl (Cg), quinolinyl (C9), 8-hydroxy-quinolinyl (C9), and isoquinolinyl (C9). 5) C1—C6 tethered cyclic hydrocarbyl units (whether carbocyclic units, C6 or C10 aryl units, heterocyclic units, or heteroaryl units) which connected to another moiety, unit, or core of the molecule by way of a C1-C6 alkylene unit. Non-limiting examples of tethered cyclic hydrocarbyl units include benzyl C1-(C6) haVing the formula: m —%\/ wherein Ra is optionally one or more independently chosen substitutions for hydrogen. Further examples include other aryl units, inter alia, (2— hydroxyphenyl)hexyl C6-(C6); naphthalen-2—ylmethyl C1-(C10), 4-fluorobenzyl C1- (C6), 2—(3 -hydroxyphenyl)ethyl C2-(C6), as well as substituted and unsubstituted C3— C10 alkylenecarbocyclic units, for example, cyclopropylmethyl C1-(C3), cyclopentylethyl ), cyclohexylmethyl C1-(C6);. Included within this category are substituted and unsubstituted C1-C10 alkylene-heteroaryl units, for example a 2— picolyl C1-(C6) unit haVing the formula: —CH,QRa wherein Ra is the same as defined above. In addition, C1—C12 tethered cyclic hydrocarbyl units e C1-C10 alkyleneheterocyclic units and alkylene-heteroaryl units, miting examples of which include, aziridinylmethyl Cl-(Cz) and — 2—ylmethyl Cl—(C3).

For the purposes of the present disclosure carbocyclic rings are from C3 to C20; aryl rings are C6 or C10; heterocyclic rings are from C1 to C9; and heteroaryl rings are from C1 to For the purposes of the present disclosure, and to provide consistency in defining the present disclosure, fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be characterized and referred to herein as being encompassed by the cyclic family corresponding to the heteroatom containing ring, although the artisan may have alternative characterizations. For example, l,2,3,4- tetrahydroquinoline having the a: is, for the purposes of the present disclosure, defined as a heterocyclic unit. 6,7—Dihydro— 5H—cyclopentapyrimidine having the formula: Nfi?MN/ is, for the purposes of the present disclosure, is defined as a heteroaryl unit. When a fused ring unit contains heteroatoms in both a non-aromatic ring (heterocyclic ring) and an aryl ring (heteroaryl ring), the aryl ring will predominate and determine the type of ry to which the ring is ed herein for the purposes of describing the invention. For example, l,2,3,4-tetrahydro-[1,8]naphthpyridine having the formula: N E is, for the purposes of the t sure, is defined as a aryl unit.

The term “substituted” is used throughout the specification. The term “substituted” is applied to the units described herein as “substituted unit or moiety is a hydrocarbyl unit or , whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several substituents as defined herein below.” The units, when substituting for hydrogen atoms are capable of replacing one hydrogen atom, two hydrogen atoms, or three en atoms of a hydrocarbyl moiety at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety, or unit. For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two en atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from nt carbon atoms includes epoxy, and the like. Three hydrogen replacement includes cyano, and the like. The term substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain; can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as “substituted” any number of the hydrogen atoms may be ed. For example, 4-hydroxyphenyl is a “substituted ic carbocyclic ring (aryl ring)”, (N,N—dimethylamino)octanyl is a “ tuted Cg linear alkyl unit, 3-guanidinopropyl is a “substituted C3 linear alkyl unit,” and 2-carboxypyridinyl is a “substituted heteroaryl unit.” The following are non-limiting examples of units which can tute for hydrogen atoms on a carbocyclic, aryl, heterocyclic, or heteroaryl unit: i) substituted or unsubstituted C1—C12 linear, C3—C12 branched, or C3—C12 cyclic alkyl, alkenyl, and l; methyl (C1), ethyl (C2), ethenyl (C2), ethynyl (C2), n—propyl (C3), iso—propyl (C3), cyclopropyl (C3), enyl (C3), 1— propenyl (also 2—methylethenyl) (C3), isopropenyl (also ylethenyl) (C3), prop-2—ynyl (also propargyl) (C3), propyn—l—yl (C3), n—butyl (C4), sec— butyl (C4), iso—butyl (C4), tert—butyl (C4), cyclobutyl (C4), buten—4—yl (C4), entyl (C5), cyclohexyl (C6); ii) substituted or unsubstituted C6 or C10 aryl; for e, phenyl, naphthyl (also referred to herein as naphthylen-l-yl (C10) or naphthylenyl (C10)); iii) substituted or unsubstituted C7 or C11 alkylenearyl; for example, benzyl, 2- phenylethyl, naphthylenylmethyl; iV) substituted or unsubstituted C1—C9 heterocyclic rings; as described herein below; V) substituted or unsubstituted C1—C9 heteroaryl rings; as described herein below; Vi) —(CR1023R102b)aOR101; for example, —OH, , —OCH3, —CHZOCH3, —OCH2CH3, —CH20CH2CH3, —OCH2CH2CH3, and —CH20CH2CH2CH3; vii) —(CR1023R102b)aC(O)R101; for example, —COCH3, —CH2COCH3, —COCH2CH3, —CH2COCH2CH3, —COCH2CH2CH3, and —CH2COCH2CH2CH3; viii) —(CR102aR102b)aC(O)OR101; for example, —C02CH3, —CH2COZCH3, —COZCH2CH3, —CH2COZCH2CH3, —COZCH2CH2CH3, and —CH2COZCH2CH2CH3; ix) zaRlozb)aC(O)N(R101)2; for example, —CONH2, —CH2CONH2, H3, —CH2CONHCH3, —CON(CH3)2, and N(CH3)2; x) —(CR1023R102b)aN(R101) C(0)R101, for example, —NHCOCH3, —CH2NHCOCH3, —NHCOCH2CH3, and COCH2CH3; xi) —(CR102aR102b)aN(R101) C(O)2R101; for example, —NHCOZCH3, —CH2NHCOZCH3, —NHCOZCH2CH3, and —CH2NHCOZCH2CH3; xii) 2aR102b)aN(R101)2, for example, —NH2, —CH2NH2, —NHCH3, —CH2NHCH3, —N(CH3)2, and —CH2N(CH3)2; xiii) halogen; —F, —Cl, —Br, and —I; xiv) —(CR102aR102b)aCN; xv) —(CR102aR102b)aNOZ; xvi) —(CHj,Xka)aCHJ-Xk; wherein X is halogen, the index j is an integer from 0 to 2,j + k = 3; the indexj’ is an integer from 0 to 2, j’ + k’ = 2; for example, —CH2F; —CHF2; —CH2CH2F; —CH2CHF2; —CF3; —CC13; 01' —CBI‘3; xvii) —(CR102aR102b),SR101, —SH, —CHZSH, —SCH3, —CHZSCH3, —SC6H5, and —CstC6H5; xviii) —(CR102aR102b)aSOzR101; for example, —SOzH, —CHZSOZH, —SOZCH3, —CHZSOZCH3, —SOZC6H5, and ZC6H5; and xix) —(CR1023R102b)aSO3R101; for e, —so3H, 3H, —SO3CH3, —CstO3CH3, —SO3C6H5, and —CstO3C6H5; wherein each R101 is independently hydrogen, substituted or unsubstituted C1—C6 linear, C3— C6 branched, or C3—C6 cyclic alkyl, phenyl, benzyl, heterocyclic, or aryl; or two R101 units can be taken together to form a ring comprising 3-7 atoms; R102a and R10% are each independently hydrogen or C1—C4 linear or C3—C4 branched alkyl; the index “a” is from 0 to The substitutions for hydrogen defined herein above, for example, substituted C1—C12 linear, C3-C12 branched, or C3-C12 cyclic alkyl, alkenyl, and alkynyl, substituted C6 or C10 2012/040833 aryl, substituted C7 or C11 alkylenearyl, substituted C1—C9 heterocyclic rings, substituted C1— C9 heteroaryl rings, and R101, can be ally substituted by one or more of the following substitutions for hydrogen: 0 C1—C12 linear, C3—C12 ed, or C3-C12 cyclic alkyl, alkenyl, and alkynyl; methyl (C1), ethyl (C2), ethenyl (C2), ethynyl (C2), n—propyl (C3), iso—propyl (C3), cyclopropyl (C3), 3—propenyl (C3), l—propenyl (also 2—methylethenyl) (C3), isopropenyl (also ylethen—2—yl) (C3), prop—2—ynyl (also propargyl) (C3), propyn-l-yl (C3), n—butyl (C4), sec—butyl (C4), iso—butyl (C4), tert—butyl (C4), cyclobutyl (C4), buten—4—yl (C4), cyclopentyl (C5), cyclohexyl (C6); ii) C6 or C10 aryl; for example, phenyl, naphthyl (also referred to herein as naphthylen- l -yl (C10) or naphthylenyl ; iii) C7 or C11 alkylenearyl; for example, , 2—phenylethyl, naphthylen-2— ylmethyl; iV) C1—C9 heterocyclic rings; as described herein below; C1-C9 heteroaryl rings; as described herein below; Vi) —(CR2023R202b)bOR201; for example, —OH, —CH20H, —OCH3, —CHZOCH3, —OCH2CH3, —CH20CH2CH3, —OCH2CH2CH3, and —CH20CH2CH2CH3; Vii) —(CR202aR202b)bC(O)R201; for example, —COCH3, —CH2COCH3, —COCH2CH3, CH2CH3, —COCH2CH2CH3, and —CH2COCH2CH2CH3; viii) —(CR202aR202b)bC(O)OR201; for example, —COzCH3, —CH2C02CH3, —COzCH2CH3, —CH2COZCH2CH3, —COzCH2CH2CH3, and —CH2COZCH2CH2CH3; ix) —(CR2023R202b)bC(O)N(R201)2; for example, —CONH2, —CH2CONH2, H3, —CH2CONHCH3, —CON(CH3)2, and —CH2CON(CH3)2; —(CR202aR202b)bN(R201) C(O)R201; for example, —NHCOCH3, —CH2NHCOCH3, —NHCOCH2CH3, and —CH2NHCOCH2CH3; xi) 23R202b)bN(R201) C(O)2R201; for example, —NHC02CH3, —CH2NHC02CH3, CH2CH3, and —CH2NHCOZCH2CH3; xii) —(CR2023R202b)bN(R201)2; for example, —NH2, —CH2NH2, —NHCH3, —CH2NHCH3, —N(CH3)2, and —CH2N(CH3)2; xiii) halogen; —F, —Cl, —Br, and —I; xiv) —(CR202aR202b)bCN; xv) —(CR202aR202b)bNOZ; xvi) —(CHj,Xk,)aCHJ-Xk; wherein X is halogen, the index j is an integer from 0 to 2,j + k = 3; the indexj’ is an integer from 0 to 2, j’ + k’ = 2; for example, —CH2F, —CHF2, —CH2CH2F, —CH2CHF2, —CF3, —CCl3, or —CBr3; xvii) —(CR202aR202b)bSR201, —SH, —CHZSH, —SCH3, H3, —SC6H5, and 6H5; xviii) —(CR2023R202b)bSOZR201; for example, —SOzH, —CHZSOZH, 3, —CHZSOZCH3, —SOZC6H5, and —CHZSOZC6H5; and xix) —(CR2023R202b)bSO3R201; for example, —so3H, —CHZSO3H, —SO3CH3, —CHZSO3CH3, —SO3C6H5, and —CH2803C6H5; wherein each R201 is independently hydrogen, C1—C6 linear, C3—C6 branched, or C3—C6 cyclic alkyl, phenyl, benzyl, heterocyclic, or aryl; or two R201 units can be taken together to form a ring comprising 3-7 atoms; R202a and R20% are each independently hydrogen or C1— C4 linear or C3-C4 ed alkyl; the index “b” is from 0 to 4.

For the purposes of the present disclosure the terms “compound,” “analog,” and “composition of matter” stand y well for each other and are used interchangeably throughout the specification. The disclosed compounds include all enantiomeric forms, diastereomeric forms, salts, and the like.

The compounds disclosed herein include all salt forms, for example, salts of both basic groups, inter alia, amines, as well as salts of acidic , inter alia, carboxylic acids. The following are non-limiting examples of anions that can form salts with protonated basic groups: de, bromide, iodide, e, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, te, lactate, oxalate, malonate, e, ate, tartrate, fumarate, citrate, and the like. The following are non-limiting examples of cations that can form salts of acidic groups: ammonium, sodium, lithium, potassium, calcium, magnesium, bismuth, lysine, tromethamine, meglumine and the like.

The disclosed process can be used to prepare compounds having the formula: / OH OH 0 wherein R and R1 are further defined herein.

Compounds having the formula: \N O / S‘Liou OH 0 wherein L is a linking group defined herein. have been found to exhibit prolyl hydroxylasc inhibition (antagonism). Compounds of this formula have also been found to stabilize hypoxia ble factor-2 alpha (HIP-2a). It has also been found that esters and amides having the formula: o \ N o H i 3 i H l 4 N R w R ‘1. 0’ / I“ L If on o and on o R5 can hydrolyze in vivo, in vitro and ex vivo to the ponding carboxylic acids shown above. As such, these esters and amides are referred to herein as "prodrugs." In a ular embodiment, the present invention provides a process for preparing a compound having the formula: wherein R1 is chosen from: i) substituted or unsubstituted C6 or C10 aryl; or ii) substituted or unsubstituted C1-C9 heteroaryl; L is a linking unit having the formula: —(CR7°R7")n— R7a and R7” are each independently: i) hydrogen; or ii) C1-C6 linear, C3-C6 ed or C3-C5 cyclic alkyl; R8 is chosen from hydrogen, methyl, or ethyl; and the index n is an integer from 1 to 4; 13 (followed by 13A) or a pharmaceutically acceptable salt thereof, comprising: A) reacting a boronic acid or ester having the a: wherein Y is OR2°, R20 is hydrogen or C1-C6 linear, C3-C6 branched, or C3-C6 cyclic alkyl, or two OR20 units can be taken together to form a 5-member to 7- member C3-C10 cyclic ester, with a 3,5-dihalocyanopyridine having the each Z is independently chloro or bromo, in the presence of a catalyst, to form a 5-aryl or 5-heteroarylhalocyanopyridine having the formula: B) reacting the S-aryl or 5-heteroarylhalocyanopyridine formed in step (A) with an alkoxide anion having the formula: 9 0R2 wherein R2 is C1-C12 linear alkyl or C3-C12 branched alkyl, to form a 5-a1y1 or —heteroa1yl—3-alkoxy—2-cyanopyridine having the formula: 13A (followed by 133) C) reacting the S-aryl or 5-heteroaryl-3—alkoxycyanopyridine formed in step 03) with an acid to form a 5-aryl or 5-heteroarylhydroxycarboxypyridine having the formula: / OH OH 0 'and D) reacting the S-aryl or 5-heteroa1yl-3—hydroxycarboxypyridine formed in step (C) with an amino acid having the formula: N com H \(CR7HR7h)n/ “ In another embodiment, the present invention provides a process for preparing a compound having the formula: N {:8 O / N \(CR7aR7b)nAX 0H 0 wherein A is a ring chosen from: i) substituted or unsubstituted C6 or C10 aryl; or ii) substituted or unsubstituted C1-C9 aryl; Rlo represents one or more ndently chosen optionally present substitutions for hydrogen; X is chosen from: i) —OH; ii) —0R3; iii) ; and iv) —OM1; 13B (followed by 13C) R3 is C1-C12 linear, C3-C12 branched or C3-C12 cyclic alkyl; C2-C12 linear, C3—C12 branched or C3-C12 cyclic alkenyl; or C2-C12 linear, C3-C12 branched or C3-C12 cyclic alkynyl, or benzyl; R4 and R5 are each independently hydrogen, C1-C12 linear, C3-C12 branched or C3-C12 cyclic alkyl; C2-C12 linear, C3-C12 branched or C3-C12 cyclic l; or C2-C12 linear, C3-C12 branched or C3-C12 cyclic alkynyl; benzyl; or R4 and R5 can be taken together with the nitrogen atom to form a 3 to 10 member ring, wherein the ring can optionally contain one or more heteroatoms chosen from oxygen (0), nitrogen (N), or sulfur (S); M1 is a pharmaceutically acceptable cation; R7” and R7” are each independently: i) hydrogen; or ii) C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl; R8 is chosen from hydrogen, , or ethyl; and the index n is an r from 1 to 4; or a pharmaceutically acceptable salt thereof, comprising: A) reacting a boronic acid or ester having the a: R'° B wherein Y is ORZO, R20 is en or C1-C6 linear, C3-C6 branched, or C3-C6 cyclic alkyl, or two OR20 units can be taken together to form a S-member to 7- member C3-C1o cyclic ester, with a 3,5-dihalocyanopyridine having the formula: each Z is independently chloro or bromo, in the presence of a catalyst, to form a 5-aryl or 5-heteroaryl—3-halocyanopyridine having the formula: 13C (followed by 130) B) reacting the S-aryl or 5-heteroarylhalocyanopyridine formed in step (A) with an alkoxide anion having the formula: 9 0R2 n R2 is C1-C12 linear alkyl or C3-C12 branched alkyl, to form a 5-ary1 or —heteroaryl—3-alkoxy—2-cyanopy1idine having the formula: C) reacting the 5-aryl or 5-heteroaryl—3-alkoxy—2-cyanopyridine formed in step (B) with an acid to form a 5-aryl or 5-heteroarylhydroxycarboxypyridine having the formula: / OH OH O ;and D) reacting the S-aryl or 5—heteroaryl-3—hydroxy-2—carboxypyridine formed in step (C) with a compound having the formula: R8 0 H \(CR7aR7b))L Xn 13D (followed by 13E) 13E wed by 14) WO 70377 When a ring is formed from R4 and R5 and the ring contains a ring en other than the nitrogen atom to which R4 and R5 are bonded, then the nitrogen atom can have the form —NR9— or =N—, wherein R9 can be hydrogen or methyl. Non-limiting examples of this embodiment includes compounds having the formula: \N R1 0 \ O / \L N/fi / N\L N/\N 0R2 O K/NH and OR2 0 K/ In one aspect, X is hydroxyl, —OH.

In a further aspect, X is —OR3. One embodiment of this aspect relates to X units wherein R3 is C1-C6 linear alkyl, for example, methyl (C1), ethyl (C2), n-propyl (C3), n-butyl (C4), n-pentyl (C5), and n-hexyl (C6). Non-limiting examples include the methyl ester, the ethyl ester, the n-propyl ester, and the like.

Another embodiment of this aspect relates to X units wherein R3 is C3-C6 branched alkyl non-limiting examples of which include iso—propyl (C3), sec—butyl (C4), iso—butyl (C4), tert—butyl (C4), l-methylbutyl (C5), 2-methylbutyl (C5), 3-methylbutyl (C5), and 4- methylpentyl (C6).

A further embodiment of this aspect s to X units wherein R3 is C3—C6 cyclic alkyl, for example, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), and cyclohexyl (C6).

In r aspect, X is —NR4R5. One embodiment of this aspect relates to X units wherein R4 and R5 are both en; —NH2_ A further embodiment of this aspect relates to X units wherein R4 and R5 are independently chosen from hydrogen, C1-C4 linear alkyl, C3-C4 branched alkyl, or C3-C4 cyclic alkyl, for e, methyl (C1), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), sec—butyl (C4), tyl (C4), and tert—butyl (C4). Non-limiting es of this embodiment include —NH2, —NHCH3, —N(CH3)2, —NHC2H5, —N(C2H5)2, and — N(CH3)(C2H5).

L is a linking unit having the formula —(CR7aR7b)n— wherein R7a and R7b can be independently chosen from hydrogen, C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl.

The index n is an integer from 1 to 4.

In one aspect of L units, R7a and R7b are both en and the index n is an r from 1 to 4, i.e., —CH2— (methylene), —CH2CH2— (ethylene), —CH2CH2CH2— (propylene), and —CH2CH2CH2CH2— (butylene). One ion of L units according to this aspect relates to nds having the formula: R1 R] R1 \ o \ \ N N 0 N o / E\Jkon mfi$ow mfidkmfiw OR2 o OR2 o and OR2 o , , A further aspect of L units relates to L units n R7a and R7b are independently chosen from hydrogen, methyl (C1), ethyl (C2), n-propyl (C3), and iso-propyl (C3) and the index n is an integer from 1 to 4. One embodiment of this aspect relates to L units wherein R7a is hydrogen and R7b is chosen from methyl (C1), ethyl (C2), n—propyl (C3), and iso— propyl (C3), and the index n is an integer from 1 or 3. Non-limiting examples of this embodiment includes —CH(CH3)—, —CH2CH(CH3)—, —CH(CH3)CH2—, —CH(CH3)CH2CH2—, —CH2CH(CH3)CH2—, and —CH2CH2CH(CH3)—.

A yet further aspect of L units relates to L units wherein R7a and R7b are independently chosen from methyl (C1), ethyl (C2), yl (C3), and iso-propyl (C3) and the index n is an integer from 1 to 4. A non-limiting example of this aspect has the formula —C(CH3)2—.

In a still further aspect of L units, L units can be derived from the reaction of an amino acid with a 5—aryl or 5—heteroaryl—3—hydroxy—2—carboxypyridine as described herein below in the disclosure of process step D. One embodiment of this aspect of L relates to L units n R7b is hydrogen and R7a is chosen from hydrogen, methyl, iso—propyl, iso— butyl, sec-butyl, hydroxymethyl, l-hydroxyethyl, thiomethyl, 2-(methylthio)ethyl, benzyl, (4-hydroxyphenyl)methyl, indolylmethyl, imidazolylmethyl, 3-gunidinylpropyl, 4- aminobutyl, carboxymethyl, 2—carboxyethyl, ide, or R8 and R7a can be taken together to form a idinyl ring, for example, when proline is reacted with the 5-aryl or 5— heteroarylhydroxycarboxypyridine.

The index n can be any integer from 1 to 4, for example n can equal 1, n can equal 2, n can equal 3, and n can equal 4.

R8 is en, methyl (C1) or ethyl (C2). In one aspect R8 is hydrogen. In a further aspect R8 is methyl (C1). In another aspect R8 is ethyl (C2).

R1 Units R1 units are chosen from: i) substituted or unsubstituted C6 or C10 aryl; and ii) substituted or unsubstituted C1—C9 heteroaryl.

Non-limiting examples of tutions for a hydrogen atom on R1 units, or alternatively an R10 unit when R1 is represented by an A ring, include: i) C1—C12 linear, C3—C12 branched, or C3-C12 cyclic alkyl, alkenyl, and alkynyl; for e, methyl (C1), ethyl (C2), ethenyl (C2), ethynyl (C2), n-propyl (C3), iso—propyl (C3), cyclopropyl (C3), 3—propenyl (C3), l—propenyl (also 2— methylethenyl) (C3), isopropenyl (also 2-methylethenyl) (C3), prop-2—ynyl (also propargyl) (C3), —l—yl (C3), n—butyl (C4), sec—butyl (C4), iso— butyl (C4), tert—butyl (C4), cyclobutyl (C4), 4—yl (C4), entyl (C5), cyclohexyl (C6); ii) C6 or C10 aryl; for example, phenyl, naphthyl (also referred to herein as naphthylen- l -yl (C10) or naphthylenyl (C10)); iii) C7 or C11 alkylenearyl; for example, benzyl, 2—phenylethyl, naphthylen-2— ylmethyl; iV) C1—C9 heterocyclic rings; as described herein below; C1-C9 heteroaryl rings; as described herein below; Vi) —(CR1023R102b)aOR101; for e, —OH, , —OCH3, —CHZOCH3, —OCH2CH3, —CHZOCH2CH3, —OCH2CH2CH3, and —CH20CH2CH2CH3; Vii) —(CR1023R102b)aC(O)R101; for example, —COCH3, —CH2COCH3, —COCH2CH3, —CH2COCH2CH3, —COCH2CH2CH3, and —CH2COCH2CH2CH3; viii) —(CR1023R102b)aC(O)OR101; for example, —COzCH3, —CH2COZCH3, —COzCH2CH3, —CH2COzCH2CH3, —COzCH2CH2CH3, and —CH2COZCH2CH2CH3; ix) —(CR1ozaRlozb)aC(O)N(R101)2; for example, —CONH2, —CH2CONH2, —CONHCH3, —CH2CONHCH3, —CON(CH3)2, and —CH2CON(CH3)2; —(CR1023R102b)aN(R101) C(O)R101; for example, —NHCOCH3, —CH2NHCOCH3, —NHCOCH2CH3, and COCH2CH3; xi) —(CR102aR102b),N(R101) C(O)2R101; for example, —NHCOZCH3, —CH2NHC02CH3, —NHCOzCH2CH3, and —CH2NHCOzCH2CH3; xii) —(CR1023R102b)aN(R101)2; for example, —NH2, —CH2NH2, , —CH2NHCH3, —N(CH3)2, and CH3)2; xiii) halogen; —F, —Cl, —Br, and —I; xiv) _(CR102aR102b)aCN; xv) 2aR102b)aNOZ; xvi) —(CHj,Xk,)aCHJ-Xk; wherein X is halogen, the index j is an integer from 0 to 2,j + k = 3; the indexj’ is an integer from 0 to 2, j’ + k’ = 2; for example, — CHZF, —CHF2, —CF3, —CCl3, or —CBr3; xvii) —(CR102aR102b),SR101, —SH, —CHZSH, —SCH3, —CHZSCH3, , and —CHZSC6H5; xviii) —(CR102aR102b)aSOZR101; for example, —SOzH, —CstOzH, —SOzCH3, —CHZSOZCH3, —SOZC6H5, and —CHZSOZC6H5; and xix) —(CR1023R102b)aSO3R101; for example, —so3H, —CHZSO3H, —SO3CH3, 3CH3, —SO3C6H5, and —CHZSO3C6H5; or xx) two substitutions for hydrogen can be taken together to form a substituted or unsubstituted C2—C8 heterocyclic ring, n the ring substitution can be one or more of the substitutions defined in (i) to (xix) herein above and the ring can comprise one or more heteroatoms chosen from oxygen (0) sulfur (S), or nitrogen (N); wherein each R101 is independently hydrogen, substituted or tituted C1—C6 linear, C3— C6 branched, or C3—C6 cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R101 units can be taken together to form a ring comprising 3-7 atoms; R102a and R10% are each independently hydrogen or C1-C4 linear or C3-C4 branched alkyl; the index “a” is from 0 to 4.

Stated in another way, the disclosed process relates to the formation of compounds haVing the formula: / R OH 0 wherein the A ring represents R1 units wherein R1 can be: i) substituted or unsubstituted C6 or C10 aryl; and ii) substituted or unsubstituted C1—C9 heteroaryl; wherein the substitutes for en atoms on the A ring are one or more R10 units that are independently chosen and further described herein.

One aspect of R1 relates to substituted or tituted C6 aryl, i.e., substituted or tituted phenyl. A first embodiment of this aspect relates to R1 equal to phenyl, for example, compounds having the formula: A further aspect of R1 relates to R1 units that are substituted phenyl having the formula: R10 | \ \N / R OH 0 n R10 represents from 1 to 5 independently chosen substitutions for hydrogen; or two R10 units can be taken together to form a tuted or unsubstituted C4—C8 cycloalkyl ring, a substituted or unsubstituted C6 aryl ring (phenyl), a substituted or unsubstituted C2—C8 heterocyclic ring, or a substituted or unsubstituted C3 to C5 heteroaryl ring, wherein the heterocyclic and heteroaryl rings comprise one or more hetero atoms independently chosen from oxygen (0), nitrogen (N), or sulfur (S).

One embodiment of this aspect of R1 units relates to compounds comprising substitutions on R1 of one or more units independently chosen from: i) C1-C12 linear, C3-C12 branched or C3-C12 cyclic alkyl; ii) C1-C12 , C3-C12 ed or C3-C12 cyclic alkoxy; and iii) halogen: —F, —Cl, —Br, and —1.

One iteration of this embodiment relates to compounds comprising one or more R10 units that are halogen, thereby forming the following non-limiting examples of R1 units: 2- fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5— difluorophenyl, 2-chlorophenyl, rophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4- dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3,5-dichlorophenyl, 2,3,4-trifluorophenyl, trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, trifluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4- dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5- trichlorophenyl, 3,4,5-trichlorophenyl, and 2,4,6-trichlorophenyl.

WO 70377 A further iteration relates to compounds comprising one or more R10 units that are C1—C4 linear, C3—C4 branched or C3-C4 cyclic alkyl, thereby forming the following non- limiting examples of R1 units: 2—methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3- dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4- dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5- trimethylphenyl, 2,4,6-trimethylphenyl, 2—ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,3- diethylphenyl, ethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, triethylphenyl, triethylphenyl, 2,3,6-triethylphenyl, triethylphenyl, 2,4,6- triethylphenyl, 2—isopropylphenyl, 3-isopropylphenyl, and 4-isopropylphenyl. r iteration relates to compounds comprising one or more R10 units that are C1—C4 linear, C3—C4 branched or C3-C4 cyclic alkoxy, thereby forming the following non- limiting examples of R1 units: 2—methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3- dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4- oxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6- trimethoxyphenyl, 2,4,5-trimethoxyphenyl, trimethoxyphenyl, 2—ethoxyphenyl, 3- ethoxyphenyl, 4-ethoxyphenyl, 2,3-diethoxyphenyl, 2,4-diethoxyphenyl, 2,5- diethoxyphenyl, 2,6-diethoxyphenyl, 3,4-diethoxyphenyl, 2,3,4-triethoxyphenyl, 2,3,5- triethoxyphenyl, triethoxyphenyl, 2,4,5-triethoxyphenyl, 2,4,6-triethoxyphenyl, 2- isopropoxyphenyl, 3-isopropoxyphenyl, and 4-isopropoxyphenyl.

A yet still further iteration relates to compounds comprising one or more R10 units that comprise at least one of each substitution chosen from C1-C4 linear or halogen, thereby forming the following non-limiting examples of R1 units: 2—chloromethylphenyl, 2- chloromethylphenyl, 2-chloromethylphenyl, romethylphenyl, 3-chloro methylphenyl, 3-chloromethylphenyl, 3-chloromethylphenyl, 3-chloromethyl- phenyl, 2-fluoro-3 -methylphenyl, 2—fluoromethylphenyl, romethylphenyl, 2- fluoromethylphenyl, 3-fluoro-2—methylphenyl, 3-fluoromethylphenyl, o methylphenyl, and 3-fluoromethylphenyl.

One embodiment of this aspect of R1 units relates to compounds comprising one or more R10 units independently chosen from: i) 2aR102b)aCN; ii) —(CR102aR102b)aNOZ;and iii) —(CHj,Xk,)aCHJ-Xk; wherein X is halogen, the index j is an integer from 0 to 2,j + k = 3; the indexj’ is an integer from 0 to 2,j’ + k’ = 2.

On ion of this embodiment relates to compounds comprising one or more R10 units that are —(CH2)aCN, wherein the index a is 0 or 1, thereby forming the following non- limiting es of R1 units: 2—cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2- (cyanomethyl)phenyl, 3-(cyanomethyl)phenyl, 4-(cyanomethyl)phenyl, 2,3-dicyanophenyl, 3,4-dicyanophenyl, and 3,5-dicyanophenyl.

Another iteration of this embodiment relates to compounds comprising one or more R10 units that are —(CH2)aN02, n the index a is 0 or 1, thereby forming the following non-limiting examples of R1 units: 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2- (nitromethyl)phenyl, 3-(nitromethyl)phenyl, 4-(nitromethyl)phenyl, 2,3-dinitrophenyl, 3,4- dinitrophenyl, and 3,5-dinitrophenyl.

A further iteration of this embodiment relates to compounds comprising one or more R10 units that are —CHJ-Xk; wherein X is halogen, the index j is an integer from 0 to 2, j + k = 3, n the index a is 0 or 1, y forming the following miting examples of R1 units: —CH2F, —CH2CH2F, —CHF2, —CH2CHF2, —CF3, —CH2CF3, —CHFCH2F, —CF2CHF2, —CF2CF3, —CH2Cl, —CH2CH2Cl, —CHClz, —CH2CHClz, —CCl3, —CH2CCl3, —CHClCH2Cl, —CClzCHClz, and —CClzCCl3.

One embodiment of this aspect of R1 units relates to compounds comprising one or more R10 units independently chosen from: i) —(CR102aR102b)aN(R101)2; ii) —(CR1ozaRlozb)aC(O)N(R101)2; and iii) —(CR1ozaRl02b)aN(R101)C(O)2R101.

One iteration of this embodiment relates to compounds comprising one or more R10 units that are —(CR102aR102b)aN(R101)2, wherein the index a is 0 or 1, thereby forming the following miting examples of R1 units: 2—aminophenyl, ophenyl, 4- aminophenyl, 2,3-diaminophenyl, 3,4-diaminophenyl, aminophenyl, 2- methylaminophenyl, 3-methylaminophenyl, 4-methylaminophenyl, 2,3- (dimethylamino)phenyl, 3,4-(dimethylamino)phenyl, 3,5-(dimethylamino)phenyl, 2,3,4- triaminophenyl, 2,3,5-triaminophenyl, 2,3,6-triaminophenyl, 2,4,5-triaminophenyl, 2,4,6- triaminophenyl, 2,4-(dimethylamino)phenyl, 2,5-(dimethylamino)phenyl, 2,6- (dimethylamino)phenyl, 3,4-(dimethylamino)phenyl, 2,3,4-(dimethylamino)phenyl, 2,3,5- (dimethylamino)phenyl, 2,3,6-(dimethylamino)phenyl, 2,4,5-(dimethylamino)phenyl, 3,4,5- (dimethylamino)phenyl, and 2,4,6-(dimethylamino)phenyl.

Another iteration of this embodiment relates to compounds comprising one or more R10 units that are —(CR1ozaRlozb)aC(O)N(R101)2, wherein R101 is chosen from hydrogen, C1— C6 linear, C3-C6 ed alkyl or C3-C6 cyclic alkyl, and the index a is 0 or 1, thereby forming the following non-limiting examples of R1 units: —C(O)NH2, —C(O)NHCH3, —CH2C(O)NHCH3, —C(O)N(CH3)2, —CH2C(O)N(CH3)2, —C(O)NHCH2CH3, —CH2C(O)NHCH2CH3, —C(O)N(CH2CH3)2, O)N(CH2CH3)2, —C(O)NHCH(CH3)2, —CH2C(O)NHCH(CH3)2, —C(O)N[CH(CH3)2]2, and —CH2C(O)N[CH(CH3)2]2.

Another iteration of this embodiment relates to compounds comprising one or more R10 units that are —(CR1ozaRlozb)aC(O)N(R101)2, n two R101 units are taken together to form a ring haVing from 3 to 7 atoms and the index a is 0 or 1, thereby forming R1 units haVing, for example, the formulae: 51., A further iteration of this embodiment relates to compounds comprising one or more R10 units that are —(CR1ozaRl02b)aN(R101)C(O)2R101; n R101 is chosen from hydrogen, C1-C6 linear, C3-C6 branched alkyl or C3-C6 cyclic alkyl, and the index a is 0 or 1, y forming the ing non-limiting examples of R1 units: —NHC(O)CH3, —CH2NHC(O)CH3, —NHC(O)CH2CH3, —CH2NHC(O)CH2CH3, —NHC(O)CH2CH2CH3, —CH2NHC(O)CH2CH2CH3, —NHC(O)(cyclopropyl), and —CH2NHC(O)(cyclopropyl).

Another aspect of R1 relates to R1 units that are substituted or unsubstituted C1—C9 heteroaryl. One embodiment of this aspect relates to R1 equal to C1-C9 heteroaryl, for example, compounds having the a: / R OH O wherein ring A ent a C1-C9 heteroaryl unit non-limiting examples of which include: l,2,3,4—tetrazolyl (C1), [1,2,3]triazolyl (C2), ]triazolyl (C2), [1,2,4]oxadiazolyl (C2), ]oxadiazolyl (C2), [1,2,4]thiadiazolyl (C2), [l,3,4]thiadiazolyl (C2), isothiazolyl (C3), thiazolyl (C3), imidazolyl (C3), oxazolyl (C3), isoxazolyl (C3), lyl (C3), pyrrolyl (C4), furanyl (C4), thiophenyl (C4), triazinyl (C3), pyrimidinyl (C4), pyrazinyl (C4), pyridazinyl (C4), pyridinyl (C5), purinyl (C5), xanthinyl (C5), hypoxanthinyl (C5), benzimidazolyl (C7), indolyl (Cg), quinazolinyl (Cg), quinolinyl (C9), and isoquinolinyl (C9).

In a r embodiment of this aspect the C1—C9 heteroaryl unit can be bonded to the core pyridine ring at any suitable position, non-limiting examples of which include: N§ \ _ $193 _§_<\N,E, -3 / IfH §\N /§N _§_<§‘N —3 \ 7 +13%; \NJ; iii) —Hi 3“?»)1] NH iV) Mléfl,NH We ifli iv“\ 0\ vii) N\ 0\ —H\N])_ -§—<\Nj“ viii) -§—<\ l N ; M1£0 _§_<j _§@; H? -%i, ‘HJ xii) HZ]. if; —34©i xiii) -§—<\:1%—<\:\j“. xiv) -3—<\:l_ _§—<\Nj£>E <\Njk/:L,.s{; E E “if E a ~ <\Nj£> <\Njij/ m xvi) «do <1;N N <1:N N N “UL S ; S (SE; S ; S ; <0S xvii) Er: <1; myN N N N <0N ”BL 0 ; O .52; O ; O ; O xviii) woodedE E E E goE m xiv) E «NI/IN\ 9'2 All?! N\ E N\ E N\ ; <11ng _§_<\NL1; <\N I /1 «NU ; <30 EENJQN; GQN “Y” ;and xvi) E J1“?! E E «NUN\t1'7. N\ N\ N\ ; <E31); _3—<\ND ; <\N:£2 Another embodiment of this aspect relates to R1 units equal to substituted C1—C9 heteroaryl, for e, compounds having the formula: / R 01-10 wherein ring A represent a C1-C9 heteroaryl unit non—limiting examples of which include: 4-tetrazolyl (C1), [1,2,3]triazolyl (C2), [1,2,4]triazolyl (C2), [1,2,4]oxadiazolyl (C2), [1,3,4]oxadiazolyl (C2), ]thiadiazolyl (C2), [1,3,4]thiadiazolyl (C2), isothiazolyl (C3), thiazolyl (C3), imidazolyl (C3), oxazolyl (C3), isoxazolyl (C3), pyrazolyl (C3), pyrrolyl (C4), furanyl (C4), thiophenyl (C4), triazinyl (C3), pyrimidinyl (C4), pyrazinyl (C4), pyridazinyl (C4), pyridinyl (C5), purinyl (C5), xanthinyl (C5), nthinyl (C5), benzimidazolyl (C7), indolyl (Cg), quinazolinyl (Cg), inyl (C9), and isoquinolinyl (C9).

Non-limiting es of tutions for a hydrogen atom on R1 C1-C9 heteroaryl units include: i) C1—C12 linear, C3—C12 branched, or C3-C12 cyclic alkyl, alkenyl, and alkynyl; methyl (C1), ethyl (C2), ethenyl (C2), ethynyl (C2), n—propyl (C3), iso—propyl (C3), cyclopropyl (C3), 3—propenyl (C3), l—propenyl (also ylethenyl) (C3), isopropenyl (also 2—methylethen—2—yl) (C3), prop—2—ynyl (also propargyl) (C3), propyn-l-yl (C3), n—butyl (C4), sec—butyl (C4), iso—butyl (C4), tert—butyl (C4), cyclobutyl (C4), 4—yl (C4), cyclopentyl (C5), cyclohexyl (C6); ii) C6 or C10 aryl; for example, phenyl, naphthyl (also referred to herein as naphthylen- l -yl (C10) or naphthylenyl (C10)); iii) C7 or C11 alkylenearyl; for example, benzyl, 2—phenylethyl, naphthylen-2— ylmethyl; iV) C1—C9 heterocyclic rings; as described herein below; C1-C9 heteroaryl rings; as described herein below; Vi) 23R102b)aOR101; for example, —OH, —CHZOH, —OCH3, H3, —OCH2CH3, —CH20CH2CH3, —OCH2CH2CH3, and —CH20CH2CH2CH3; Vii) —(CR102aR102b)aC(O)R101; for example, —COCH3, —CH2COCH3, —COCH2CH3, —CH2COCH2CH3, —COCH2CH2CH3, and —CH2COCH2CH2CH3; viii) —(CR1023R102b)aC(O)OR101; for example, —C02CH3, —CH2COZCH3, —COzCH2CH3, —CH2COzCH2CH3, 2CH2CH3, and —CH2C02CH2CH2CH3; ix) —(CR1ozaRlozb)aC(O)N(R101)2; for example, —CONH2, —CH2CONH2, —CONHCH3, —CH2CONHCH3, —CON(CH3)2, and —CH2CON(CH3)2; WO 70377 x) —(CR102aR102b)aN(R101) C(0)R101, for example, —NHCOCH3, —CH2NHCOCH3, —NHCOCH2CH3, and —CH2NHCOCH2CH3; xi) —(CR1023R102b)aN(R101) C(O)2R101; for example, —NHCOZCH3, COZCH3, CH2CH3, and —CH2NHCOZCH2CH3; xii) —(CR102aR102b)aN(R101)2, for example, —NH2, —CH2NH2, —NHCH3, —CH2NHCH3, —N(CH3)2, and —CH2N(CH3)2; xiii) halogen; —F, —Cl, —Br, and —I; xiv) _(CR102aR102b)aCN; xv) _(CR102aR102b)aNOZ; xvi) —(CHjana)aCHJ-Xk; wherein X is halogen, the index j is an integer from 0 to 2,j + k = 3; the indexj’ is an integer from 0 to 2, j’ + k’ = 2; for example, — CHZF, —CHF2, —CF3, —CCl3, or —CBr3; xvii) 2aR102b),SR101, —SH, —CHZSH, —SCH3, —CHZSCH3, —SC6H5, and —CH2$C6H5; xviii) —(CR102aR102b)aSOZR101; for example, —SOzH, —CHZSOZH, —SOZCH3, —CHZSOZCH3, —SOzC6H5, and —CHZSOZC6H5; and xix) —(CR1023R102b)aSO3R101; for example, —so3H, —CHZSO3H, 3, —CH2803CH3, —SO3C6H5, and —CHZSO3C6H5; wherein each R101 is independently hydrogen, substituted or unsubstituted C1—C6 linear, C3— C6 branched, or C3—C6 cyclic alkyl, , benzyl, heterocyclic, or heteroaryl; or two R101 units can be taken together to form a ring comprising 3-7 atoms; R102a and R10% are each independently hydrogen or C1-C4 linear or C3-C4 branched alkyl; the index “a” is from 0 to Non-limiting examples of substituted C5-C9 R1 heteroaryl units include 2— thiazolyl, lthiazolyl, 2—(n-propyl)thiazolyl, 2—(is0-propyl)thiazolyl, 4,5-dimethylthiazolyl, 4-ethylmethylthiazolyl, 4-methylethylthiazol-2—yl, 4,5- diethylthiazolyl, 3-methyl-l,2,4-oxadiazolyl, 4,5-dimethylimidazol-2—yl, 4-ethyl methylimidazol-2—yl, 4-methylethylimidazolyl, 4,5-diethylimidazolyl, 2,5- dimethylthiazolyl, 2,4-dimethylthiazolyl, 3-methyl-1,2,4-oxadiazolyl, 4,5- dimethyloxazol-2—yl, 4-ethylmethyloxazol-2—yl, ylethyloxazol-2—yl, 4,5- loxazolyl, 2-methyloxazolyl, 2-ethyloxazolyl, 2—(n-propyl)oxazolyl, 2- (iso-propyl)oxazolyl, 2-methyloxazolyl, 2—ethyloxazolyl, 2-(n-propyl)oxazolyl, 2-(is0-propyl)oxazolyl, 5-methyl[l,2,4]oxadiazolyl, 5-ethyl[l,2,4]—oxadiazolyl, 5- propy1[1,2,4]0xadiazol-3 -y1, 5-cyclopr0py1[1,2,4]0xadiazoly1, y1[1,2,4]0xadiazol- -y1, 3-ethy1[1,2,4]0xadiazoly1, r0py1)[1,2,4]0xadiazoly1, 3-(is0— propy1)[1,2,4]0xadiazoly1, 2,5-dimethy1thiazoly1, 2,4-dimethy1thiazoly1, 4- ethylthiazol-Z-yl, 3-methy1—1,2,4-0xadiazoly1, 4,5-dimethy1pyrimidin-2—y1, 4,5- diethylpyrimidin-Z-yl, 4-methy1—5-ethy1—pyrimidin-2—y1, 4-ethy1—5-methy1—pyrimidiny1, 4- (thiopheny1)pyrimidin-2—y1, 5-(thi0pheny1)pyrimidin-2—y1, 4-(thi0phen y1)pyrimidiny1, and 5-(thi0pheny1)pyrimidin-3 -y1.

Non—limiting examples of substituted C2—C4 5—member heteroaryl rings include: .g 0\ MN H C 3 MN CH3 7 x“; \ N 5‘“ “'1" CH3, iii) DN\N CH3; iv) 55" OCH 3" WAN—g WAN—g0C H / 3 / 2 5 N§N O N§N O 551%” 0cm g:bII c2115 N§N O N§N O 7 ; J‘m J‘w \ O 5 O N“ /N\)J\ N‘3 ,N N OCH3 N OC2H5 Vii) viii) “741.

Ucm MDN 7 ' A yet further aspect of R1 units relates to rings comprising two R10 substitutions for hydrogen that are taken together to form a substituted or unsubstituted C2—C8 heterocyclic ring. One embodiment of this aspect relates to R1 units wherein two R10 units are taken together to form a tuted or unsubstituted C7—C9 heterocyclic R1 ring system wherein the heterocyclic ring formed by the two R10 substitutions contains one or more nitrogen atoms. Non-limiting iterations of this ment include R1 units haVing the formulae: CO co CO\ J‘IA g flandHNcoft. 7 , Another embodiment of this aspect relates to R1 units wherein two R10 units are taken together to form a substituted or unsubstituted C7—C9 heterocyclic R1 ring system wherein the heterocyclic ring formed by the two R10 substitutions contains one or more oxygen atoms. miting iterations of this embodiment include R1 units haVing the formulae: <ZI>ng<O [O “i" [:Dys: m and I R2 Units R2 units are chosen from C1-C12 linear alkyl or C3-C12 branched alkyl. In one embodiment R2 can represent hydrogen. In another embodiment, R2 is C1-C4 linear alkyl. miting examples include methyl, ethyl and n-propyl. In one example, R2 is .

R2 units relate to the de unit haVing the formula: 9 OR2 that is used in the process disclosed herein. As it relates to the alkoxide, the alkoxide can be derived from any suitable , i.e., sodium methoxide, lithium ethoxide, and the like which the formulator can choose.

A further aspect of the present disclosure relates to a process for preparing intermediates having the formula: / OH OH 0 wherein Rlis the same as defined herein above. This aspect also includes salts of acids, for example, compounds having the formula: wherein M is a salt forming cation and N represents the cationic charge on M and the number of corresponding anionic units of the disclosed intermediates. The M units can comprise in one embodiment inorganic cations, inter alia, ammonium, sodium, lithium, potassium, calcium, magnesium, bismuth, and the like. In another embodiment, M units can comprise organic cation forming units, inter alia, lysine, ine, glycine, alanine, or other amino acids, basic c compounds, inter alia, methylamine, dimethylamine, trimethylamine, and the like.

Another aspect of the present sure relates to a process for preparing intermediates having the formula: wherein W is a salt g anion and Y represents the anionic charge on W and the number of corresponding number of the disclosed intermediates in this salt form. The W units can comprise in one embodiment inorganic anions, inter alia, chloride, bromide, iodide, e, bisulfate, ate, bicarbonate, phosphate, and the like. In another embodiment, W units can comprise organic anion forming units, inter alia, e, acetate, propionate, butyrate, pyruvate, lactate, e, malonate, maleate, succinate, tartrate, fumarate, citrate, and the like.

In one , the disclosed prolyl hydroxylasc inhibitors can be isolated as a pharmaceutically acceptable salt having the formula: \N o N I H . A M‘N / I\ ‘L 09 OH 0 wherein M is a salt forming cation and N represents the cationic charge on M and the number of ponding anionic units present in the salt.

In a particular embodiment, the present invention provides a compound having the formula: \N o N H A M+N / N ‘L 06 0H 0 wherein M is a salt forming cation and N represents the cationic charge on M; A is C10 aryl; Rlo units represent at least one optionally present substitutions for a ring hydrogen atom; or two Rlo units can be taken together to form a substituted or unsubstituted C4— Cs cycloalkyl ring, a tuted or unsubstituted C6 or C10 aryl ring, a substituted or unsubstituted C2-C8 heterocyclic ring, or a substituted or unsubstituted C3 to C5 heteroaryl ring, n the heterocyclic and heteroaryl rings comprise one or more hetero atoms independently chosen from oxygen (0), nitrogen (N), or sulfur (S).

L is a linking unit having the formula: —(CR7’R7")n— R7a and R7” are each independently: i) hydrogen; or (followed by 30A) ii) C1-C6 linear, C3-C6 ed or C3-C6 cyclic alkyl; and the index n is an integer from 1 to 4. 30A (followed by 31) One iteration of this embodiment relates to cations wherein each of Ra, Rb and R0 are hydrogen or C1-C12 linear alkyl. Non-limiting examples include methyl ammonium (CH3)], dimethyl ammonium [HN+H(CH3)2], trimethyl ammonium H3)3], ethyl ammonium [HN+H2(CH2CH3)], diethyl ammonium [HN+H(CH2CH3)2], triethyl ammonium [HN+(CH2CH3)3], dimethylethyl ammonium H3)2(CH2CH3)], and methyldiethyl ammonium H3)(CH2CH3)2].

Another iteration of this embodiment relates to cations wherein one or more of Ra, Rb and Rc are chosen from hydrogen, unsubstituted C1—C12 linear, C3—C12 branched, or C3— C12 cyclic alkyl or substituted C1—C12 linear, C3—C12 branched, or C3—C12 cyclic alkyl. One embodiment relates to organic s haVing one or more C1-C12 linear, C3-C12 branched, or C3—C12 cyclic alkyl chains substituted with hydroxy. Non-limiting examples include 2- hydroxyethyl ammonium (cation of monoethanolamine, cholinate) [HN+H2(CH2CHZOH)], methyl-2—hydroxyethyl um [H2N+(CH3)(CH2CHZOH)], di(2-hydroxyethyl) ammonium [H2N+(CH2CHZOH)2], tri(2—hydroxyethyl) ammonium [HN+(CH2CHZOH)3], and tris(hydroxymethyl)methyl ammonium (cation of tris(hydroxymethyl)aminomethane) [H3N+C[(CHZOH)]3]. Also included are cations formed from amino sugars, for example, amino sugars haVing the formula H2N+(CH3)[(CHOH)HCHZOH] wherein n is from 1 to 7. A non-limiting example of an amino sugar suitable for g an organic cation is meglumine (l-deoxy- l lamino-sorbitol).

A further iteration of this embodiment relates to cations formed from amino acids.

Non-limiting examples include lysine, omithine, arginine, glutamine, and the like.

Another aspect of organic amines suitable for forming salts of the sed stabilizer include amines n one or more of Ra, Rb and R0 are taken together to form a heterocyclic ring that can comprise from 3 to 20 atoms and optionally one or more atoms chosen from nitrogen, oxygen and sulfur. Non-limiting examples e piperazine, piperidine, line, thiomorpholine, and the like.

In addition, di-Valent cations can be used wherein the salts of these examples have the formula: \N o 121 A 9 OH O 2 Non-limiting examples of di-valent cations includes calcium magnesium, barium and the like.

Another example of salts includes the di-anions having the formula: O \ N 0 e l 09 2M / \L/u\09 O O and 9 2 wherein M is the same as defined herein above.

The ance of the herein disclosed ediates lies in the fact that the formulator can prepare an admixture comprising a plurality of final compounds in one step by the choice of reactants in the final process step as described herein. For example, it is known by the artisan that, although two or more analogs can have approximately equal pharmacological ty, other properties such as bioavailability can be different. Using the disclosed ediates to form admixtures of final analogs can provide the formulator with a final composition which es the disparate pharmacological activities of the les to e for a nt level of a desired property. For example, one analog in the admixture can have immediate bioavailability while a second or third compound has a slower bioavailability which can provide a pharmacologically active composition that has a steady or near steady level of drug active in a user.

PROCESS Disclosed herein is a process for preparing the herein above disclosed [(5—phenyl—3— hydroxypyridinecarbonyl)-amino]alkanoic acids and [(5-heteroarylhydroxypyridine- 2-carbonyl)-amino]alkanoic acids. As disclosed herein, the 5-phenyl and 5-heteroaryl rings can be substituted by one or more independently chosen substitutions for hydrogen.

The following is a summary of the steps that comprise the disclosed process.

Step A Z R10 Y \ R10 B/ \ + —> \Y / CN I Al A2 A3 Step A relates to the condensation of an aryl or heteroaryl borate precursor, Al, and a 3,5-dihalocyanopyridine, A2, n each Z is independently chloro or bromo, to form a 5-aryl or 5-heteroarylhalocyanopyridine, A3.

The borate precursor, Al, comprises ring A wherein ring A can be: A) substituted or unsubstituted C6 or C10 aryl; and ii) substituted or tituted C1—C9 heteroaryl; wherein the substitutes for hydrogen atoms on the A ring are one or more R10 units that are independently chosen and further described herein. Y is ORZO, wherein R20 is hydrogen or C1—C6 linear, C3—C6 branched, or C3-C6 cyclic alkyl, or two OR20 units can be taken together to form a 5—member to 7—member C3-C10 cyclic ester, for e, a cyclic ester having the formula: C10 (on 1‘3’0 0 1'3’0 or .

One aspect of borate precursors relates to phenyl boronic acid having the formula: 0B/OH Another aspect of borate precursors relates to tuted boronic acids having the formula: R10 | \ 1'3/0H wherein R10 represents from 1 to 5 substitutions as d herein above. Non-limiting examples of this aspect includes borate precursors having the formula: /©\ 0 OH E0 OH c1 13’ 0 1'3’ (IDH and 0H The 3,5-dihalocyanopyridine, A2, is chosen from 3,5-dichlorocyanopyridine, 3—chloro—5—bromo—2—cyanopyridine, 3,5—dibromo—2—cyanopyridine and 3—bromo—5—chloro—2— cyanopyridine.

Step A is conducted in the presence of a catalyst, for example, a Suzuki coupling catalyst. The formulator can choose the catalyst and conditions that are compatible with the reagents, i.e., borate precursor and 3,5—dihalo—2—cyanopyridine. (See, Suzuki, A. Pure Appl.

Chem.1991, 63, 419—422; Suzuki, A., J. Organometallic Chem. 1999, 576, 147—168; Barder, T. E. et al., “Catalysts for Suzuki—Miyaura Coupling Processes: Scope and Studies of the Effect of Ligand Structure,” J. Am. Chem. Soc. 2005, 127, 4685—4696 included herein by reference in their entirety.) In one embodiment, the catalyst is [1,1’-bis(diphenyphosphino)ferrocene]dichloro— ium(II) [PdClz(dppf)].

Another ry of catalysts include metalated catalysts with alkylphosphine ligands of the general formula [Pd(X)(K2N,C—C6H4CH2NMe2)(PR3)] wherein R is Cy, X is trifluoroacetate, trifluoromethanesufonyl, chloro, or iodo; PR3 is PCy2(0-biphenyl), X is trifluoroacetate). Non-limiting examples of this category include [{Pd(u-TFA)(K2N,C- 2NMe2)}2] and [{Pd(TFA)(K2N,C—C6H4CH=NiPr)}2].

The catalyst can be preformed, for example, purchased from a al supplier or the catalyst can be generated in situ. One non-limiting example of Step A n the catalyst is generated in situ includes the following ure. Pd(OAc)2 (1.5 mmol %), 3 ,3 ’-dimethyl- l l ’(2,4-bismethylenemesitylene)(4,4,5,6-tetrahydropyrimidinium) chloride (1.5 mmol %), a borate precursor (1.5 mmol), a 3,5-dihalocyanopyridine (1.0 mmol), K2C03 (2 mmol), water (3 mL)-DMF (3 mL) are added to a small Schlenk tube and the mixture heated at 80 0C for 5 hours. At the conclusion of the reaction, the mixture is collected, removed by extraction with suitable solvent, and the desired product isolated by methods known to the artisan.

Step A is conducted in the presence of a base. Non—limiting examples of suitable bases that can be used in Step A includes LiOH, NaOH, KOH, Ca(OH)2, LizCO3, NazCO3, K2CO3, and CaCO3. In one embodiment, the base is K2C03. In another embodiment, the base is NazCO3.

Step A can be optionally ted in the presence of a solvent. miting examples of solvents include water, formic acid, acetic acid; alcohols, for example, methanol, ethanol, trichlorethanol, propanol, isopropanol, butanol, tert—butanol, and the like; ketones, for example, acetone, methyl ethyl ketone, diethyl ketone, and the like; esters, for example, methyl acetate, ethyl acetate, methyl propionate, ethyl propionate, and the like; ethers, for e, l ether, methyl utyl ether, tetrahydrofuran, dimethoxyethane, bis(2—methoxyethyl) ether (diglyme), l,4-dioxane,and the like; alkanes, for example, e, isopentane, petroleum ether, hexane, mixtures of hexanes, cyclohexane, 35eptanes, isoheptane, octane, isooctane, and the like; halogenated solvents, for example, dichloromethane, chloroform, carbon hloride, l,l-dichloroethane, l,l,l- trichloroethane, l,2-dichloroethane, chlorobenzene, and the like; aromatic hydrocarbons, for example, e, toluene, l,2—dimethylbenzene (ortho-xylene), l,3-dimethylbenzene (meta—xylene), l,4—dimetylbenzene (para-xylene), nitrobenzene, and the like; r aprotic solvents, for example, acetonitrile, dimethylsulfoxide, N,N—dimethylformamide, N,N—diethylformamide, N,N—dimethylacetamide, N,N—diethylacetamide, N—methyl-2— pyrrolidinone, carbon disulfide, and hexamethylphosphoramide; and mixtures of one or more solvents.

The reaction can be conducted at any ature sufficient to provide the desired products or desired products.

Step B A3 B Step B relates to the conversion of a 5-aryl or 5-heteroarylhalocyanopyridine, A3, to a 5-aryl or 5-heteroarylalkoxycyanopyridine, B.

Compound A3 is d with an alkoxide having the formula: 9 OR2 wherein R2 is C1-C12 linear alkyl or C3-C12 branched alkyl. In one embodiment of step B, intermediate A3 can be reacted with ide anion. The ide anion can be generated in situ, for example, by the addition of an alkali metal to methanol. In one example, from 1 lent to 10 equivalents of sodium metal based upon the amount of A3 to be converted in Step B, is added to an excess of methanol. In another example, an alkali metal is added to an excess of methanol, the t removed, and the resulting sodium methoxide retained for use when, for example, Step B is conducted in a solvent other than methanol.

In another embodiment, the intermediate A3 can be reacted with ethoxide anion generated from ethanol. In still r embodiment, the ediate A3 can be reacted with isopropoxy anion generated from isopropanol.

As such, step B can be conducted at any temperature sufficient to provide the desired ts or desired products. In on, step B can be conducted in any solvent or mixtures of solvents that do not react with methoxide anion under the conditions chosen by the formulator.

Step C R10 R10 \N \N / / OH 0R2 OH 0 B C Step C relates to the conversion of the 5—aryl or 5—heteroaryl—3—alkoxy—2— cyanopyridine formed in step B to form a 5-aryl or 5-heteroarylhydroxy carboxypyridine, C, (5-aryl or 5-heteroaryl-3 -hydroxypicolinic acid). This conversion can be conducted in the presence of any acid capable of hydrolysis of the cyano moiety to a carboxylic acid moiety and the methoxy moiety to a hydroxyl moiety. In one embodiment, 48% aqueous HBr can be used. In another embodiment, 37% aqueous HCl can be used.

The compounds having formula C can be isolated as the free acid or as a salt, for e, as a compound having the formula: as further described herein. Depending upon the intended use of the products of step C, the formulator can proceed to step D or retain the ts of step C for use in preparing admixtures of prolyl hydroxylase inhibitors or for preparing prodrugs of prolyl hydroxylase inhibitors.

Step D / on R10 \N O OH 0 118 + N\(CR7aR7b))J\Xn OH 0 1'18 0 H’N\(CR7aR7b)n/u\x D1 D2 Step D relates to the reaction of the 5-aryl or 5-heteroaryl-3 -hydroxy ypyridine formed in step C with a compound having formula D1, wherein X is chosen from —OH, —OR3, —NR4R5 or —OM1 as defined herein above, to form one of the following: i) a prolyl hydroxylase inhibitor; ii) a prolyl hydroxylase inhibitor prodrug; iii) an admixture of prolyl hydroxylase inhibitors; iv) an admixture of prolyl hydroxylase inhibitor prodrugs; or V) le pharmaceutical salts thereof.

One aspect of step D relates to ion of a prolyl hydroxylase inhibitor according to the ing scheme: / OH \ 8 OH O N I If + / CO H \(CR7aR7b)n/ 2 If8 on o /N CO H H \(CR7aR7b)n/ 2 l5 D wherein R73, R7b, R8 and the index n are defined herein above.

Another aspect of step D relate to formation of a prolyl hydroxylase ester prodrug according to the following scheme: 2012/040833 / OH \ 8 OH 0 N _> If + / N\(CR73R7b)/COZRn I OH 0 N COZR3 H’ \(CR7aR7b)n/ wherein R3, R7a, R7b, R8 and the index n are defined herein above.

A further aspect of step D relate to formation of a prolyl hydroxylase amide prodrug according to the following scheme: / OH OH O \N + / If CONR4R5 \(CR7aR7b)n/ N OH O CONR4R5 H’ \(CR7aR7b)n/ wherein R4, R5, R7a, R7b, R8 and the index n are defined herein above.

Step D relates to the coupling of a 5-aryl or roarylhydroxycarboxy- pyridine, C, prepared in Step C with an amino acid, amino acid ester, or amino acid amide.

Any coupling reagent compatible with the 5-aryl or 5-heteroarylhydroxycarboxy- pyridine, amino acid, amino acid ester, or amino acid amide can be used to prepare the desired prolyl hydroxylase inhibitors or prodrugs thereof. Non-limiting examples of coupling reagents includes carbonyldiimidazole (CD1), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and ethyl-(N’,N’-dimethylamino)propylcarbodiimide (EDC), (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), zotriazol-l-yl)-N,N,N’N’-tertaetyluronium hexafluorophosphate (HBTU), O- (benzotriazol-l-yl)-N,N,N’N’-tertamethyluronium tetrafluoroborate (TBTU), O-(7- azabenzotriazol- l -yl)-N,N,N’N’-tetramethyluronium uorophosphate (HATU), O—(6— chlorobenzotriazol-l-yl)-N,N,N’N’-tetramethyluronium hexafluorophosphate (HCTU), O- (3 ,4-dihydrooxo- l ,2,3 -benzotriazine-3 -yl)-N,N,N’N’ -tetramethyluronium uorophosphate ), and 3-(diethylphosphoryloxy)—l,2,3-benzotriazin-4(3H)- one (DEPBT). In one iteration, wherein R8 is not hydrogen, step D can be ted With a suitable reagent such as bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP).

A further iteration of the reaction outlined in step D es an in situ generated mixed anhydride of the 5-aryl or 5-heteroarylhydroxy-2—carboxypyridine, for e, reacting compound C with a mixed anhydride forming t. Non-limiting examples include isobutylchloro-formate (IBCF), ethylchoroformate, isopropylchloroformate, and the like. Other coupling reagents e 2-chloro-3,6-dimethoxy-1,3,5-triazine, pivalolyl chloride and triphosgene. In another iteration, acyl chlorides can be used to activate the carbonyl moiety of compound C for the coupling exemplified in step D.

In a yet further embodiment pivaloyl chloride in THF are used to catalyze the coupling reaction.

An organic or inorganic base can be used for conducting step D. Non-limiting examples of suitable organic bases include diisopropylethylamine, and the like.

Step D can be conducted in one or more solvents. Non—limiting examples of ts include dimethylformamide (DMF), diethylformamide (DEF), dimethylacetamide (DMA), diethylacetamide(DEA), dimethyl sulfoxide(DMSO), dioxane, and water. In one embodiment, a mixture of water and one or more polar c solvents can be used, for example, DMF/water, DMSO/water, dioxane/water, DMF/dioxane/water, and the like.

In some embodiments of the disclosed process, due to the type of substitution R10 on ring A, the formulator can form a prodrug prior then further process the prodrug to the final prolyl hydroxylase inhibitor. For example, the intermediate C may se an R10 unit that has a protecting group present, i.e., carbobenzyloxy, tert—butoxycarbonyl, and the like.

In such examples it can be more convenient for the formulator to form the final product in prodrug form, remove the protecting group then in a Step E, hydrolyze the g to the free acid. The hydrolysis can be conducted in any suitable acid or base.

The ions of Step D can be modified by the formulator to meet the ties of the reagents.

Scheme I herein below outlines and Example 1 describes a non-limiting example of the sed process for the preparation of a prolyl hydroxylase ester pro-drug. + —> \ / N B/OH CN I c1 CN Reagents and conditions: (a) K2C03, PdC12(dppf), DMF; 45 0C, 18 hr.

Reagents and ions: (b) NaOCH3, CH3OH; reflux, 20 hr. c] C1 / / OCH3 OH 0 2 3 Reagents and conditions: (c) 48% HBr; reflux, 20 hr. c1 c1 \N + “Qt —» \N I o OCH3 wkH / 0H / OCH3 OH 0 OH 0 3 4 Reagents and conditions: (d) CD1, DIPEA, DMSO; rt, 2.5 hr.

EXAMPLE 1 Methyl {[5-(3 -chlorophenyl)hydroxypyridinyl]amino}acetate (4) Preparation of 5-(3-chlorophenyl)-3 -chlorocyanopyridine (1): To a 100 mL round bottom flask adapted for ic stirring and equipped with a nitrogen inlet was charged (3 —chlorophenyl)boronic acid (5 g, 32 mmol), 3,5—dichloro—2—cyanopyridine (5.8 g, 34 mmol), K2C03 (5.5 g, 40 mmol), [1,1’—bis(diphenyphosphino)ferrocene]dichloro— palladium(II) [PdClz(dppf)] (0.1 g, 0.13 mmol), dimethylformamide (50 mL) and water (5mL). The reaction solution was agitated and heated to 45 0C and held at that temperature for 18 hours after which the reaction was determined to be complete due to the disappearance of 3,5—dichloro—2-cyanopyridine as measured by TLC analysis using ethyl acetate/methanol (4: 1) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction solution was then cooled to room temperature and the contents partitioned between ethyl acetate (250 mL) and saturated aqueous NaCl (100 mL). The organic phase was isolated and washed a second time with saturated aqueous NaCl (100 mL). The organic phase was dried for 4 hours over MgSO4, the MgSO4 removed by filtration and the solvent removed under reduced pressure. The residue that remained was then slurried in methanol (50 mL) at room temperature for 20 hours. The resulting solid was collected by ion and washed with cold methanol (50 mL) then s (60 mL) and dried to afford 5.8 g (73% yield) of an admixture containing a 96:4 ratio of the desired regioisomer. 1H NMR (DMSO—ds) 8 9.12 (d, 1H), 8.70 (d, 1H), 8.03 (t, 1H) 7.88 (m, 1H), and 7.58 (m, 2H).

Preparation of 5-(3-chlorophenyl)-3 -methoxycyanopyridine (2): To a 500 mL round bottom flask adapted for magnetic stirring and fitted with a reflux condenser and nitrogen inlet was charged with hlorophenyl)-3 -chlorocyanopyridine, 1, (10 g, 40 mmol), sodium methoxide (13.8 mL, 60 mmol) and methanol (200 mL). With stirring, the reaction on was heated to reflux for 20 hours. The reaction was ined to be complete due to the earance of 5—(3 -chlorophenyl)—3—chloro—2—cyanopyridine as measured by TLC analysis using hexane/ethyl e (6:3) as the mobile phase and UV 435 nm to visualize the reaction components. The on mixture was cooled to room temperature and combined with water (500 mL). A solid began to form. The mixture was cooled to 0 0C to 5 °C and stirred for 3 hours. The resulting solid was collected by filtration and washed with water, then hexane. The resulting cake was dried in vacuo at 40 °C to afford 9.4 g (96% yield) of the desired product as an off—white solid. 1H NMR (DMSO—d6) 8 8.68 (d, 1H), 8.05 (d, 1H), 8.01 (s, 1H) 7.86 (m, 1H), 7.59 (s, 1H), 7.57 (s, 1H) and 4.09 (s, 3H).

Preparation of 5-(3-chlorophenyl)hydroxypyridinecarboxylic acid (3): To a 50 mL round bottom flask adapted for magnetic stirring and fitted with a reflux condenser was charged 5-(3 -chlorophenyl)-3 -methoxycyanopyridine, 2, (1 g, 4 mmol) and a 48% aqueous solution of HBr (10 mL). While being stirred, the reaction solution was heated to reflux for 20 hours. The reaction was determined to be complete due to the disappearance of 5-(3-chlorophenyl)-3 -methoxycyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to Visualize the on components. The reaction contents was then cooled to 0 0C to 5 0C with stirring and the pH was adjusted to imately 2 by the slow addition of 50% aqueous NaOH. Stirring was then continued at 0 °C to 5 0C for 3 hours. The resulting solid was collected by filtration and washed with water, then . The resulting cake was dried in vacuo at 40 °C to afford 1.03 g (quantitative yield) of the desired product as an off-white solid. 1H NMR (DMSO—dg) 8 8.52 (d, 1H), 7.99 (d, 1H), 7.95 (s, 1H) 7.81 (t, 1H), 7.57 (s, 1H), and 7.55 (s, 1H).

Preparation of methyl {[5-(3 -chlorophenyl)hydroxypyridinyl]amino}acetate (4): To a 50 mL round bottom flask adapted for magnetic stirring and fitted with a en inlet tube was charged 5-(3-chlorophenyl)hydroxypyridinecarboxylic acid, 3, (1 gm, 4 mmol), N,N’ nyldiimidazole (CD1) (0.97 g, 6 mmol) and dimethyl sulfoxide (5 mL).

The reaction mixture was stirred at 45 0C for about 1 hour then cooled to room temperature. e methyl ester hydrochloride (1.15 g, 12 mmol) is added followed by the dropwise addition of diisopropylethylamine (3.2 mL, 19 mmol). The mixture was then d for 2.5 hours at room ature after which water (70 mL) was added. The contents of the reaction flask was cooled to 0 °C to 5 0C and 1N HCl was added until the solution pH is approximately 2. The solution was extracted with dichloromethane (100 mL) and the organic layer was dried over MgSO4 for 16 hours. Silica gel (3 g) is added and the solution ed for 2 hours after which the solids are removed by filtration. The filtrate is concentrated to dryness under reduced pressure and the resulting residue was slurried in methanol (10 mL) for two hours. The resulting solid was collected by ion and washed with cold methanol (20 mL) then hexane and the resulting cake is dried to afford 0.85 g of the desired product as an off-white solid. The filtrate was treated to afford 0.026 g of the desired product as a second crop. The combined crops afford 0.88 g (68% yield) of the desired product. 1H NMR (DMSO—d6) 8 12.3 (s, 1H), 9.52 (t, 1H), 8.56 (d, 1H), 7.93 (s, 1H), 7.80 (q, 2H), 7.55 (t, 2H), 4.12 (d, 2H), and 3.69 (s, 3H).

The formulator can readily scale up the above disclosed synthesis. Disclosed herein below is a synthesis wherein the sed process is scaled up for commercial use.

EXAMPLE 2 Methyl {[5-(3 -chlorophenyl)hydroxypyridinyl]amino}acetate (4) ation of 5-(3-chlorophenyl)-3 -chlorocyanopyridine (1): A 20 L reactor equipped with a mechanical stirrer, dip tube, thermometer and nitrogen inlet was charged with (3—chlorophenyl)boronic acid (550 g, 3.52 mol), chloro—2—cyanopyridine (639 g, 3.69 mol), K2CO3 (5.5 g, 40 mmol), [1,1’—bis(diphenyphosphino)ferrocene]dichloro— palladium(H) (dppf)] (11.5 g, 140 mmol), and dimethylformamide (3894 g, 4.125 L).

The reaction solution was agitated and purged with nitrogen h the dip-tube for 30 minutes. Degassed water (413 g) was then charged to the reaction e while maintaining a temperature of less than 50 °C 25 hours. The reaction was determined to be complete due to the earance of 3,5—dichloro—2—cyanopyridine as measured by TLC analysis using ethyl acetate/methanol (4: 1) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction solution was then cooled to 5 0C and charged with heptane (940 g, 1.375 L) and agitated for 30 minutes. Water (5.5 L) was charged and the e was further agitated for 1 hour as the temperature was allowed to rise to 15 0C. The solid product was isolated by filtration and washed with water (5.5 L) followed by heptane (18881 g, 2750 ML). The resulting cake was air dried under vacuum for 18 hours and then triturated with a mixture of 2-propanol (6908 g, 8800 mL0 and heptane (1 g, 2200mL0 at 50 0C for 4 hours, cooled to ambient ature and then agitated at ambient temperature for 1 hour. The product was then isolated by filtration and washed with cold 2-propanol (3450 g, 4395 mL) followed by heptane (3010 g, 4400mL). The resulting solid was dried under high vacuum at 40 °C for 64 hours to afford 565.9 g (65% yield) of the desired product as a beige solid. Purity by HPLC was 98.3. 1H NMR (DMSO—d6) 8 9.12 (d, 1H), 8.70 (d, 1H), 8.03 (t, 1H) 7.88 (m, 1H), and 7.58 (m, 2H).

Preparation of 5-(3-chlorophenyl)methoxycyanopyridine (2): A 20 L reactor equipped with a mechanical stirred, condenser, meter and nitrogen inlet was charged with 5-(3 -chlorophenyl)chlorocyanopyridine, 1, (558 g, 2.24 mol) and sodium methoxide (25% solution in methanol, 726.0 g, 3.36 mol). With agitation, the on solution was heated to reflux for 24 hours, resulting in a beige—colored suspension. The reaction was determined to be complete due to the disappearance of 5—(3 —chlorophenyl)—3— chlorocyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to Visualize the reaction components. The reaction mixture was cooled to 5 0C and then charged with water (5580 mL). The resulting slurry was agitated for 3 hours at 5 0C. The solid product was ed by filtration and washed with water (5580 mL) until the filtrate had a pH of 7. The filter cake was air dried under vacuum for 16 hours. The filter cake was then charged back to the reactor and triturated in MeOH (2210 g, 2794 mL) for 1 hour at ambient temperature. The solid was collected by filtration and washed with MeOH (882 g, 1116 mL, 5 0C) followed by heptane (205 mL, 300mL), and dried under high vacuum at 45 0C for 72 hours to afford 448 g (82% yield) of the desired product as an ite solid. Purity by HPLC was 97.9%. 1H NMR (DMSO— d6) 8 8.68 (d, 1H), 8.05 (d, 1H), 8.01 (s, 1H) 7.86 (m, 1H), 7.59 (s, 1H), 7.57 (s, 1H) and 4.09 (s, 3H).

Preparation of 5-(3-chlorophenyl)-3 -hydroxypyridinecarboxylic acid (3): A 20 L reactor equipped with a mechanical stirrer, condenser, thermometer, nitrogen inlet and 25% aqueous NaOH trap was charged 5—(3 —chlorophenyl)methoxycyanopyridine, 2, (440.6 g, 1.8 mol) and 37% aqueous solution of HCl (5302 g). While being agitated, the reaction solution was heated to 102 0C for 24 hours. Additional 37% aqueous HCl (2653 g) was added followed by agitation for 18 hours at 104 0C. The on contents was then cooled to 5 0C, d with water (4410 g) and then agitated at 0 0C for 16 hours. The resulting itated t was isolated by filtration and washed with water until the filtrate had a pH of 6 (about 8,000 L of water). The filter cake was pulled dry under reduced pressure for 2 hours. The cake was then transferred back into the reactor and triturated in THF (1958 g, 2201 mL) at ambient temperature for 2 hours. The solid product was then isolated by filtration and washed with THF (778 g, 875 mL) and dried under reduced re at 5 °C for 48 hours to afford 385 g (89% yield) of the desired product as an off—white solid. HPLC purity was 96.2%. 1H NMR (DMSO—d6) 8 8.52 (d, 1H), 7.99 (d, 1H), 7.95 (s, 1H) 7.81 (t, 1H), 7.57 (s, 1H), and 7.55 (s, 1H).

Preparation of methyl {[5-(3 -chlorophenyl)hydroxypyridinyl]amino}acetate (4): A 20 L reactor equipped with a mechanical r, condenser, thermometer and nitrogen inlet was charged with 5-(3 -chlorophenyl)-3 -hydroxypyridinecarboxylic acid, 3, (380 g, 1.52 mol) and diisopropylethylamine )(295 g, 2.28 mol). With agitation, the solution was cooled to 3 0C and charged with trimethylacetyl chloride (275.7 g, 2.29 mol) while maintaining a temperature of less than 11 0C, The mixture was then agitated at ambient temperature for 2 hours. The e was then cooled to 10 0C and charged with a slurry of glycine methyl ester HCl (573.3 g, 4. 57 mol) and THF (1689 g, 1900mL), then charged with DIPEA (590.2 g, 4.57 mol) and agitated at ambient temperature for 16 hours.

The mixture was then charged with EtOH (1500 g, 1900 mL) and concentrated under d pressure to a reaction volume of about 5.8 L. The EtOH addition and concentration was repeated twice more. Water (3 800g) was then added and the mixture was agitated for 16 hours at ambient temperature. The resulting solid product was isolated by filtration and washed with a mixture of EtOH (300g, 380 mL) and water (3 80 g), followed by water (3 800g), dried under reduced pressure for 18 hours at 50 °C to afforded 443 g (91% yield) of the desired product as an off—white solid. Purity by HPLC was 98.9%. 1H NMR (DMSO— d6) 8 12.3 (s, 1H), 9.52 (t, 1H), 8.56 (d, 1H), 7.93 (s, 1H), 7.80 (q, 2H), 7.55 (t, 2H), 4.12 (d, 2H), and 3.69 (s, 3H).

Scheme 11 herein below outlines and Example 2 describes a non-limiting example of the disclosed process for ing a prolyl hydroxylase inhibitor from an ester prodrug.

Scheme 11 C1 C1 N —> \ o N o H H / NA / NA OCH3 OH OH O OH O 4 5 Reagents and conditions: (a) NaOH, THF; 2 hr. {[5-(3 -Chlorophenyl)hydroxypyridinyl]amino}acetic acid (5) ation of {[5-(3 -chlorophenyl)hydroxypyridinyl]amino}acetic acid (5): To a 50 mL flask is charged methyl {[5-(3-chlorophenyl)hydroxypyridinyl]amino}- acetate, 4, (0.45 g, 1.4 mmol), tetrahydrofuran (4.5 mL) and 1 M NaOH (4.5 mL, 4.5 mmol). The mixture was stirred for 2 hours at room temperature after which it was determined by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to Visualize the reaction ents that the reaction was complete. The reaction on was adjusted to pH 1 with concentrated HCl and the solution was heated at 35 0C under vacuum until all of the tetrahydrofuran had been removed. A slurry forms as the solution is trated. With efficient stirring the pH is adjusted to ~2 with the slow addition of 1 M NaOH. The solid which forms was collected by filtration, washed with water, followed by hexane, then dried under vacuum to afford 0.38 g (88% yield) of the desired t as a white solid. 1H NMR (DMSO—d6) 8 12.84 (s, 1H), 12.39 (s, 1H), 9.39 (t, 1H), 8.56 (d, 1H), 7.94 (s, 1H), 7.81 (m, 2H), 7.55 (q, 2H), and 4.02 (d, 2H).

The ator can readily scale up the above disclosed synthesis. Disclosed herein below is a synthesis wherein the disclosed process is scaled up for commercial use. {[5-(3 -Chlorophenyl)hydroxypyridinyl]amino}acetic acid (5) Preparation of {[5-(3 -chlorophenyl)hydroxypyridinyl]amino}acetic acid (5): To a 20 L reactor equipped with a mechanical stirrer, condenser, meter and nitrogen inlet was charged methyl {[5-(3 -chlorophenyl)-3 -hydroxypyridinyl]amino}-acetate, 4, (440 g, 1.42 mol), tetrahydrofuran (3912 g, 4400 mL) and 1 M NaOH (4400 mL). The mixture was stirred for 2 hours at room temperature after which it was determined by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components that the on was complete. The reaction solution was acidified to a pH of 2 with slow addition of 2M HCl (2359 g). The resulting mixture was concentrated under reduced pressure to a volume of about 7.5 L. Ware (2210 g) was added and the solution cooled to ambient temperature and agitated for 18 hours. The solid product was isolated by filtration and washed with water (6 L). the crude product was transferred back into the reactor and triturated with 2215 g o deionized water at 70 0C for 16 hours.

The mixture was cooled to ambient temperature, The solid product was ed by filtration and washed with water (500 mL) and dried under d pressure at 70 °C for 20 hours to afford 368 g (87% yield) of the desired product as an off—white solid. Purity by HPLC was 99.3%. 1H NMR (DMSO—dg) 8 12.84 (s, 1H), 12.39 (s, 1H), 9.39 (t, 1H), 8.56 (d, 1H), 7.94 (s, 1H), 7.81 (m, 2H), 7.55 (q, 2H), and 4.02 (d, 2H).

Scheme III herein below outlines and Example 3 describes a non-limiting example of the disclosed s for preparing a prolyl hydroxylase amide prodrug.

Scheme III ts and conditions: (a) EDCI, HOBt, DIPEA, DMF; rt.

EXAMPLE 5 —(3—Chlorophenyl)-N—(2-aminooxoethyl)hydroxylpyridinyl amide Preparation of hlorophenyl)-N—(2-aminooxoethyl)hydroxylpyridinyl amide (6): To a solution of 5-(3-chlorophenyl)hydroxypyridinecarboxylic acid, 3, (749 mg, 3 mmol) in DMF (20 mL) at room temperature under N2 is added 1-(3—dimethyl— aminopropyl)—3—ethylcarbodiimide (EDCI) (0.925 g, 5.97 mmol) and 1—hydroxybenzo— triazole (HOBt) (0.806 g, 5.97 mmol). The resulting solution is stirred for 15 s then 2-aminoacetamide hydrochloride (0.66 g, 5.97 mmol) and diisopropylethylamine (1.56 ml, 8.96 mmol) are added. The reaction is monitored by TLC and when the reaction is complete the reaction mixture is trated under reduced pressure and H20 added. The product can be isolated by normal work—up: The following data have been reported for compound (6). 1H NMR (250 MHz, DMSO—d6) 8 ppm 12.46 (1 H, s), 9.17 (1 H, t, J= 5.9 Hz), 8.55 (1 H, d, J= 2.0 Hz), 7.93 (1 H, d, J= 0.9 Hz), 7.75 — 7.84 (2 H, m), 7.49 — 7.60 (3 H, m), 7.18 (1 H, s), 3.91 (2 H, d, J= 5.9 Hz). HPLC—MS: m/z 306 [M+H]+.

Scheme IV herein below depicts a non-limiting example the hydrolysis of an amide pro-drug to a prolyl hydroxylase inhibitor after removal of a R10 protecting group.

Scheme IV 9\ j]: NH2 0 NH —’ \ N o {I} NH2 / \Jk OH O OH O NH2 NH2 H H / NdL / NA NH2 OH OH O OH 0 While particular embodiments of the present sure have been rated 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 (27)

WHAT IS CLAIMED IS:

1. A s for preparing a compound having the formula: wherein R1 is chosen from: i) substituted or unsubstituted C6 or C10 aryl; or ii) substituted or unsubstituted C1-C9 heteroaryl; L is a linking unit having the formula: –(CR7aR7b)n– R7a and R7b are each independently: i) hydrogen; or ii) C1-C6 linear, C3-C6 ed or C3-C6 cyclic alkyl; R8 is chosen from hydrogen, , or ethyl; and the index n is an integer from 1 to 4; or a pharmaceutically acceptable salt thereof, comprising: A) reacting a boronic acid or ester having the formula: wherein Y is OR20, R20 is hydrogen or C1-C6 linear, C3-C6 branched, or C3- C6 cyclic alkyl, or two OR20 units can be taken together to form a 5-member to 7-member C3-C10 cyclic ester, with a 3,5-dihalocyanopyridine having the formula: each Z is ndently chloro or bromo, in the presence of a catalyst, to form a 5-aryl or 5-heteroarylhalocyanopyridine having the formula: B) reacting the 5-aryl or 5-heteroarylhalocyanopyridine formed in step (A) with an alkoxide anion having the formula: wherein R2 is C1-C12 linear alkyl or C3-C12 branched alkyl, to form a 5-aryl or 5-heteroarylalkoxycyanopyridine having the formula: C) reacting the 5-aryl or 5-heteroarylalkoxycyanopyridine formed in step (B) with an acid to form a 5-aryl or 5-heteroarylhydroxy carboxypyridine having the formula: ; and D) reacting the 5-aryl or roarylhydroxycarboxypyridine formed in step (C) with an amino acid having the formula:

2. The process according to Claim 1, wherein the boronic acid in step (A) is a substituted or unsubstituted phenyl boronic acid.

3. The process according to either Claim 1 or 2, wherein the boronic acid in step (A) is a phenyl boronic acid substituted with one or more units independently chosen from: i) C1-C12 linear, C3-C12 branched, or C3-C12 cyclic alkyl, alkenyl, and l; ii) C6 or C10 aryl; iii) C7 or C11 alkylenearyl; iv) C1-C9 cyclic rings; v) C1-C9 heteroaryl rings; vi) –(CR102aR102b)aOR101; vii) –(CR102aR102b)aC(O)R101; viii) –(CR102aR102b)aC(O)OR101; ix) –(CR102aR102b)aC(O)N(R101)2; x) –(CR102aR102b)aN(R101) C(O)R101; xi) 2aR102b)aN(R101) 101; xii) –(CR102aR102b)aN(R101)2; xiii) halogen; xiv) –(CR102aR102b)I; xv) –(CR102aR102b)aNO2; xvi) –(CHj’Xk’)aCHjXk; wherein X is halogen, the index j is an integer from 0 to 2, j + k = 3; the index j’ is an integer from 0 to 2, j’ + k’ = 2; xvii) –(CR102aR102b)aSR101; xviii) –(CR102aR102b)aSO2R101; and xix) –(CR102aR102b)aSO3R101; wherein each R101 is ndently hydrogen, substituted or unsubstituted C1-C6 linear, C3-C6 branched, or C3-C6 cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R101 units can be taken together to form a ring comprising 3-7 atoms; R102a and R102b are each independently hydrogen or C1-C4 linear or C3-C4 ed alkyl; the index “a” is from 0 to 4

4. The process according to any one of Claims 1 to 3, wherein the boronic acid in step (A) is substituted by one or more units ndently chosen from: i) C1-C12 linear, C3-C12 ed or C3-C12 cyclic alkyl; ii) C1-C12 linear, C3-C12 branched or C3-C12 cyclic alkoxy; or iii) halogen.

5. The process according to any one of Claims 1 to 4, wherein the boronic acid in step (A) is chosen from 2-fluorophenylboronic acid, 3-fluorophenylboronic acid, 4- fluorophenylboronic acid, 2-chlorophenylboronic acid, 3-chlorophenylboronic acid, 4-chlorophenylboronic acid, 2-methylphenylboronic acid, 3-methylphenylboronic acid, 4-methylphenylboronic acid, 2-methoxyphenylboronic acid, 3-methoxyphenylboronic acid, 4-methoxyphenylboronic acid, 2-cyanophenylboronic acid, 3-cyanophenylboronic acid, 4-cyanophenylboronic acid, 2-nitrophenylboronic acid, 3-nitrophenylboronic acid, ophenylboronic acid, 2-trifluoromethylphenylboronic acid, 3-trifluoromethylphenylboronic acid, 4-trifluoromethylphenylboronic acid, 2- carbamoylphenylboronic acid, 3-carbamoylphenylboronic acid, 4-carbamoylphenylboronic acid, 2-(pyrrolidinecarbonyl)phenylboronic acid, rolidine yl)phenylboronic acid, 4-(pyrrolidinecarbonyl)phenylboronic acid, 2-(cyclopropanecarbonylamino)phenylboronic acid, 3-(cyclopropanecarbonylamino )phenylboronic acid, and 4-(cyclopropanecarbonylamino)phenylboronic acid.

6. The process according to any one of Claims 1 to 5, wherein the catalyst in step (A) is [1,1’-bis(diphenyphosphino)ferrocene]dichloro-palladium(II).

7. The process according to any one of Claims 1 to 6, wherein the alkoxide in step (B) is methoxide.

8. The process according to any one of Claims 1 to 7, n the amino acid of step (D) is chosen from glycine, alanine, isoleucine, leucine, valine, 2-aminomethylpropanoic acid, 3-aminobutanoic acid, 3-aminomethylbutanoic acid, 3-amino methylbutanoic acid, and 4-aminobutanoic acid.

9. A process for ing a compound having the formula: n A is a ring chosen from: i) substituted or unsubstituted C6 or C10 aryl; or ii) substituted or unsubstituted C1-C9 heteroaryl; R10 represents one or more independently chosen optionally present substitutions for hydrogen; X is chosen from: i) –OH; ii) –OR3; iii) –NR4R5; and iv) –OM1; R3 is C1-C12 linear, C3-C12 branched or C3-C12 cyclic alkyl; C2-C12 linear, C3-C12 branched or C3-C12 cyclic alkenyl; or C2-C12 linear, C3-C12 branched or C3-C12 cyclic alkynyl, or benzyl; R4 and R5 are each independently hydrogen, C1-C12 linear, C3-C12 branched or C3- C12 cyclic alkyl; C2-C12 linear, C3-C12 branched or C3-C12 cyclic alkenyl; or C2-C12 linear, C3-C12 branched or C3-C12 cyclic alkynyl; benzyl; or R4 and R5 can be taken er with the nitrogen atom to form a 3 to 10 member ring, wherein the ring can optionally contain one or more heteroatoms chosen from oxygen (O), nitrogen (N), or sulfur (S); M1 is a pharmaceutically acceptable cation; R7a and R7b are each ndently: i) hydrogen; or ii) C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl; R8 is chosen from hydrogen, methyl, or ethyl; and the index n is an integer from 1 to 4; or a pharmaceutically acceptable salt thereof, sing: A) reacting a boronic acid or ester having the formula: wherein Y is OR20, R20 is hydrogen or C1-C6 , C3-C6 branched, or C3- C6 cyclic alkyl, or two OR20 units can be taken together to form a 5-member to 7-member C3-C10 cyclic ester, with a 3,5-dihalocyanopyridine having the formula: each Z is independently chloro or bromo, in the presence of a st, to form a 5-aryl or 5-heteroarylhalocyanopyridine having the formula: B) reacting the 5-aryl or 5-heteroarylhalocyanopyridine formed in step (A) with an alkoxide anion having the a: wherein R2 is C1-C12 linear alkyl or C3-C12 branched alkyl, to form a 5-aryl or 5-heteroarylalkoxycyanopyridine having the formula: C) reacting the 5-aryl or 5-heteroarylalkoxycyanopyridine formed in step (B) with an acid to form a 5-aryl or 5-heteroarylhydroxy carboxypyridine having the formula: ; and D) reacting the 5-aryl or 5-heteroarylhydroxycarboxypyridine formed in step (C) with a compound having the a:

10. The process according to Claim 9, wherein the boronic acid in step (A) is a substituted or unsubstituted phenyl boronic acid.

11. The process according to either Claim 9 or 10, wherein the c acid in step (A) is a phenyl boronic acid wherein R10 represents one or more substitutions for en independently chosen from: i) C1-C12 linear, C3-C12 branched, or C3-C12 cyclic alkyl, alkenyl, and alkynyl; ii) C6 or C10 aryl; iii) C7 or C11 alkylenearyl; iv) C1-C9 heterocyclic rings; v) C1-C9 heteroaryl rings; vi) –(CR102aR102b)aOR101; vii) –(CR102aR102b)aC(O)R101; viii) –(CR102aR102b)aC(O)OR101; ix) –(CR102aR102b)aC(O)N(R101)2; x) –(CR102aR102b)aN(R101) C(O)R101; xi) –(CR102aR102b)aN(R101) C(O)2R101; xii) –(CR102aR102b)aN(R101)2; xiii) halogen; xiv) –(CR102aR102b)I; xv) –(CR102aR102b)aNO2; xvi) Xk’)aCHjXk; wherein X is halogen, the index j is an integer from 0 to 2, j + k = 3; the index j’ is an integer from 0 to 2, j’ + k’ = 2; xvii) –(CR102aR102b)aSR101; xviii) –(CR102aR102b)aSO2R101; and xix) –(CR102aR102b)aSO3R101; wherein each R101 is independently hydrogen, substituted or unsubstituted C1-C6 linear, C3-C6 branched, or C3-C6 cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R101 units can be taken er to form a ring comprising 3-7 atoms; R102a and R102b are each independently hydrogen or C1-C4 linear or C3- C4 branched alkyl; the index “a” is from 0 to 4.

12. The process ing to any one of Claims 9 to 11, wherein R10 is one or more units independently chosen from: i) C1-C12 , C3-C12 branched or C3-C12 cyclic alkyl; ii) C1-C12 linear, C3-C12 branched or C3-C12 cyclic alkoxy; or iii) n.

13. The process according to any one of Claims 9 to 12, wherein the c acid in step (A) is chosen from 2-fluorophenylboronic acid, 3-fluorophenylboronic acid, 4- fluorophenylboronic acid, 2-chlorophenylboronic acid, 3-chlorophenylboronic acid, 4-chlorophenylboronic acid, 2-methylphenylboronic acid, 3-methylphenylboronic acid, 4-methylphenylboronic acid, 2-methoxyphenylboronic acid, 3-methoxyphenylboronic acid, 4-methoxyphenylboronic acid, 2-cyanophenylboronic acid, 3-cyanophenylboronic acid, 4-cyanophenylboronic acid, 2-nitrophenylboronic acid, 3-nitrophenylboronic acid, 4-nitrophenylboronic acid, 2-trifluoromethylphenylboronic acid, 3-trifluoromethylphenylboronic acid, 4-trifluoromethylphenylboronic acid, 2- carbamoylphenylboronic acid, 3-carbamoylphenylboronic acid, 4-carbamoylphenylboronic acid, 2-(pyrrolidinecarbonyl)phenylboronic acid, 3-(pyrrolidine carbonyl)phenylboronic acid, rolidinecarbonyl)phenylboronic acid, 2-(cyclopropanecarbonylamino)phenylboronic acid, 3-(cyclopropanecarbonylamino )phenylboronic acid, and 4-(cyclopropanecarbonylamino)phenylboronic acid.

14. The process according to any one of Claims 9 to 13, n the catalyst in step (A) is [1,1’-bis(diphenyphosphino)ferrocene]dichloro-palladium(II).

15. The process according to any one of Claims 9 to 14, wherein the compound of step (D) is chosen from glycine, alanine, isoleucine, leucine, , 2-aminomethylpropanoic acid, obutanoic acid, 3-aminomethylbutanoic acid, 3-amino methylbutanoic acid, and 4-aminobutanoic acid.

16. The process ing to any one of Claims 9 to 14, wherein X is –OR3 or –NR4R5 further comprising the step of hydrolyzing the compound formed in step (D) to form a compound wherein X is –OH.

17. The process according to Claim 16, wherein the hydrolysis is conducted in the presence of an acid catalyst.

18. The process according to Claim 16, wherein the hydrolysis is conducted in the presence of a base catalyst.

19. A nd having the formula: wherein M is a salt forming cation and N represents the cationic charge on M; A is C10 aryl; R10 units represent at least one optionally present substitutions for a ring hydrogen atom; or two R10 units can be taken together to form a substituted or unsubstituted C4-C8 cycloalkyl ring, a substituted or unsubstituted C6 or C10 aryl ring, a substituted or unsubstituted C2-C8 heterocyclic ring, or a tuted or unsubstituted C3 to C5 aryl ring, wherein the heterocyclic and heteroaryl rings comprise one or more hetero atoms independently chosen from oxygen (O), nitrogen (N), or sulfur (S). L is a linking unit having the formula: –(CR7aR7b)n– R7a and R7b are each independently: i) hydrogen; or ii) C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl; and the index n is an integer from 1 to 4.

20. The compound according to Claim 19, wherein A is tuted by one or more R10 units ndently chosen from: i) C1-C12 linear, C3-C12 branched, or C3-C12 cyclic alkyl, l, and alkynyl; ii) C6 or C10 aryl; iii) C7 or C11 alkylenearyl; iv) C1-C9 heterocyclic rings; v) C1-C9 heteroaryl rings; vi) –(CR102aR102b)aOR101; vii) –(CR102aR102b)aC(O)R101; viii) –(CR102aR102b)aC(O)OR101; ix) –(CR102aR102b)aC(O)N(R101)2; x) –(CR102aR102b)aN(R101) C(O)R101; xi) –(CR102aR102b)aN(R101) C(O)2R101; xii) –(CR102aR102b)aN(R101)2; xiii) halogen; xiv) –(CR102aR102b)I; xv) –(CR102aR102b)aNO2; xvi) –(CHj’Xk’)aCHjXk; wherein X is halogen, the index j is an integer from 0 to 2, j + k = 3; the index j’ is an integer from 0 to 2, j’ + k’ = 2; xvii) –(CR102aR102b)aSR101; xviii) –(CR102aR102b)aSO2R101; and xix) –(CR102aR102b)aSO3R101; n each R101 is independently hydrogen, substituted or unsubstituted C1-C6 linear, C3-C6 branched, or C3-C6 cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R101 units can be taken together to form a ring comprising 3-7 atoms; R102a and R102b are each independently hydrogen or C1-C4 linear or C3-C4 ed alkyl; the index “a” is from 0 to 4.

21. The compound according Claim 19 or 20, wherein A is substituted by one or more R10 units independently chosen from: i) C1-C12 linear, C3-C12 branched or C3-C12 cyclic alkyl; ii) C1-C12 linear, C3-C12 branched or C3-C12 cyclic alkoxy; or iii) halogen.

22. The compound according to Claim 19, wherein two R10 units are be taken together to form a substituted or unsubstituted C2-C8 cyclic ring, wherein the heterocyclic ring comprises one or more hetero atoms independently chosen from oxygen (O), nitrogen (N), or sulfur (S).

23. A compound or a pharmaceutically acceptable salt thereof, prepared by the process of any one of claims 1 to 18.

24. A process according to claim 1, substantially as herein described or exemplified.

25. A process according to claim 9, substantially as herein described or exemplified.

26. A compound ing to claim 19, ntially as herein described or exemplified.

27. A compound or a ceutically acceptable salt thereof according to claim 23, substantially as herein described or exemplified.