KR20070030938A - A method for preparing pyrrolotriazine compounds - Google Patents

Abstract

The present invention relates to a method for amination of pyrrole derivatives and to a process for preparing pyrrolotriazine compounds of formula (V).

<Formula V>

Pyrrole derivatives, pyrrolotriazines, anticancer agents, kinase inhibitors

Description

Process for preparing pyrrolotriazine compound {A METHOD FOR PREPARING PYRROLOTRIAZINE COMPOUNDS}

Related Applications

This application claims priority under title 35 [§] 119 (e) to US Provisional Application No. 60 / 584,382, filed June 30, 2004, the contents of which are incorporated herein by reference.

The present invention relates to a process for the preparation of pyrrolotriazine compounds useful as components or precursors in the synthesis of pharmaceutical compounds having utility as anticancer and kinase inhibitors. The present invention also includes methods for effective amination of pyrrole compounds useful for the synthesis of pyrrolotriazines and other N-aminedated heterocyclic compounds.

Pyrrolotriazine-containing compounds have been found to be useful as anti-cancer agents as well as kinase inhibitors. See for example WO 00/71129, WO 03/042172, WO 04/013145, WO 04/009784, WO 04/009601, WO 03/090912, WO 03/091229 and US Pat. No. 6,670,357 (these are in common) Assigned to Bristol-Myers Squibb Co.). Each disclosure of these patent applications, patents, and publications is incorporated herein by reference.

Summary of the Invention

The present invention relates to various methods of preparing pyrrolotriazine compounds as described in the claims appended hereto. The pyrrolotriazine compound has the structure of formula (V)

Where

R ₁ and R ₃ are each independently hydrogen, halogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloal Kenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR _a , SR _a , S (= 0) R _e , S (= 0) ₂ R _e , P (= 0) ₂ R _e , S (= O) ₂ OR _e , P (= O) ₂ OR _e , NR _b R _c , NR _b S (= O) ₂ R _e , NR _b P (= O) ₂ R _e , S (= O) ₂ NR _b R _c , P (= O) ₂ NR _b R _c , C (= 0) OR _e , C (= 0) R _a , C (= 0) NR _b R _c , OC (= O) R _a , OC (= 0) NR _b R _c , NR _b C (= 0) OR _e , NR _d C (= 0) NR _b R _c , NR _d S (= 0) ₂ NR _b R _c , NR _d P (= 0) ₂ NR _b R _c , NR _b C (= 0) R _a or NR _b P (= 0) ₂ R _e ;

X is -O-, -OC (= O)-, -S-, -S (= O)-, -S (= O) _2- , -C (= O)-, -C (= O) O -, -NR _d- , -NR _d C (= 0)-, -C (= 0) NR _d- , -NR _d C (= 0) NR _d- , -NR _d C (= 0) O-, -OC (= 0) NR _d- , -NR _d S (= 0) _2- , -NR _d S (= 0) ₂ NR _d- , -S (= 0) ₂ NR _d- , halogen, nitro, cya Furnace or bond;

R ₂ is a) hydrogen, provided that X is -S (= 0)-, -SO _2- , -OC (= 0)-, -OC (= 0) NR _d -or -S (= 0) ₂ NR _{when d-} , R ₂ is not hydrogen);

b) alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl; And

c) is selected from heterocycle or substituted heterocycle, aryl or substituted aryl, and when X is halogen, nitro or cyano, then R ₂ is absent;

R ₁ and R ₂ together may optionally form an optionally substituted 3-7 membered carbocyclic ring or an optionally substituted 3-7 membered heterocyclic ring;

R ₆ is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl Or heterocycle or substituted heterocycle;

R _a is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted Heterocycle or aryl or substituted aryl;

R _b , R _c and R _d are each independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle or aryl or substituted aryl, wherein R _b and R _c are Optionally together with N to which they are attached form a heterocycle or a substituted heterocycle;

R _e is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle Or aryl or substituted aryl.

The present invention also relates to a method for amination of pyrrole derivatives useful for the synthesis of pyrrolotriazine and other N-aminedated heterocyclic compounds.

Abbreviation

For ease of reference, the following abbreviations are used herein, including the preparation methods and the examples that follow.

AP = area% in HPLC

t-Bu = tertiary butyl

Me = methyl

dec. = Decomposition

Et = ethyl

EtOAc = ethyl acetate

OMe = Methoxyl

OEt = ethoxyl

Boc = tert-butyloxycarbonyl

DCM = dichloromethane

DMF = Dimethyl Formamide

NMP = 1-methyl-2-pyrrolidinone

DMSO = dimethyl sulfoxide

THF = tetrahydrofuran

Et ₃ N = triethylamine

CSA = camphorsulfonic acid

MeSO ₃ H = methanesulfonic acid

EtSO ₃ H = ethanesulfonic acid

TsOH = p-toluenesulfonic acid

PhSO ₃ H = phenylsulfonic acid

4-NO ₂ -PhSO ₃ H = 4-nitrophenylsulfonic acid

KOtBu = potassium t-butoxide

min = minute (s)

L-liter

mL = milliliters

g = gram (s)

mg = milligram (s)

mol = mol

mmol = millimolar (s)

RT or rt = room temperature

sat or sat'd = saturation

aq. = Aqueous

HPLC = high performance liquid chromatography

MS = mass spectroscopy

NMR = nuclear magnetic resonance

mp or Mp = melting point

Justice

The following are the definitions of terms used herein. The original definitions provided for groups or terms herein apply unless otherwise indicated throughout the specification, either individually or as part of another group for that group or term.

The terms "alkyl" and "alk" refer to straight or branched chain alkane (hydrocarbon) radicals containing from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4 -Trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. The term “C ₁ -C ₄ alkyl” refers to straight or branched chain alkane (hydrocarbon) radicals containing 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and Refers to isobutyl. "Substituted alkyl" refers to an alkyl group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (eg, forming a single halogen substituent or multiple halo substituents, in the latter CF ₃ , or an alkyl group containing Cl ₃₎ ; Same group, cyano, nitro, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR _a , SR _a , S (= 0) R _e , S (= 0) ₂ R _e , P (= O) ₂ R _e , S (= O) ₂ OR _e , P (= O) ₂ OR _e , NR _b R _c , NR _b S (= O) ₂ R _e , NR _b P (= O) ₂ R _e , S (= 0) ₂ NR _b R _c , P (= 0) ₂ NR _b R _c , C (= 0) OR _e , C (= 0) R _a , C (= 0) NR _b R _c , OC (= O) R _a , OC (= O) NR _b R _c , NR _b C (= 0) OR _e , NR _d C (= 0) NR _b R _c , NR _d S (= 0) ₂ NR _b R _c , NR _d P (= 0) ₂ NR _b R _c , NR _b C (= 0) R _a or NR _b P (= 0) ₂ R _e wherein R _a is hydrogen, alkyl, cycloalkyl , alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R _b, R _c and R _d are independently hydrogen, alkyl, cycloalkyl, heterocycle, O Or, wherein R _b and R _c is optionally form a heterocycle together with N they are attached to; the R _e is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl) referred to above. In exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl may themselves be optionally substituted.

The term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Exemplary such groups include ethenyl or allyl. "Substituted alkenyl" refers to an alkenyl group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, alkyl or substituted alkyl, and those described above as exemplary alkyl substituents.

The term "alkynyl" refers to a straight or branched chain hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon to carbon triple bond. Exemplary such groups include ethynyl. "Substituted alkynyl" refers to an alkynyl group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, alkyl or substituted alkyl, and those described above as exemplary alkyl substituents.

The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. "Substituted cycloalkyl" refers to a cycloalkyl group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, and groups described above as exemplary alkyl substituents. Exemplary substituents also include spiro-attached or fused cyclic substituents, in particular spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycles (except heteroaryl), fused cycloalkyl, Fused cycloalkenyl, fused heterocycle or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents may themselves be optionally substituted.

The term "cycloalkenyl" refers to partially unsaturated cyclic hydrocarbons containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, and those described above as exemplary alkyl substituents. Exemplary substituents also include spiro-attached or fused cyclic substituents, in particular spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycles (except heteroaryl), fused cycloalkyl, Fused cycloalkenyl, fused heterocycle or fused aryl, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents may themselves be optionally substituted.

The term "aryl" refers to cyclic aromatic hydrocarbon groups having 1 to 5 aromatic rings, in particular monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. If it contains two or more aromatic rings (such as bicyclic, etc.), the aromatic rings of the aryl groups can be bonded to a single point (for example biphenyl) or can be fused (for example naphthyl, phenanthrenyl Etc). "Substituted aryl" refers to an aryl group substituted at any point of attachment with one or more substituents, preferably one to three substituents. Exemplary substituents include, but are not limited to, nitro, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, cyano, alkyl or substituted alkyl, and those described above as exemplary alkyl substituents. Does not. Exemplary substituents also include fused cyclic groups, in particular fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle mentioned above And aryl substituents may themselves be optionally substituted.

The terms "heterocycle" and "heterocyclic" refer to fully saturated or partially or fully unsaturated compounds, including aromatic (ie "heteroaryl") cyclic groups having one or more heteroatoms in one or more carbon atom-containing rings. Refers to a click group (eg 4 to 7 membered monocyclic, 7 to 11 membered bicyclic or 10 to 16 membered tricyclic ring system). Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms are optionally oxidized Nitrogen heteroatoms may be optionally quaternized. (The term “heteroaryllium” refers to heteroaryl having quaternary nitrogen atoms and having a positive charge). Heterocyclic groups may be attached to the rest of the molecule at any heteroatom or carbon atom of the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxa Zolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadizolyl, piperidinyl, pipe Ferrazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, Pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3 -Dioxolane, tetrahydro-1,1, -dioxothienyl, and the like. Exemplary bicyclic heterocyclic groups include indolyl, isoindoleyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoqui Nolinyl, benzimidazolyl, benzopyranyl, indolinyl, benzofuryl, benzofurazanyl, chromonyl, coumarinyl, benzopyranyl, cinnaolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furo Pyridinyl (for example furo [2,3-c] pyridinyl, furo [3,2-b] pyridinyl] or furo [2,3-b] pyridinyl), dihydroisoindolyl, dihydroquinazoli Yl (for example, 3,4-dihydro-4-oxo-quinazolinyl), triazinylazinyl, tetrahydroquinolinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenantridinyl, xanthenyl and the like.

"Substituted heterocycle" and "substituted heterocyclic" (eg "substituted heteroaryl") are heterocycles substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Or heterocyclic group. Exemplary substituents include those described above as cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, nitro, oxo (ie = 0), cyano, alkyl or substituted alkyl, and exemplary alkyl substituents. But it is not limited thereto. Exemplary substituents also include spiro-attached or fused cyclic substituents at any available point of attachment, in particular spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycles (except heteroaryl) ), Fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle and aryl substituents mentioned above may themselves be optionally substituted. have.

The term "halogen" or "halo" refers to chlorine (Cl), bromine (Br), fluorine (F) or iodine (I).

The term “carbocyclic” refers to aromatic or non-aromatic 3-7 membered monocyclic and 7-11 membered bicyclic groups in which all atoms of the ring or rings are carbon atoms. "Substituted carbocyclic" refers to a carbocyclic group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Exemplary substituents include, but are not limited to, nitro, cyano, OR _a , wherein R _a is as defined above, and exemplary cycloalkyl substituents described above.

When a functional group is referred to as "protected," it is meant that the group is in a form that is modified to prevent, in particular, undesirable side reactions at the protected site. Suitable protecting groups for the methods and compounds described herein include, but are not limited to, standard texts, such as those described in Greene, TW et al., Protective Groups in Organic Synthesis, Wiley, NY (1999). .

Unless otherwise indicated, any heteroatom having an unsaturated valency is assumed to have a hydrogen atom sufficient to satisfy the valence.

The compounds of the present invention may also form salts within the scope of the present invention. Reference to a compound of Formulas I to V is understood to include reference to salts thereof unless otherwise indicated. The term "salt (s)" as used herein denotes acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, when the compound contains both basic residues such as, but not limited to, pyridine or imidazole, and acidic residues such as, but not limited to, zwitterions (“internal salts”) are formed. Which is included within the term “salt (s)” as used herein. Pharmaceutically acceptable (ie non-toxic, physiologically acceptable) salts are preferred, but other salts may be useful, for example, in an isolation or purification step that can be used during manufacture. Salts of the compounds can be formed, for example, by reacting an amount of an acid or base, such as an equivalent, with the compound in a medium or aqueous medium, such as where the salt is precipitated, followed by lyophilization.

Compounds of the invention containing basic residues such as, but not limited to, amines or pyridine or imidazole rings can form salts with various organic and inorganic acids. Exemplary acid addition salts include acetates (for example those formed with acetic acid or trihaloacetic acid, for example trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzene Sulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate , Hemisulphate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate (e.g. 2-hydroxyethanesulfonate), lactate, maltate, methanesulfo Nates, naphthalenesulfonates (eg 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, Pectinate, persulfate, phenylpropionate (eg 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g. formed with sulfuric acid And sulfonates, tartrates, thiocyanates, toluenesulfonates, for example tosylate, undecanoate, and the like.

Compounds of the invention containing acidic residues such as, but not limited to, carboxylic acids can form salts with various organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (eg organic amines), for example Benzatin, dicyclohexylamine, hydrabamine (formed from N, N-bis (dehydroabiethyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butyl Salts with amines and amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups include lower alkyl halides (eg methyl, ethyl, propyl and butyl chloride, bromide and iodide), dialkyl sulfates (eg dimethyl, diethyl, dibutyl and diamyl sulfate), Long chain halides (eg decyl, lauryl, myristyl and stearyl chloride, bromide and iodide), aralkyl halides (eg benzyl and phenethyl bromide) and the like.

Also contemplated herein are prodrugs and solvates of the compounds of the invention. As used herein, the term “prodrug” refers to a compound that, upon administration to a subject, is chemically converted by metabolic or chemical processes to be a compound of Formulas I-V or salts and / or solvates thereof. Examples of solvates of the compounds of the formulas (I) to (V) include hydrates.

The compounds of formulas I to V and salts thereof may exist in their tautomeric forms (eg amides or imino ethers). All such tautomeric forms are contemplated herein as part of the present invention.

All stereoisomers of the compounds of the invention, including enantiomeric and diastereomeric forms, for example those that may be present due to asymmetric carbons on various substituents, are contemplated within the scope of the invention. Individual stereoisomers of the compounds of the invention may be substantially free from, for example, other isomers (e.g., pure or substantially pure optical isomers with specified activity), for example as racemates, or all other Or with other selected stereoisomers. The chiral center of the present invention may have an S or R configuration as defined by IUPAC 1974 Cheon. Racemic forms can be cleaved by physical methods such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemate by any suitable method, including, but not limited to, conventional methods such as, for example, crystallization after salt formation with optically active acids.

Isomers of all configurations of the compounds of the invention are contemplated in mixtures or in pure or substantially pure form. Definitions of compounds of the present invention include both cis (Z) and trans (E) alkene isomers, and both cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.

Throughout this specification, groups and substituents thereof may be selected to provide suitable moieties and compounds.

Manufacturing method

The process for preparing the pyrrolotriazine compound is illustrated by the following scheme. Solvents, temperatures, pressures and other reaction conditions can be readily selected by one skilled in the art. Starting materials are commercially available or can be readily prepared by those skilled in the art.

Amination agents of formula III wherein R ₄ is H, C ₁ -C ₄ alkyl, nitro, cyano, halogen, OMe or OEt and n is 1, 2 or 3 can be prepared according to Scheme 1 below. For example, the salt form of the benzoyl hydroxyl amine of formula IV may be prepared by reacting the benzoyl chloride of formula 1 with a hydroxyl amine such as N-Boc-hydroxyamine in the presence of a base such as triethylamine, followed by MeSO ₃ H, EtSO ₃ H, TsOH, CSA, 4-NO ₂ -PhSO ₃ H, CF ₃ SO ₃ H, HCl, H ₃ PO ₄ , HNO ₃ , H ₂ SO ₄ , PhSO ₃ H or HBr It can be obtained by the addition of. The free hydroxyl amine of formula III can be prepared by treating the salt of formula IV with a base such as aqueous NaHCO ₃ in an organic solvent such as CH ₂ Cl ₂ .

X, R ₁ , R ₂ , R ₃ , R ₄ , n, and R ₆ are as defined above, and D is —C (═O) OR _p , wherein R _p is H, C ₁ -C ₆ alkyl Or aryl, preferably R _p is Me or Et). The pyrrolotriazine of Formula V can be prepared according to Scheme 2 below. Aminopyrroles of formula (II) can be synthesized by reacting pyrroles of formula (I) with an aminating agent of formula (III) in the presence of a base such as KOtBu in an aprotic solvent such as NMP. Compound II is preferably cyclized with an amide of formula R ₆ (C═O) NH ₂ in the presence of an acid to form a compound of formula V.

Alternatively, compounds of Formula (V) wherein R ₁ , X, R ₂ , R ₃ , R ₄ , n, and R ₆ are as defined above can be prepared according to Scheme 3 below. The pyrrole of formula (Ia) is reacted with the aminizing agent of formula (III) in the presence of a base such as KOtBu in an aprotic solvent such as NMP, followed by cooling with a base such as KOH to form compound IIa.

Compound IIa is reacted with an aqueous base such as KOH at room temperature to form compound IIb. Compound IIb is reacted with an acylating agent of formula R ₆ (= 0) -W, wherein W is Cl or OH, such as formic acid, in an aqueous solvent to form compound IIc. Compound IIc is cyclized with a base such as sodium methoxide while heating in an organic solvent such as MeOH to form compound V.

Compound Ia can be obtained from substituted pyrroles by formylation, for example by reaction with phosphorus oxychloride and DMF. Methylpyrrole can be obtained by reduction of formylpyrrole, for example by reaction with lithium aluminum hydride.

In addition, as shown in Scheme 4 below, the pyrrole derivative of formula (Ib) can be reacted with the amination agent of formula (III) in the presence of a base such as KOtBu in an aprotic solvent such as NMP to form a compound of formula (IId). Compound IId is preferably cyclized with an amide of formula R ₆ C (═O) NH ₂ in the presence of an acid to form a compound of formula Va. In Scheme 4, R ₃ and R ₆ are as defined above; R ₅ is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl or heterocycle or substituted heterocycle; R ₇ and R ₈ are each independently hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, halogen, cyano, nitro, aryl or substituted aryl, heterocycle or substituted Heterocycle, OR _a , SR _a or NR _b R _c ; R _p is alkyl or substituted alkyl or aryl or substituted aryl, preferably R _p is C ₁ -C ₄ alkyl, more preferably R _p is Me or Et.

The following examples are provided to further illustrate the present invention. The above examples illustrate the invention and are not intended to be limiting.

HPLC conditions used in the examples below are as follows.

Column: Waters XTerra RP-18, 4.6 × 50 mm, 3.5 μm;

Mobile phase: solvent A-0.2% aqueous H ₃ PO ₄ ; Solvent B-MeCN / water (90/10);

Flow rate: 2.5 mL / min;

Linear, gradient time: 8 minutes (starting solvent% B = 1; final solvent% B = 100); And

Wavelength: 256 nm.

Example 1

Preparation of Compound 2:

Triethylamine (5.82 g, 57 mmol) was added to a solution of N-Boc-hydroxyamine (6.80 g, 50 mmol) in 30 mL of dichloromethane at room temperature. The solution was cooled to 0 ° C. A solution of 3,4,5-trimethoxylbenzoyl chloride (Compound 1, wherein (R ₄ ) _n is 3,4,5-trimethoxy, 11.9 g, 52 mmol) in dichloromethane (40 mL) It was added slowly to the solution over 35 minutes at -5 ° C. The resulting mixture was stirred at 0-5 ° C. for 5 minutes and then warmed to 15-20 ° C. for 1 hour. Water (45 mL) was added to quench the reaction. After stirring for 20 minutes, the organic layer was separated, washed with aqueous NaHCO ₃ (1%, 35 mL) and then treated with methanesulfonic acid (8.15 g, 84.9 mmol) at room temperature for 16 hours. The mixture was treated with heptane (20 mL) for 20 minutes. The white solid was collected by filtration and washed with heptane-dichloromethane (1: 2, 35 mL). The wet cake was dried under vacuum at 40 ° C. for 16 hours to give 14.4 g (87%) of product 2 (X being 3,4,5-trimethoxyl) as a white solid.

Example 2

Preparation of Compound 3:

A solution of aqueous NaHCO ₃ (6%, 20 mL) was diluted with O-4-methoxyl benzoyl hydroxylamine methanesulfonate salt in dichloromethane (40 mL) at room temperature (Compound 2, wherein (R ₄ ) _n is 4-OMe. , 4.55 g, 17.3 mmol). After stirring for 15 minutes, the organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were treated with heptane (30 mL) and concentrated to about 30 mL. The resulting slurry was stirred at room temperature for 1 hour. The white solid was collected by filtration and washed with heptanes (10 mL). The wet cake was dried under vacuum at room temperature for 20 hours to give 2.6 g (89%) of compound 3 ((R ₄ ) _n is 4-0Me) as a white solid.

Example 3

Preparation of Alternatives to Compound 3

Triethylamine (40.7 g, 402 mmol) was added to a solution of N-Boc-hydroxyamine (50.0 g, 368 mmol) in 200 mL of dichloromethane at room temperature. The solution was cooled to 0 ° C. A solution of 4-nitrobenzoyl chloride (Compound 1, wherein (R ₄ ) _n is 4-nitroim, 69.1 g, 365 mmol) in dichloromethane (320 mL) was added to the solution at 65 ° C. over 65 minutes. It was. The resulting mixture was stirred at 0-5 ° C. for 5 minutes and then warmed to 15-20 ° C. Water (300 mL) was added to quench the reaction. After stirring for 5 minutes, the organic layer was separated, washed with aqueous K ₂ HPO ₄ (4%, 200 mL) and then treated with methanesulfonic acid (52.6 g, 548 mmol) at room temperature for 20 hours. The mixture was treated with aqueous K ₂ HPO ₄ (20%, 610 g) at room temperature for 5-10 minutes. Tetrahydrofuran (520 mL) was added to the mixture. The organic layer was separated, washed with brine (25%, 530 g) and dried over Na ₂ SO ₄ (50 g) for 30 minutes. After Na ₂ SO ₄ was removed by filtration, the filtrate was concentrated to about 355 g at 25-35 ° C. under vacuum. Heptane (440 mL) was added to the mixture to crystallize. The solid was collected by filtration, washed with THF-heptane (1: 2, 90 mL) and dried under vacuum at 25-35 ° C. to slightly yellow compound 3 ((R ₄ ) _n is 4-nitroim, 56.6 g, 85%, 99.2 AP).

Example 4

Preparation of Compound 5

A solution of potassium t-butoxide in THF (1 M, 1.1 mL) was added to a solution of compound 4 (225 mg, 1 mmol) in NMP (1-methyl 2-pyrrolidinone, 1.3 mL) at 20 ° C. After 15 minutes, a solution of Amination 3 (1.1 mmol) in NMP (0.8 mL) was added to the solution with stirring at 20 ° C. The mixture was stirred at 20 ° C. for 20 minutes to 6 hours. The conversion of compound 4 was determined by HPLC analysis. The reaction mixture was treated with brine (7%, 4 mL) and toluene (4 mL). The organic layer was separated and the aqueous layer was extracted with toluene (4 mL). The combined organic layers were washed with aqueous sodium bicarbonate solution (5%, 3 mL) and water (2 mL). The solution was concentrated to give crude compound 5 (about 240 mg).

The same morphology is converted to the amination agent 3, where (R ₄ ) _n is 4-nitro, 4-F, 3-Cl, 4-Cl, 4-Br, 4-OMe, 2,6-dimethoxy, 3,4 , 5-trimethoxy or 2,4-dimethoxy), and corresponding conversions are listed above.

Example 5

Preparation of Alternatives to Compound 5

Amination agent salt (Compound 2, wherein (R ₄ ) _n is 4-methyl, 820 mg, 3.3 mmol), a mixture of dichloromethane (9 mL), and aqueous NaHCO ₃ (6%, 5 mL) at room temperature Stir for minutes. The organic layer was separated and dried over anhydrous sodium sulfate (2 g). Solid sodium sulfate was removed by filtration and DMF (2.2 mL) was added to the filtrate. The filtrate was concentrated in vacuo at room temperature to give a solution of amination agent 3 (free base as shown in Example 3, where (R ₄ ) _n is 4-methyl) in DMF. To another reaction vessel, compound 3 (225 mg, 1 mmol), N-methyl-2-phyllolidinone (1.1 mL) and potassium t-butoxide (1 M in TMF, 1.08 mL) were added. To the mixture was added the amination agent 3 in DMF (0.9 mL) at room temperature. After stirring for 1.5 hours at room temperature, the reaction mixture was treated with brine (7%, 4 mL) and toluene (4 mL). The organic layer was separated and the aqueous layer was extracted with toluene (4 mL). The combined organic layers were washed with aqueous sodium bicarbonate solution (5%, 3 mL) and water (2 mL). The solution was concentrated to give crude compound 5 (240 mg, 94% purity by HPLC).

Similar morphology was achieved using Amination Agent 3, _where (R ₄ ) _n is H, with a conversion of 91%.

Example 6

Preparation of Compound 6

Crude compound 5 (21 g) was treated with formamide (160 mL) and phosphoric acid (85%, 1.45 g). The mixture was heated to 120-125 ° C. for 18 hours and then cooled to 90 ° C. Water (140 mL) was slowly added to the mixture over 45 minutes to crystallize. The mixture was cooled to room temperature for 1-4 hours. The solid was collected by filtration, washed with water (2 × 80 mL) and toluene (120 mL) and dried at 55 ° C. under vacuum to give compound 6 (13.8 g, 70%, 99.4 AP).

Claims (18)

A process for preparing a compound of formula (II) comprising reacting a compound of formula (I) with a benzoyl hydroxyl amine of formula (III) in the presence of a base to form a compound of formula (II). <Formula I>

<Formula II>

<Formula III>

Where R ₁ and R ₃ are each independently hydrogen, halogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloal Kenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR _a , SR _a , S (= 0) R _e , S (= 0) ₂ R _e , P (= 0) ₂ R _e , S (= O) ₂ OR _e , P (= O) ₂ OR _e , NR _b R _c , NR _b S (= O) ₂ R _e , NR _b P (= O) ₂ R _e , S (= O) ₂ NR _b R _c , P (= O) ₂ NR _b R _c , C (= 0) OR _e , C (= 0) R _a , C (= 0) NR _b R _c , OC (= O) R _a , OC (= 0) NR _b R _c , NR _b C (= 0) OR _e , NR _d C (= 0) NR _b R _c , NR _d S (= 0) ₂ NR _b R _c , NR _d P (= 0) ₂ NR _b R _c , NR _b C (= 0) R _a or NR _b P (= 0) ₂ R _e ; X is -O-, -OC (= O)-, -S-, -S (= O)-, -S (= O) _2- , -C (= O)-, -C (= O) O -, -NR _d- , -NR _d C (= 0)-, -C (= 0) NR _d- , -NR _d C (= 0) NR _d- , -NR _d C (= 0) O-, -OC (= 0) NR _d- , -NR _d S (= 0) _2- , -NR _d S (= 0) ₂ NR _d- , -S (= 0) ₂ NR _d- , halogen, nitro, cya Furnace or bond; R ₂ is a) hydrogen, provided that X is -S (= 0)-, -SO _2- , -OC (= 0)-, -OC (= 0) NR _d -or -S (= 0) ₂ NR _{when d-} , R ₂ is not hydrogen); b) alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl; And c) is selected from heterocycle or substituted heterocycle, aryl or substituted aryl, and when X is halogen, nitro or cyano, then R ₂ is absent; R ₁ and R ₂ together may optionally form an optionally substituted 3-7 membered carbocyclic ring or an optionally substituted 3-7 membered heterocyclic ring; D is CHO, CN, C (= 0) R _a , C (= 0) OR _e or C (= 0) NR _b R _c ; R _a is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted Heterocycle or aryl or substituted aryl; R _b , R _c and R _d are each independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle or aryl or substituted aryl, wherein R _b and R _c are Optionally together with N to which they are attached form a heterocycle or a substituted heterocycle; R _e is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle Or aryl or substituted aryl; R ₄ is H, nitro, cyano, halogen, C ₁ -C ₄ alkyl, OMe or OEt; n is 1, 2 or 3. The process of claim 1, wherein the benzoyl hydroxyl amine of formula III is prepared by reacting a pharmaceutically acceptable salt of benzoyl hydroxyl amine with a base. The method of claim 1, wherein the benzoyl hydroxyl amine of formula III is prepared by reacting a salt of formula IV with a base. <Formula IV>

Where R ₄ is H, nitro, cyano, halogen, C ₁ -C ₄ alkyl, OMe or OEt, n is 1, 2 or 3, Y is _{MeSO 3 -, EtSO 3 -,} 4-Me-PhSO 3 -,

4-NO ₂ -PhSO ₃ -CF ₃ SO _3- , -Cl, -H ₂ PO ₄ , -NO ₃ , -HSO ₄ , PhSO ₃ -or -Br. (a) reacting a compound of formula I with a benzoyl hydroxyl amine of formula III in the presence of a base to form a compound of formula II; And (b) further reacting the compound of formula II with an amide of formula R ₆ C (= 0) NH ₂ , wherein R ₆ is as defined below to form a compound of formula V A method for producing a compound of formula (V) comprising a. <Formula I>

<Formula II>

<Formula III>

<Formula V>

Where R ₁ and R ₃ are each independently hydrogen, halogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloal Kenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR _a , SR _a , S (= 0) R _e , S (= 0) ₂ R _e , P (= 0) ₂ R _e , S (= O) ₂ OR _e , P (= O) ₂ OR _e , NR _b R _c , NR _b S (= O) ₂ R _e , NR _b P (= O) ₂ R _e , S (= O) ₂ NR _b R _c , P (= O) ₂ NR _b R _c , C (= 0) OR _e , C (= 0) R _a , C (= 0) NR _b R _c , OC (= O) R _a , OC (= 0) NR _b R _c , NR _b C (= 0) OR _e , NR _d C (= 0) NR _b R _c , NR _d S (= 0) ₂ NR _b R _c , NR _d P (= 0) ₂ NR _b R _c , NR _b C (= 0) R _a or NR _b P (= 0) ₂ R _e ; X is -O-, -OC (= O)-, -S-, -S (= O)-, -S (= O) _2- , -C (= O)-, -C (= O) O -, -NR _d- , -NR _d C (= 0)-, -C (= 0) NR _d- , -NR _d C (= 0) NR _d- , -NR _d C (= 0) O-, -OC (= 0) NR _d- , -NR _d S (= 0) _2- , -NR _d S (= 0) ₂ NR _d- , -S (= 0) ₂ NR _d- , halogen, nitro, cya Furnace or bond; R ₂ is a) hydrogen, provided that X is -S (= 0)-, -SO _2- , -OC (= 0)-, -OC (= 0) NR _d -or -S (= 0) ₂ NR _{when d-} , R ₂ is not hydrogen); b) alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl; And c) is selected from heterocycle or substituted heterocycle, aryl or substituted aryl, and when X is halogen, nitro or cyano, then R ₂ is absent; R ₁ and R ₂ together may optionally form an optionally substituted 3-7 membered carbocyclic ring or an optionally substituted 3-7 membered heterocyclic ring; R ₆ is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl Or heterocycle or substituted heterocycle; R _a is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted Heterocycle or aryl or substituted aryl; R _b , R _c and R _d are each independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle or aryl or substituted aryl, wherein R _b and R _c are Optionally together with N to which they are attached form a heterocycle or a substituted heterocycle; R _e is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle Or aryl or substituted aryl; D is —C (═O) OR _p , wherein R _p is selected from H, C ₁ -C ₆ alkyl or aryl; R ₄ is H, nitro, cyano, halogen, C ₁ -C ₄ alkyl, OMe or OEt; n is 1, 2 or 3. The process of claim 4, wherein the benzoyl hydroxyl amine of formula III is prepared by reacting a pharmaceutically acceptable salt of benzoyl hydroxyl amine with a base. The method of claim 4, wherein the benzoyl hydroxyl amine of formula III is prepared by reacting a salt of formula IV with a base. <Formula IV>

Where R ₄ is H, nitro, cyano, halogen, C ₁ -C ₄ alkyl, OMe or OEt, n is 1, 2 or 3, Y is _{MeSO 3 -, EtSO 3 -,} 4-Me-PhSO 3 -,

4-NO ₂ -PhSO ₃ -CF ₃ SO _3- , -Cl, -H ₂ PO ₄ , -NO ₃ , -HSO ₄ , PhSO ₃ -or -Br. The method of claim 4, wherein R ₆ is H and R _p is Me or Et. (a) reacting a compound of Formula Ia with a benzoyl hydroxyl amine and a base of Formula III to form a compound of Formula IIb; (b) further reacting a compound of formula IIb with an acylating agent of formula R ₆ C (= 0) -W, wherein W is OH or Cl and R ₆ is as defined below; Forming a; And (c) cyclizing the compound of formula IIc in the presence of a base to provide a compound of formula V A method for producing a compound of formula (V) comprising a. <Formula Ia>

<Formula IIb>

<Formula IIc>

<Formula III>

<Formula V>

Where R ₁ and R ₃ are each independently hydrogen, halogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloal Kenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR _a , SR _a , S (= 0) R _e , S (= 0) ₂ R _e , P (= 0) ₂ R _e , S (= O) ₂ OR _e , P (= O) ₂ OR _e , NR _b R _c , NR _b S (= O) ₂ R _e , NR _b P (= O) ₂ R _e , S (= O) ₂ NR _b R _c , P (= O) ₂ NR _b R _c , C (= 0) OR _e , C (= 0) R _a , C (= 0) NR _b R _c , OC (= O) R _a , OC (= 0) NR _b R _c , NR _b C (= 0) OR _e , NR _d C (= 0) NR _b R _c , NR _d S (= 0) ₂ NR _b R _c , NR _d P (= 0) ₂ NR _b R _c , NR _b C (= 0) R _a or NR _b P (= 0) ₂ R _e ; X is -O-, -OC (= O)-, -S-, -S (= O)-, -S (= O) _2- , -C (= O)-, -C (= O) O -, -NR _d- , -NR _d C (= 0)-, -C (= 0) NR _d- , -NR _d C (= 0) NR _d- , -NR _d C (= 0) O-, -OC (= 0) NR _d- , -NR _d S (= 0) _2- , -NR _d S (= 0) ₂ NR _d- , -S (= 0) ₂ NR _d- , halogen, nitro, cya Furnace or bond; R ₂ is a) hydrogen, provided that X is -S (= 0)-, -SO _2- , -OC (= 0)-, -OC (= 0) NR _d -or -S (= 0) ₂ NR _{when d-} , R ₂ is not hydrogen); b) alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl; And c) is selected from heterocycle or substituted heterocycle, aryl or substituted aryl, and when X is halogen, nitro or cyano, then R ₂ is absent; R ₁ and R ₂ together may optionally form an optionally substituted 3-7 membered carbocyclic ring or an optionally substituted 3-7 membered heterocyclic ring; R ₆ is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl Or heterocycle or substituted heterocycle; R _a is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted Heterocycle or aryl or substituted aryl; R _b , R _c and R _d are each independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle or aryl or substituted aryl, wherein R _b and R _c are Optionally together with N to which they are attached form a heterocycle or a substituted heterocycle; R _e is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle Or aryl or substituted aryl; R ₄ is H, nitro, cyano, halogen, C ₁ -C ₄ alkyl, OMe or OEt; n is 1, 2 or 3. The method of claim 8, wherein the benzoyl hydroxyl amine of formula III is prepared by reacting a pharmaceutically acceptable salt of benzoyl hydroxyl amine with a base. The process of claim 8, wherein step (a) (i) reacting a compound of Formula Ia with a benzoyl hydroxyl amine and a base of Formula III to form a compound of Formula IIa; And (ii) further reacting a compound of formula (IIa) with a base to provide a compound of formula (IIb). <Formula Ia>

<Formula IIa>

<Formula IIb>

<Formula III>

Where R ₁ , X, R ₂ and R ₃ are as defined in claim 8, R ₄ is H, nitro, cyano, halogen, C ₁ -C ₄ alkyl, OMe or OEt, n is 1, 2 or 3. The method of claim 8, wherein R ₆ is H and W is OH. A process for preparing a compound of formula (IId) comprising reacting a compound of formula (Ib) with a benzoyl hydroxyl amine of formula (III) in the presence of a base to form a compound of formula (IId). <Formula Ib>

<Formula IId>

<Formula III>

Where R ₃ is hydrogen, halogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloal Kenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR _a , SR _a , S (= 0) R _e , S (= 0) ₂ R _e , P (= 0) ₂ R _e , S ( = O) ₂ OR _e , P (= O) ₂ OR _e , NR _b R _c , NR _b S (= O) ₂ R _e , NR _b P (= O) ₂ R _e , S (= O) ₂ NR _b R _c , P (= O) ₂ NR _b R _c , C (= O) OR _e , C (= O) R _a , C (= O) NR _b R _c , OC (= O) R _a , OC (= O) NR _b R _c , NR _b C (= 0) OR _e , NR _d C (= 0) NR _b R _c , NR _d S (= 0) ₂ NR _b R _c , NR _d P (= 0 ) ₂ NR _b R _c , NR _b C (= 0) R _a or NR _b P (= 0) ₂ R _e ; R ₅ is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl or heterocycle or substituted heterocycle; R ₇ and R ₈ are each independently hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, halogen, cyano, nitro, aryl or substituted aryl, heterocycle or substituted Heterocycle, 0R _a , SR _a or NR _b R _c ; R _p is alkyl or substituted alkyl or aryl or substituted aryl; R _a is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted Heterocycle or aryl or substituted aryl; R _b , R _c and R _d are each independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle or aryl or substituted aryl, wherein R _b and R _c are Optionally together with N to which they are attached form a heterocycle or a substituted heterocycle; R _e is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cyclo alkenyl, heterocycle or substituted heterocycle Or aryl or substituted aryl; R ₄ is H, nitro, cyano, halogen, C ₁ -C ₄ alkyl, OMe or OEt; n is 1, 2 or 3. 13. The process of claim 12, wherein the benzoyl hydroxyl amine of formula III is prepared by reacting a pharmaceutically acceptable salt of benzoyl hydroxyl amine with a base. 13. The process of claim 12, wherein the benzoyl hydroxyl amine of formula III is prepared by reacting a salt of formula IV with a base. <Formula IV>

Where R ₄ is H, nitro, cyano, halogen, C ₁ -C ₄ alkyl, OMe or OEt, n is 1, 2 or 3, Y is _{MeSO 3 -, EtSO 3 -,} 4-Me-PhSO 3 -,

4-NO ₂ -PhSO ₃ -CF ₃ SO _3- , -Cl, -H ₂ PO ₄ , -NO ₃ , -HSO ₄ , PhSO ₃ -or -Br. (a) reacting a compound of formula Ib with a benzoyl hydroxyl amine of formula III in the presence of a base to form a compound of formula IId; And (b) further reacting the compound of formula IId with an amide of formula R ₆ C (= 0) NH ₂ , wherein R ₆ is as defined below to form a compound of formula Va A method of preparing a compound of the following formula Va. <Formula Ib>

<Formula IId>

<Formula III>

<Formula Va>

Where R ₃ is hydrogen, halogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloal Kenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR _a , SR _a , S (= 0) R _e , S (= 0) ₂ R _e , P (= 0) ₂ R _e , S ( = O) ₂ OR _e , P (= O) ₂ OR _e , NR _b R _c , NR _b S (= O) ₂ R _e , NR _b P (= O) ₂ R _e , S (= O) ₂ NR _b R _c , P (= O) ₂ NR _b R _c , C (= O) OR _e , C (= O) R _a , C (= O) NR _b R _c , OC (= O) R _a , OC (= O) NR _b R _c , NR _b C (= 0) OR _e , NR _d C (= 0) NR _b R _c , NR _d S (= 0) ₂ NR _b R _c , NR _d P (= 0 ) ₂ NR _b R _c , NR _b C (= 0) R _a or NR _b P (= 0) ₂ R _e ; R ₅ is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl or heterocycle or substituted heterocycle; R ₆ is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl Or heterocycle or substituted heterocycle; R ₇ and R ₈ are each independently hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, halogen, cyano, nitro, aryl or substituted aryl, heterocycle or substituted Heterocycle, 0R _a , SR _a or NR _b R _c ; R _p is alkyl or substituted alkyl or aryl or substituted aryl; R _a is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted Heterocycle or aryl or substituted aryl; R _b , R _c and R _d are independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle or aryl or substituted aryl, wherein R _b and R _c are they Optionally forms a heterocycle or substituted heterocycle with N bonded; R _e is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle Or aryl or substituted aryl; R ₄ is H, nitro, cyano, halogen, C ₁ -C ₄ alkyl, OMe or OEt; n is 1, 2 or 3. The method of claim 15, wherein the benzoyl hydroxyl amine of formula III is prepared by reacting a pharmaceutically acceptable salt of benzoyl hydroxyl amine with a base. The method of claim 15, wherein the benzoyl hydroxyl amine of formula III is prepared by reacting a salt of formula IV with a base. <Formula IV>

Where R ₄ is H, nitro, cyano, halogen, C ₁ -C ₄ alkyl, OMe or OEt, n is 1, 2 or 3, Y is _{MeSO 3 -, EtSO 3 -,} 4-Me-PhSO 3 -,

4-NO ₂ -PhSO ₃ -CF ₃ SO _3- , -Cl, -H ₂ PO ₄ , -NO ₃ , -HSO ₄ , PhSO ₃ -or -Br. The method of claim 15, wherein R ₆ is H and R _p is Me or Et.