Matrix metalloproteinase inhibitors

1. A process for preparing a compound of Formula XX comprising:

a. reacting a compound of Formula LXVII

R 1 -hal  Formula LXVII

with a compound of Formula LXVIII

(OH) 2 B-Q-CHO  Formula LXVIII

to give a compound of Formula LXIX, carried out in the presence of a metal catalyst such as tetrakis(triphenylphosphine) palladium (0), tetrakis(tricyclohexylphosphine) palladium (0), tetrakis(tri-tert-butylphosphine) palladium (0), or palladium acetate and triphenylphosphine in the presence of a base such as potassium carbonate or cesium carbonate, and an organic solvent;

R 1 -Q-CHO  Formula LXIX

b. converting the compound of Formula LXIX to a compound of Formula LXX, carried out by reacting with phosphonate carbanions (produced in situ by treating trimethylphosphonoacetate or triethylphosphonoacetate with a base such as sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, triethylamine in an organic solvent;

c. hydrogenating the compound of Formula LXX to give a compound of Formula LXXI, carried with palladium on carbon in the presence of hydrogen, in a suitable solvent such as methanol, ethanol, propanol, tetrahydrofuran, ethyl acetate, or mixture(s) thereof;

d. reducing the compound of Formula LXXI to give a compound of Formula LXXII, carried out in the presence of a reducing agent such as lithium aluminum hydride, lithium triethyl borohydride, or sodium borohydride, in the presence of an additive such as lithium chloride or aluminum chloride, in an organic solvent;

e. oxidizing the compound of Formula LXXII to give a compound of Formula LXXIII, carried out using a Swern oxidation reaction (dimethylsulfoxide and oxalyl chloride) or Corey-Kim oxidation (N-chlorosuccinimide and dimethylsulfide) in the presence of a base such as triethylamine or diisopropylethylamine in a solvent such as dichloromethane or toluene, or is oxidized using dichloromethane or chloroform with an oxidizing agent such as a Dess-Martin reagent, pyridinium chlorochromate (PCC), or pyridinium dichromate (PDC), or the oxidation is carried out catalytically using 2,2,6,6,-tetramethylpiperidine N-oxyl (TEMPO) or 4-substituted derivatives such as 4-methoxy-TEMPO, 4-ethoxy-TEMPO, 4-acetoxy-TEMPO, 4-acetamino-TEMPO, 4-hydroxy-TEMPO, 4-benzoyloxy-TEMPO, 4-amino-TEMPO, N,N-dimethylamino-TEMPO, or 4-oxo-TEMPO as a catalyst, in the presence of a co-catalyst such as potassium bromide or sodium bromide, with an oxidant such as sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium hypobromite, or potassium hypobromite in a solvent or mixtures of solvent;

f. reacting the compound of Formula LXXIII with a compound of Formula LXXIV

to give a compound of Formula LXXV, carried out by generating the enolates with titanium chloride, dibutyl boron triflate, dialkyl boron chloride, or tin(II) triflate, in the presence of a base such as diisopropylethylamine, tetramethylethelenediamine, tributylamine, N-ethylpiperidine, 1,4-diazabicyclo[2.2.2]octane, 1,8-Diazabicyclo[5.4.0]undec-7-ene, tetramethylpropylenediamine, or (−) sparteine; and

g. hydrolyzing the compound of Formula LXXV to give a compound of Formula XX, carried out with hydrogen peroxide and lithium hydroxide, in the presence of a solvent or mixture(s) of solvents,

wherein

R 2 is a substituted or (un)substituted benzotriazinone wherein the substituents are halogen, alkyl or alkoxy;

E is an alkyl group;

hal is Cl, Br or I;

Q is an optionally substituted phenyl or heteroaryl wherein the optional substituents are alkyl or fluoro;

R 1 is, optionally substituted aryl, heterocyclyl, or heteroaryl, wherein the optional substituents are selected from one or more of alkyl, halogen, hydroxy, trifluoroalkyl, OCF 3 , SO 2 alkyl, or alkoxy;

Y and W are independently oxygen or sulphur; and

R 10 is alkyl, aryl, or aralkyl.

2. The process according to claim 1 wherein the compounds of Formula XX is selected from:

(2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic acid (Compound No. 86),

(2S,3R)-3-hydroxy-5-[4-(5-methylpyridin-2-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic acid (Compound No. 209),

(2S,3R)-5-[4-(6-fluoropyridin-3-yl)phenyl]-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic acid (Compound No. 210),

(2S,3R)-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic acid (Compound No. 214),

(2S,3R)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic acid (Compound No. 215),

(2S,3R)-5-(2′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic acid (Compound No. 216),

((2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic acid (Compound No. 217),

(2S,3R)-5-(3′-fluoro-4′-methoxybiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic acid (Compound No. 218),

(2S,3R)-3-hydroxy-5-[4-(2-methoxypyrimidin-5-yl)phenyl]-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic acid (Compound No. 219),

(2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic acid (Compound No. 220),

(2S,3R)-3-hydroxy-5-(4′-methylbiphenyl-4-yl)-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic acid (Compound No. 221),

(2S,3R)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]-5-[4′-(trifluoromethoxy)biphenyl-4-yl]pentanoic acid (Compound No. 222),

(2S,3R)-3-hydroxy-5-[4-(6-methylpyridin-3-yl)phenyl]-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic acid (Compound No. 223),

(2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic acid (Compound No. 224), and

(2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic acid (Compound No. 225).