SK2072003A3 - Process for making N-aryl-anthranilic acids and their derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of N-arylanthranilic acids, and a process for the preparation of N-aryl anthranilic esters, amides, and hydroxamic esters.

Description

The present invention relates to a process for the preparation of N-aryl-anthranilic acids which are valid (useful) pharmaceutical agents and are, for example, known anti-inflammatory agents. In addition, N-aryl-anthranilic acids can serve as intermediates in the preparation of N-aryl-anthranilic amides, Naryl-anthranilic hydroxamic acids, and esters of N-aryl-anthranilic hydroxamic acids. Some N-aryl-anthranilic hydroxamic acids and N-aryl-anthranilic hydroxamic acid esters inhibit certain kinases with dual specificity in diseases caused by cell proliferation, such as cancer and restenosis.

BACKGROUND OF THE INVENTION

Diseases caused by cellular proliferation are caused by a defect in the intracellular signaling system or signal transduction mechanism of certain proteins. For example, cancer is generally caused by a series of disorders in these signaling proteins, resulting in a change in either their intrinsic activity or their cellular concentrations. For example, a cell may produce a growth factor that binds to its own receptor, resulting in an autocrine loop that constantly stimulates cell proliferation. A mutation or disorder of expression of intracellular signaling proteins such as Ras may result in false mitogenic signals within the cell. Some of the most common mutations occur in genes encoding Ras, a G-protein that is in the activated state when it binds to GTP and in the inactivated state when it binds to GDP. Activation and inactivation of Ras is regulated in normal cells.

When the aforementioned growth factor receptors and many other mitogenic receptors are activated, this results in the Ras state being changed from GDP-bound to GTP-bound. This signal is considered an absolute prerequisite for cell proliferation in most cell types. Defects in this signaling system, particularly in the inactivation of the Ras-GTP complex, are a common feature of cancers and lead to a signaling cascade of Ras that is chronically activated.

Activation of Ras leads in turn to the activation of a cascade of serine / threonine kinases. One of the kinase families known to require active Ras-GTP for its own activation is the Raf family of kinases. Raf kinase activates mitogen-activated protein kinase ("MAP kinase" or "MAPK") / extracellular signal-regulated kinase ("ERK", also known as "MAP / ERK kinase" ("MEK"), which then activates at least one of Activation of MAP kinase by mitogens appears to be essential for cellular proliferation, and basic activation of these kinases is considered sufficient to induce cell transformation, blocking the Ras output signal, for example by using a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether it is induced by cell surface receptors or oncogenic Ras mutants.

Although Ras itself is not a protein kinase, it is involved in the activation of Raf and other kinases. This participation is most likely accomplished by a phosphorylation mechanism. For example, once Raf and other kinases are once activated, they are known to phosphorylate MEK to two closely adjacent serine residues, namely S ²¹⁸ and S ²²² in the case of MEK-1, which is a prerequisite for activation of MEK as a kinase. Phosphorylated MEK in return phosphorylates MAP kinase to tyrosine Y ¹⁸⁵ and threonine T ¹⁸³ . This double phosphorylation activates the MAP kinase and results in an activated MAP kinase catalyzing the phosphorylation of a large number of proteins, including several transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activating for a target protein, whether the target protein is another kinase transcription factor or a cellular protein.

MEK is also activated by several kinases other than Raf-1, including MEK itself, which appears to be a signal integrating kinase. To date, MEK is highly specific for MAP kinase phosphorylation. In fact, to date no substrate for MEK other than MAP kinase has been demonstrated and MEK does not phosphorylate peptides based on the sequence of phosphorylated MAP kinase or even denatured MAP kinase. It also appears that MEK is strongly associated with MAP kinase prior to its phosphorylation, suggesting that phosphorylation of MAP kinase MEK may require a prior strong interaction between the two proteins. This suggests that selective MEK inhibitors, acting by an allosteric mechanism rather than the usual blocking of the ATP binding site, may be valuable.

The present invention provides methods for preparing compounds that are highly specific inhibitors of the effects of MEK kinase. The compounds prepared by the methods of the invention inhibit phosphorylation of MAP kinase by MEK kinase at both enzyme and whole cell levels. Thus, they prevent MAP kinase activation in cells in which the Ras cascade has been activated. One result of this enzyme inhibition is the inversion of the transformed phenotype of certain cell types, measured both by the ability of the transformed cells to grow and the ability of the transformed cell lines to reproduce independently of external mitogens.

Thus, a process for the synthesis of N-aryl-anthranilic acids which results in higher yields and minimizes the consumption of aniline, often expensive, difficult to synthesize or difficult to remove (unreacted or excess aniline from the reaction mixture after reaction) of the starting material is highly desirable. Such a process would allow the successful production of N-aryl-anthranilic acids on an industrial scale.

The present invention unexpectedly provides high yielding methods for preparing N-aryl-anthranilic acids and derivatives thereof, comprising pairing about 1 mole of aniline with about 1 mole of orthohalobenzoic acid.

For example, against a mass act, the yield of a product provided by the process of the present invention is unexpectedly higher than the yield of a product prepared by a process that uses 2 moles of aniline. Furthermore, the process according to the invention allows the successful production of N-aryl-anthranilic acids and their derivatives on an industrial scale. These and other advantages of the present invention will be described more fully in the following.

SUMMARY OF THE INVENTION

One embodiment of the present invention is a process, hereinafter referred to as Process Arrangement 1, of synthesizing a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is hydrogen, alkyl, alkoxy or aryl;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from:

hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro,

CN,

- (O) _m - (CH ₂ ) _n -R ¹¹ or

- [N (H)] _m -CH 2) n R ^H , wherein m, on R ¹¹ are defined below or any two substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , which are attached to adjacent carbon atoms of the ring and may together form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom to which it is attached attached by R ¹ and the carbon atom to which R ⁶ is attached and the carbon atom adjacent to said nitrogen atom to which R ¹ is attached form a 5-membered or 6-membered aromatic or dihydrogenaromatic cycle containing carbon atoms and 1 or 2 nitrogen atoms ;

R ¹¹ is hydrogen, hydroxy, -CO ₂ H or N (R ¹² ) R ¹³ ,

R and R are independently hydrogen or alkyl, or R and R together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl;

m is 0 or 1;

n is 0, 1, 2, 3, 4;

Z is COOH, C00M, COOR ^15, C (O) R ^15, -C (O) N ^{(R16) R17,}

-C (O) N (R ¹⁸ ) OR ¹⁹ , NO ₂ or CN, wherein

M is an alkali metal or alkaline earth metal cation; and

R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and

R ^16, R ^17, R ¹⁸ and R ^1-9 are independently H, alkyl, alkenyl, phenyl and benzyl,

R and R together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl;

involving the reaction of a compound of formula (A)

wherein R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above with a compound of formula (B)

R ²

R ³ wherein Z, R ² , R ³ , R ⁴ and R ⁷ are as defined above and X is halogen or O-LG, wherein LG is SO ² R ²⁰ or P (-O) (OR ²⁰ ) 2, wherein R ²⁰ is alkyl or aryl, optionally in a solvent and in the presence of from about 1 mole to about 10 moles of a base, wherein the base is selected from: alkali metal or alkaline earth metal hydrides, including lithium, sodium, potassium and calcium hydrides, dialkylamide an alkali metal or alkaline earth metal dialkylamide including lithium diisopropylamide, an alkali metal or alkaline earth metal amide, including lithium amide, sodium amide, potassium amide, and an alkali metal or alkaline earth metal alkoxide, including sodium ethoxide, potassium tert-butoxide; of magnesium ethoxide at a time and temperature sufficient to provide a compound of formula I.

Another embodiment of the present invention is a process according to Embodiment I wherein the base is selected from: lithium diisopropylamide, lithium hydride, sodium hydride, potassium hydride, lithium amide, sodium amide, potassium amide, sodium methoxide, sodium ethoxide and potassium tert-butoxide.

Another embodiment of the present invention is a process according to Embodiment I wherein the base is selected from: lithium hydride, sodium hydride and potassium hydride.

A further embodiment of the present invention is a process according to Process I, wherein the base is lithium hydride.

Another embodiment of the present invention is a process of Process Embodiment I wherein the base is selected from: lithium amide, sodium amide and potassium amide.

A further embodiment of the present invention is a process according to Process Embodiment I wherein the base is lithium amide.

Another embodiment of the present invention is a process according to Process Embodiment I wherein the base is lithium diisopropylamide.

A further embodiment of the present invention is a process according to Process Embodiment I wherein the base is selected from: sodium methoxide, sodium ethoxide and potassium tert-butoxide.

Another embodiment of the invention is a method of the Method

Embodiment I in which an equivalent of 1 to 5 moles of base is used initially and optionally an equivalent of 0.5 to 4 moles of base is added to the reaction over time either in a single dose and / or sequentially in the same or different doses in the same or different time intervals.

A further embodiment of the invention is a process according to Process I, wherein said equivalent of 0.5 to 4 moles of base is added to the reaction mixture gradually in unequal decreasing amounts.

Another embodiment of the present invention is a Process of Embodiment I wherein in the compound of formula (B) Z is COOH and the initial amount of base is equivalent to 2 moles or Z is COOM and the initial amount of base is equivalent to 1 mol and said equivalent is 0.5 to 4 moles base is added to the reaction mixture gradually in unequal decreasing amounts as follows: about 0.5 mole equivalent, sequentially followed by about 0.25 mole equivalent, about 0.13 mole, about 0.06 mole, and optionally followed by about 0.03 mole equivalent followed by an equivalent of about 0.015 mol.

Another embodiment of the present invention is a process according to Process Embodiment I wherein R ¹ is hydrogen.

Another embodiment of the present invention is a process according to Method I of Embodiment I wherein X is fluoro.

Another embodiment of the present invention is a method according to Embodiment I wherein X is O-LG, wherein LG is SO 2 CF 3 or P (= O) (OCH ₂ CH ₃ ) ₂ .

Another embodiment of the invention is a process according to Embodiment I wherein X is O-LG, wherein LG is SO ₂ CF ₃ or P (= O) (OCH ₂ CH ₃ ) ₂ further comprising an organopalladium catalyst.

Another embodiment of the present invention is a process according to Embodiment I wherein R ² , R ³ , R ⁴ and R ⁵ are independently selected from hydrogen, alkoxy, fluorine, chlorine, bromine and iodine.

Another embodiment of the present invention is a process according to Embodiment I wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from hydrogen, alkyl, fluorine, chlorine, bromine and iodine.

Another embodiment of the present invention is a method according to Method I, wherein Z is COOH or COOM.

Another embodiment of the invention is a process according to Embodiment I wherein R ¹ is hydrogen, X is fluoro, R 2, R ³ , R ⁴ and R ⁵ are independently selected from hydrogen, alkoxy, fluorine, chlorine, bromine and iodine R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from hydrogen, methyl, fluorine, chlorine, bromine and iodine and Z is COOH or COOM.

Another embodiment of the present invention is a Process of Embodiment I wherein a solvent comprising acetonitrile, tetrahydrofuran, 1,2-diethoxyethane, 2,2-dimethoxypropane, 1,2-dimethoxypropane, diethyl ether, dioxane, or methyl tert-butyl ether is present. .

A further embodiment of the present invention is a process according to Process Embodiment I wherein a solvent comprising tetrahydrofuran or acetonitrile is present.

Another embodiment of the invention is a method of the Method

Embodiment I wherein a solvent comprising a mixture of from about one volume of acetonitrile and about one volume of tetrahydrofuran to about five volumes of acetonitrile and about one volume of tetrahydrofuran is present.

Another embodiment of the present invention is a process according to Process I, wherein at the time of base addition, the temperature of the reaction mixture is from -78 ° C to 150 ° C.

Another embodiment of the present invention is a Process of Embodiment I Method or any of the embodiments of Embodiment I Method above wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a Process of Embodiment I Method or any of the embodiments of Embodiment I Method mentioned above, except immediately preceding, wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Embodiment I wherein the compound of Formula I is a compound of Formula Ia

1a, or a pharmaceutically acceptable salt thereof, wherein

R ⁶ is halogen or methyl, R ⁸ is bromo or iodo and Z is COOH, COOM, COOR ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ , -C (O) N (R ¹⁸ ) R ¹⁹ , NO ₂ or CN, wherein

M is an alkali or alkaline earth metal,

R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or

R 1 and R 2 together with the nitrogen atom to which they are attached form a 3- to R 3 atom

A 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl.

in

Another embodiment of the invention is a method of the Method

Embodiment I wherein the compound of Formula I is a compound of Formula Ib

Ib, or a pharmaceutically acceptable salt thereof, wherein

R ⁶ is halogen or methyl, R ⁸ is bromine or iodine and Z is COOH, COOM, COOR ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ , -C (O) N (R ¹⁸ ) R ¹⁹ , NO ₂ or CN, where

M is an alkali or alkaline earth metal,

R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl;

R and R together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl.

Another embodiment of the present invention is a process according to Embodiment I wherein the compound of Formula I is a compound of Formula Icl

br

F

Icl or a pharmaceutically acceptable salt thereof in which

R ⁶ is halogen or methyl, R ⁸ is bromo or iodo and Z is COOH, COOM, COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ , -C (O) N ( R ⁱ⁸⁾ R ^19, NO ₂ or CN, wherein

M is an alkali or alkaline earth metal,

R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl, or

R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3 to 3 ring

A 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl.

Another embodiment of the invention is a method of the Method

Embodiment I wherein the compound of Formula I is a compound of Formula Ic2

Cl

F

Ic2 or a pharmaceutically acceptable salt thereof, wherein

R ⁶ is halogen or methyl, R ⁸ is bromo or iodo and Z is COOH, COOM,

COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ , -C (O) N (R ¹⁸ ) OR ¹⁹ , NO ₂ or CN, wherein

M is an alkali or alkaline earth metal,

R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or

R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl .

Another embodiment of the present invention is a process according to Process Embodiment I wherein the compound of Formula I is a compound of Formula Id

F

Id, or a pharmaceutically acceptable salt thereof, wherein

R ⁶ is halogen or methyl, R ⁸ is bromo or iodo and Z is COOH, COOM, COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ , -C (O) N ( R ¹⁸ ) R ¹⁹ , NO ₂ or CN, where M is an alkali or alkaline earth metal,

R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or

R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl .

A further embodiment of the present invention is a process according to Process Embodiment I wherein the compound of Formula I is a compound of Formula

C1 or a pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a process according to Process Embodiment I wherein the compound of Formula I is a compound of Formula

Cl CH ₃

Another embodiment of the invention is a method of the Method

Embodiment I wherein the compound of formula I is a compound of formula or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Embodiment I wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Embodiment I wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Embodiment I wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Embodiment I wherein the compound of Formula I is a compound of Formula

CO ₂ H

C1 or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Embodiment I wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is a process, hereinafter referred to as Embodiment 1A, for the synthesis of a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is hydrogen, alkyl, alkoxy or aryl;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro .

CN,

- (O) _m - (CH ₂ ) _n -R ¹¹ or

- [N (H)] _m - (CH 2) _n -R ¹¹ , wherein m, on R ¹¹ are defined below or any two substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , which are attached to an adjacent cycle of carbon atoms and may be taken together to form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom, to which R ¹ and the carbon atom to which R ⁶ is attached and the carbon atom adjacent to said nitrogen atom to which R ¹ and said carbon atom to which R ⁶ is attached form a 5-membered or 6-membered member are attached; an aromatic or dihydrogenaromatic cycle containing carbon atoms and 1 or 2 nitrogen atoms;

R ¹¹ is hydrogen, hydroxy, -CO 2 H or N (R ¹² ) R ¹³ ,

R ¹² and R ¹³ are each independently hydrogen or alkyl or R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O , S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl;

m is 0 or 1;

n is 0, 1, 2, 3, 4;

Z is COOH, COOM, COOR ^15, C (O) R ^15, -C (O) N ^{(R16) R17,}

-C (O) N (R ¹⁸ ) OR ¹⁹ , NO ₂ or CN, wherein

M is an alkali metal or alkaline earth metal cation and R ¹⁵ is alkyl, alkenyl, alkynyl, aryl or heterocyclic group and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently hydrogen, alkyl, alkenyl, phenyl and benzyl;

R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form

A 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl;

involving the reaction of a compound of formula (A)

wherein R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above with a compound of formula (B)

wherein Z is COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ , -C (O) N (R ¹⁸ ) OR ¹⁹ , NO 2 or CN, and R ² -R ^5, and R ¹⁵ -R ¹⁹ are as defined above and X is halogen or O-LG, wherein LG is SO ₂ R ²⁰ or P (= O) (OR ²⁰ ) ₂ , wherein R ²⁰ is alkyl or aryl, optionally in a solvent and in the presence of from about 1 mole to about 10 moles of a base, said base selected from: an alkali metal bis (trialkylsilyl) amide or an alkaline earth bis (trialkylsilyl) amide, including lithium bis (trialkylsilyl) amide, sodium bis (trialkylsilyl) amide, bis potassium (trialkylsilyl) amide over a period of time and at a temperature sufficient to provide a compound of Formula I.

Another embodiment of the present invention is a process according to Embodiment IA wherein the base is selected from: lithium bis (trialkylsilyl) amide, sodium bis (trialkylsilyl) amide and potassium bis (trialkylsilyl) amide.

Another embodiment of the present invention is a process according to Method IA, wherein the base is selected from: lithium bis (trialkylsilyl) amide.

Another embodiment of the present invention is a Process according to the Arrangement Method IA wherein the equivalent of 1 to 5 moles of base is used initially and optionally the equivalent of 0.5 to 4 moles of base is added to the reaction over time, either in a single dose and / or sequentially at the same or different doses at the same or different time intervals.

A further embodiment of the present invention is a process according to Method IA, wherein said equivalent of 0.5 to 4 moles of base is added to the reaction mixture gradually in unequal decreasing amounts.

Another embodiment of the present invention is a process according to Method IA, wherein R ¹ is hydrogen.

Another embodiment of the present invention is a method according to Method IA, wherein X is fluorine.

Another embodiment of the invention is a method according to Embodiment Method IA wherein X is O-LG, wherein LG is SO 2 CF 3 or P (= O) (OCH ₂ CH ₃ ) 2.

Another embodiment of the present invention is a process according to Embodiment Method IA wherein X is O-LG, wherein LG is SO ₂ CF 3 or P (= O) (OCH ₂ CH ₃ ) ₂ further comprising an organopalladium catalyst.

Another embodiment of the invention is a method of the Method

Arrangements IA wherein R ² , R ³ , R ⁴ and R ⁵ are independently selected from hydrogen, alkoxy, fluorine, chlorine, bromine and iodine.

Another embodiment of the present invention is a method according to Method T T S Q 1 Λ

Arrangements IA wherein R, R, R, R, and R are independently selected from hydrogen, alkyl, fluorine, chlorine, bromine and iodine.

Another embodiment of the invention is a process according to Embodiment Method IA wherein Z is -C (O) N (R ¹⁸ ) OR ¹⁹ , wherein R ¹⁸ and R ¹⁹ are independently hydrogen, alkyl, alkenyl, phenyl, and benzyl.

Another embodiment of the present invention is a process according to Embodiment IA wherein R ¹ is hydrogen, X is fluoro, R ² , R ³ , R ⁴ and R ⁵ are independently selected from hydrogen, alkoxy, fluoro, chloro, bromo, and bromo; iodine, R ⁶ , R, R, R and R are independently selected from hydrogen, alkyl, fluorine, chlorine, bromine and iodine and Z is -C (O) N (R ¹⁸ ) OR ¹⁹ , wherein R ¹⁸ and R ^{18 19} are independently hydrogen, alkyl, alkenyl, phenyl and benzyl.

Another embodiment of the present invention is the Process of Embodiment IA wherein a solvent comprising acetonitrile, tetrahydrofuran, 1,2-diethoxyethane, 2,2-dimethoxypropane, 1,2-dimethoxypropane, diethyl ether, dioxane or methyl tert-butyl ether is present.

in

Another embodiment of the present invention is a process according to Method IA, wherein a solvent comprising tetrahydrofuran or acetonitrile is present.

Another embodiment of the present invention is a Process of Embodiment IA wherein a solvent is present containing a mixture of from about one volume of acetonitrile and about one volume of tetrahydrofuran to about five volumes of acetonitrile and about one volume of tetrahydrofuran.

A further embodiment of the present invention is a process according to Method IA, wherein at the time of base addition, the temperature of the reaction mixture is from -78 ° C to 150 ° C.

Another embodiment of the present invention is a method according to the Method of Arrangement IA or any of the embodiments according to the Method of Arrangement IA shown above, wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Embodiments IA wherein the compound of Formula I is a compound of Formula Ia

1a, or a pharmaceutically acceptable salt thereof, wherein

R ⁶ is halogen or methyl, R ⁸ is bromo or iodo and Z is COOH, COOM, COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ , -C (O) N ( R ¹⁸ ) R ¹⁹ , NO ₂ or CN, where

M is an alkali metal or alkaline earth metal cation,

R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or

R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl.

Another embodiment of the invention is a method of the Method

Embodiments IA wherein the compound of Formula I is a compound of Formula Ib

Ib, or a pharmaceutically acceptable salt thereof, wherein

R ⁶ is halogen or methyl, R ⁸ is bromo or iodo and Z is COOH, COOM, COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ , -C (O) N (R ¹⁸ ) R ¹⁹ , NO ₂ or CN, where

M is an alkali metal or alkaline earth metal cation,

R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or

R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form 3 to 3 carbon atoms

A 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl.

Another embodiment of the invention is a method of the Method

Embodiments IA wherein the compound of Formula I is a compound of Formula Icl

Icl or a pharmaceutically acceptable salt thereof in which

R ⁶ is halogen or methyl, R ⁸ is bromo or iodo and Z is COOH, COOM, COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ , -C (O) N ( R ¹⁸ ) R ¹⁹ , NO ₂ or CN, where

M is an alkali metal or alkaline earth metal cation,

R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or

R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl.

Another embodiment of the invention is a method of the Method

Embodiment IA wherein the compound of Formula I is a compound of Formula Ic2

or a pharmaceutically acceptable salt thereof, wherein

R ⁶ is halogen or methyl, R ⁸ is bromo or iodo and Z is COOH, COOM, COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ , -C (O) N ( R ¹⁸ ) R ¹⁹ , NO ₂ or CN, where

M is an alkali metal or alkaline earth metal cation,

R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or

Z 5

R 1 and R 2 together with the nitrogen atom to which they are attached form 3 to 3

A 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl.

Another embodiment of the invention is a method of the Method

Embodiments IA wherein the compound of Formula I is a compound of Formula Id1

Id1, or a pharmaceutically acceptable salt thereof, wherein

R ⁶ is halogen or methyl, R ⁸ is bromo or iodo and Z is COOH, COOM, COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ , -C (O) N ( R ¹⁸ ) R ¹⁹ , NO ₂ or CN, where

M is an alkali metal or alkaline earth metal cation,

R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or

R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl.

Another embodiment of the present invention is a Process of Embodiment IA, further comprising the hydrolysis of a compound of Formula I wherein Z is COOR ¹⁵ and R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group to form a compound of Formula Id2

Id2 or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is hydrogen, alkyl, alkoxy or aryl;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro .

CN,

- (O) _m - (CH ₂ ) _n -R ¹¹ or

- [N (H)] _m -CH ₂ ) _n -R ¹¹ , wherein m, on R ¹¹ are defined below or any two substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , which are attached to adjacent carbon atoms of the ring and may together form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom, to which R ¹ and the carbon atom to which R ⁶ is attached and the carbon atom adjacent to said nitrogen atom to which R ¹ is attached form a 5-membered or 6-membered aromatic or dihydrogenaromatic ring containing carbon atoms and 1 or 2 nitrogen atoms;

R ¹¹ is hydrogen, hydroxy, -CO ₂ H or N (R ¹² ) R ¹³ ,

R ¹² and R ¹³ are independently hydrogen or alkyl, or R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O , S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl;

m is 0 or 1;

n is 0, 1,2, 3,4.

This method is referred to below as Alignment Method 1A1.

Another embodiment of the present invention is a method according to the Method of Arrangement IA or any of the above embodiments as a method according to the Method of Arrangement IA wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Arrangements IA1 wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Arrangements IA1 wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Arrangements IA1 wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Arrangements IA1 wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Arrangements IA1 wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Arrangements IA1 wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Arrangements IA1 wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Arrangements IA1 wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a method of the Method

Arrangements IA1 wherein the compound of Formula I is a compound of Formula

CO ₂ H

or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a method, hereinafter referred to as Method of Embodiment 2, of synthesizing a compound of formula Ie

Ie, or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is hydrogen, alkyl, alkoxy or aryl;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro .

CN,

- (O) _m - (CH ₂ ) _n -R ¹¹ or

- [N (H)] _m -CH 2) n R ¹¹ , wherein m, on R ¹¹ are defined below or any two substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , which are attached to adjacent carbon atoms of the ring and may together form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom to which it is attached attached by R ¹ and the carbon atom to which R ⁶ is attached and the carbon atom adjacent to said nitrogen atom to which R ¹ is attached form a 5-membered or 6-membered aromatic or dihydrogenaromatic cycle containing carbon atoms and 1 or 2 nitrogen atoms ;

R ¹¹ is hydrogen, hydroxy, -CO 2 H or N (R ¹² ) R ¹³ ;

R and R are independently hydrogen or alkyl or R and R together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl;

m is 0 or 1;

n is 0, 1, 2, 3, 4;

Z is COOR ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ or -C (O) N (R ¹⁸ ) OR ¹⁹ , wherein

R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl and benzyl; or

R and R together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl;

comprising pairing a compound of formula If

wherein Z is COOH or C00M, wherein M is an alkali or alkaline earth metal cation and R ¹ , R ² -R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above or when Z is C00M, R ¹ is optionally an alkali metal or alkaline earth metal cation with a compound of formula II

HOR ¹⁵ II, wherein R ¹³ is as defined above, or a pharmaceutically acceptable salt thereof, or a compound of formula III

HN (R ¹⁶ ) R ¹⁷ III, wherein R ¹⁶ and R ¹⁷ are as defined above, or a pharmaceutically acceptable salt thereof, or with a compound of formula IV

HN (R ¹⁸ ) OR ¹⁹ IV, wherein R ¹⁸ and R ¹⁹ is as defined above, or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is the method of Embodiment 2 wherein R ¹⁸ is hydrogen and R ¹⁹ is selected from methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, 2-methyl-prop-1-yl 1,1-dimethyl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2 -yl, 1-methylcyclopropyl, 2-methylcyclopropyl, 1-methylcyclobutyl, 2-methylcyclobutyl, 3-methylcyclobutyl, 1-methylcyclopentyl, 2-methylcyclopentyl, 3-methylcyclopentyl, 1-methylcyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 4-methylcyclohexyl , cyclopropylmethyl, cyclopropyldifluoromethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl and benzyl.

Another embodiment of the present invention is a process according to Process Embodiment 2 wherein R ¹⁸ is hydrogen and R ¹⁹ is cyclopropylmethyl.

Another embodiment of the present invention is a method according to Method Embodiment 2 or any of the above embodiments as a method according to Method Embodiment 2 wherein the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is Process of Embodiment 2 wherein R ¹⁶ is hydrogen and R ¹⁷ is cyclopropylmethyl, 2-cyclopropylmethyl, cyclobutylmethyl, 2-cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylmethyl, cyclopropyldifluoromethyl cyclopropyl-l, l-difluoroethyl.

Another embodiment of the present invention is a process, hereinafter referred to as Method of Embodiment 2a, of synthesizing a compound of Formula Ig

or a pharmaceutically acceptable salt or compound Ih thereof

or a pharmaceutically acceptable salt or compound Ii thereof

or a pharmaceutically acceptable salt thereof, wherein:

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro .

CN,

- (O) _m - (CH ₂ ) _n -R ^H or

- [N (H)] _m -CH ₂ ) _n -R ¹¹ wherein m, on R ¹¹ are as defined below or any two substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , which are bonded to adjacent carbon atoms of the ring and may together form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms;

R ¹¹ is hydrogen, hydroxy, -CO ₂ H or N (R ¹² ) R ¹³ ,

R ¹² and R ¹³ independently of one another are hydrogen or alkyl, or R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ where R ¹⁴ is hydrogen or alkyl;

m is 0 or 1;

n is 0, 1, 2, 3, 4;

R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently hydrogen, alkyl, alkenyl, phenyl and benzyl;

R 1 and R 2 together with the nitrogen atom to which they are attached form 3 to 3

A 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or an alkyl comprising the reaction of an acid selected from trifluoroacetic acid, trichloroacetic acid, inorganic acid, alkylsulfonic acid or arylsulfonic acid with a compound of formula Ij

Wherein R ² -R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above,

M and M ^a are independently an alkali metal or alkaline earth metal cation, adding the carboxylic acid activating agent to the reaction mixture of step (a) and reacting at a time and temperature sufficient to form the corresponding activated carboxylic acid intermediates and adding, optionally in the presence of an equivalent up to 10 moles of a tertiary organic amine, a reactant selected from:

compounds of formula II

HOR ¹⁵ II, wherein R ¹⁵ is as defined above, or a pharmaceutically acceptable salt thereof, or from a compound of Formula III

HN (R ¹⁶ ) R ¹⁷ III, wherein R ¹⁶ and R ¹⁷ is as defined above, or a pharmaceutically acceptable salt thereof, or from a compound of formula IV

HN (R ¹⁸ ) OR ¹⁹ IV, wherein R ¹⁸ and R ¹⁹ is as defined above, or a pharmaceutically acceptable salt thereof, and a reaction at a time and temperature sufficient to prepare a compound of Formula Ig or Ih or Ii.

Another embodiment of the present invention is a process according to Method 2a, wherein M ^a is selected from lithium cation, sodium cation and potassium cation.

Another embodiment of the present invention is a method according to Method 2a, wherein M ^α is a lithium cation.

Another embodiment of the invention is a method of the Method

Embodiment 2a wherein the acid used in step (a) is trifluoroacetic acid, trichloroacetic acid, an inorganic acid selected from HCl, HBr or

H2SO4, an alkylsulfonic acid selected from CH3SO3H and CF3SO3H, or an arylsulfonic acid selected from phenyl-SC4H and para-toluenesulfonic acid.

Another embodiment of the present invention is a process according to Process Embodiment 2a wherein the acid used in step (a) is CH 3 SO 3 H.

Another embodiment of the present invention is a process according to Embodiment 2a wherein the carboxylic acid activating agent used in step (b) is selected from: (COCl) 2, S (O) Cl ₂ , S (O) ₂ C12 ₅ P (O C13, (phenyl) 2P (= O) Cl, 1,1'-carbonyldiimidazole, triphenylphosphine diethylazocarboxylate, EDC, EDCI and Ν, Ν'-dicyclohexylcarbodiimide.

Another embodiment of the present invention is a process according to Process Embodiment 2a wherein the carboxylic acid activating agent used in step (b) is S (O) C ₁₂ .

Another embodiment of the present invention is a process according to Process Embodiment 2a wherein the carboxylic acid activating agent used in step (b) is (phenyl) 2 P (= O) Cl.

Another embodiment of the present invention is the Process of Embodiment 2a or any of the above embodiments as the Process of Embodiment 2a wherein the reactant added in step (c) is O-cyclopropylmethyl-hydroxylamine or a pharmaceutically acceptable acid addition salt thereof.

Another embodiment of the present invention is a method of Method 2a or any of the above embodiments as a method of Method 2a wherein the compound of formula I is a compound of formula

or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a process, hereinafter referred to as Process 3, of the synthesis of a compound of formula Ik

Ik or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is hydrogen, alkyl, alkoxy or aryl;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro .

CN,

- (O) _m - (CH ₂ ) n R ^H or

- [N (H)] _m -CH ₂ ) _n -R ¹¹ , wherein m, on R ¹¹ are defined below or any two substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , which are attached to adjacent carbon atoms of the ring and may together form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom, to which R ¹ and the carbon atom to which R ⁶ is attached and the carbon atom adjacent to said nitrogen atom to which R ¹ is attached form a 5-membered or 6-membered aromatic or dihydrogenaromatic ring containing carbon atoms and 1 or 2 nitrogen atoms;

R ¹¹ is hydrogen, hydroxy, -CO ₂ H or N (R ¹² ) R ¹³ ,

R and R are independently hydrogen or alkyl or R and R together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl;

m is 0 or 1;

n is 0, 1, 2, 3, 4;

Z is COOR ¹⁵ wherein R ¹⁵ is -alkyl, alkenyl, alkynyl, aryl or heterocyclic;

comprising pairing a compound of formula If

wherein Z is COOH or COOM, wherein M is an alkali or alkaline earth metal cation and R ¹ , R ² -R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above or when Z is COOM, R ¹ is optionally an alkali metal or alkaline earth metal cation, with a compound of formula II

HOR ¹⁵ II, wherein R ¹⁵ is as defined above, or a pharmaceutically acceptable salt thereof, or a compound of formula IIa

LR ¹⁵ 11a, or a pharmaceutically acceptable salt thereof, wherein R ¹⁵ is as defined above and L is a group selected from bromine, chlorine, iodine, alkylsulfonyloxy, arylsulfonyloxy, acyloxy, optionally in the presence of a nucleophilic base.

Another embodiment of the present invention is a process, hereinafter referred to as Method of Arrangement 4, of synthesizing a compound of Formula I

I or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is hydrogen, alkyl, alkoxy or aryl;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro .

CN,

- (O) _m - (CH ₂ ) _n -R ^H or

- [N (H)] _m -CH ₂ ) n R ¹¹ , wherein m, on R ¹¹ are defined below or any two substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , which are attached to adjacent carbon atoms of the ring and may together form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom to which they are attached is attached by R ¹ and the carbon atom to which R ⁶ is attached and the carbon atom adjacent to said nitrogen atom to which R ¹ is attached form a 5-membered or 6-membered aromatic or dihydrogenaromatic cycle containing carbon atoms and 1 or 2 atoms N;

R ¹¹ is hydrogen, hydroxy, -CO ₂ H or N (R ¹² ) R ¹³ ,

R and R are independently hydrogen or alkyl or R and R together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl;

m is 0 or 1;

n is 0, 1, 2, 3, 4;

Z is COOH, C00M, COOR ^15, C (O) R ^15, -C (O) N ^{(R16) R17,}

-C (O) N (R ¹⁸ ) OR ¹⁹ , NO ₂ or CN, wherein

M is an alkali metal or alkaline earth metal cation; and

R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently hydrogen, alkyl, alkenyl, phenyl and benzyl;

R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form

A 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl; including:

(a) a step of reacting a compound of formula (A)

(A) wherein R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above, with a compound of formula (B)

R ²

R ³ (B) wherein Z, R ² , R ³ , R ⁴ and R ⁵ are as defined above, X is halogen or O-LG, wherein LG is SO ² R ²⁰ or P (= O) (OR ²⁰ ) 2, wherein R ²⁰ is alkyl or aryl, in the presence of from about 1 mole equivalent to about 10 moles of a base selected from:

alkali metal hydride or alkaline earth metal hydride including lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal dialkylamide or alkaline earth metal dialkylamide including lithium diisopropylamide, alkali metal amide or alkaline earth metal amide, including lithium amide, sodium amide and potassium amide, alkali metal alkoxide or alkaline earth metal alkoxide including sodium ethoxide, potassium tert-butoxide and magnesium ethoxide at a temperature and for a time sufficient to give the compound of Formula I and (b) purifying the compound of Formula I resulting from step (a).

Another embodiment of the present invention is a process, hereinafter referred to as Process 5, of the synthesis of a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is hydrogen, alkyl, alkoxy or aryl;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro .

CN,

- (O) _m - (CH ₂ ) _n -R ¹¹ or

- [N (H)] _m -CH 2) _n -R ^n> m wherein, the R ¹¹ are as defined below, or any two substituents selected from R ^2, R ^3, R ^4, R ^5, R ^6, R ^7, R ⁸ , R ⁹ and R ¹⁰ , which are bonded to adjacent carbon atoms of the ring and may be taken together to form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom; to which R ¹ is attached and the carbon atom to which R ⁶ is attached and the carbon atom adjacent to said nitrogen atom to which R ¹ is attached form a 5-membered or

A 6-membered aromatic or dihydrogenaromatic cycle containing carbon atoms and 1 or 2 nitrogen atoms;

R ¹¹ is hydrogen, hydroxy, -CO ₂ H or N (R ¹² ) R ¹³ ,

O T q 1 O I o

R and R are independently hydrogen or alkyl or R and R together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl;

m is 0 or 1;

n is 0, 1, 2, 3, 4;

Z is COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ ,

-C (O) N (R ¹⁸ ) OR ¹⁹ , NO ₂ or CN, wherein

R ¹⁵ is alkyl, alkenyl. alkynyl, aryl or heterocyclic group; and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ independently of one another are hydrogen, alkyl, alkenyl, phenyl and benzyl or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl;

including:

(a) a step of reacting a compound of formula (A)

(A) wherein R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above, with a compound of formula (B)

R ²

R ³ (B) wherein Z, R ² , R ³ , R ⁴ and R ⁵ are as defined above, X is halogen or O-LG, wherein LG is SO ² R ²⁰ or P (= O) (OR ²⁰ ) 2, wherein R ²⁰ is alkyl or aryl, in the presence of from about 1 mole equivalent to about 10 moles of base, wherein the base is an alkali metal bis (trialkylsilyl) amide or an alkaline earth bis (trialkylsilyl) amide, including lithium bis (trialkylsilyl) amide, bis ( trialkylsilyl) sodium amide, potassium bis (trialkylsilyl) amide at a temperature and for a time sufficient to give a compound of formula I; and (b) purifying the compound of formula I formed in step (a).

Another embodiment of the present invention is a process, hereinafter referred to as Process 6 of the Synthesis of Compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is hydrogen, alkyl, alkoxy or aryl;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro .

CN,

- (O) _m - (CH ₂ ) _n -R ^H or

- [N (H)] _m -CH ₂ ) n R ¹¹ , wherein m, on R ¹¹ are defined below or any two substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , which are attached to adjacent carbon atoms of the ring and may together form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom to which they are attached is attached by R ¹ and the carbon atom to which R ⁶ is attached and the carbon atom adjacent to said nitrogen atom to which R ¹ is attached form a 5-membered or 6-membered aromatic or dihydrogenaromatic cycle containing carbon atoms and 1 or 2 atoms N;

R ¹¹ is hydrogen, hydroxy, -CO ₂ H or N (R ¹² ) R ¹³ ,

R ¹² and R ¹³ independently of one another are hydrogen or alkyl, or R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ where R ¹⁴ is hydrogen or alkyl;

m is 0 or 1;

n is 0, 1, 2, 3, 4;

Z is COOH or COOM;

involving the reaction of a compound of formula (A)

(A) wherein R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above, with a compound of formula (B)

R ²

R ³ (B) wherein Z, R ² , R ³ , R ⁴ and R ⁵ are as defined above, X is halogen or O-LG, wherein LG is SO ² R ²⁰ or P (= O) (OR ²⁰ ) 2, wherein R ²⁰ is alkyl or aryl, optionally in a solvent and in the presence of from about 1 mole equivalent to about 10 moles of base, wherein the base is an alkali metal bis (trialkylsilyl) amide or an alkaline earth bis (trialkylsilyl) amide, including lithium bis (trialkylsilyl) amide sodium bis (trialkylsilyl) amide, potassium bis (trialkylsilyl) amide, at a temperature and for a time sufficient to produce a compound of formula I.

Another embodiment of the present invention is a method, hereinafter referred to as Arrangement Method 7, wherein the method itself is a method according to any of the Arrangement Methods 1, IA, 2, 3, 4, 5 or 6, wherein the method is implemented on an industrial scale.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods for the synthesis of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and Z are as defined above. .

As used herein, the term "alkyl" means (i) a straight or branched hydrocarbon chain containing from 1 to 20 carbon atoms, (ii) a cyclic hydrocarbon group containing from 3 to 20 carbon atoms is also known as a "cycloalkyl" group, (iii) a cyclic hydrocarbon group attached to a straight or branched hydrocarbon chain, also known as a "cycloalkyl-alkylene" group containing a total of 4 to 20 carbon atoms and the term alkylene as defined below; and (iv) an alkyl group attached to a cyclic alkylene is also known as An "alkyl-cycloalkylene" group containing a total of 4 to 20 carbon atoms and wherein the term cycloalkylene is defined below. The alkyl groups may be unsubstituted or substituted by 1 to 4 substituents as described below. Preferred straight or branched chain alkyl groups have from 1 to 8 carbon atoms. Preferred cycloalkyl groups have from 3 to 8 carbon atoms. Other preferred alkyl groups have from 4 to 8 carbon atoms. C 1 -C 6 alkyl means a straight or branched hydrocarbon chain having from 1 to 6 carbon atoms. C 3 -C 6 cycloalkyl means a cyclic hydrocarbon group having from 3 to 6 carbon atoms. Typical examples of straight or branched unsubstituted alkyl groups are methyl, ethyl, 1-propyl,

2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl,

2,2-dimethylpropyl, 1-hexyl, 1-heptyl, 4-heptyl, 2-octyl, 2-methyl-hept-2-yl, 1-nonyl, 1-decyl, 1-undecyl, 1-dodecyl, 2- dodecyl, 2,4-dimethyldecyl, 2- (1-methylethyl) -1-nonyl, 2-hexadecyl and 1-tetradecyl. Illustrative examples of unsubstituted cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclohexadecyl and cyclotetradecyl. Illustrative examples of cycloalkyl-alkylene groups are cyclopropylmethyl, 3-cyclopentylhexyl and 2-cyclopentyldecyl. Illustrative examples of alkylcycloalkylene groups are 1-methylcyclopropyl, 3-hexylcyclopentyl and 2 (dec-3-yl) -cyclopentyl. Substituted alkyls are described and described below.

The term "alkenyl" means a straight or branched hydrocarbon chain having one or two unsaturated bonds having 2 to 20 carbon atoms or a cyclic hydrocarbon group having one unsaturation having 3 to 20 carbon atoms, also known as a "cycloalkenyl" group. Alkenyl groups may be unsubstituted or substituted with from 1 to 4 substituents as described above. Preferred straight or branched chain alkenyl groups have 2 to 8 carbon atoms. Preferred cycloalkenyl groups have 5 to 8 carbon atoms. Typical examples of straight or branched chain alkenyl groups are ethenyl, 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1-buten-3-yl, 1-butadienyl, 2-pentene 2-yl, 1-hexen-6-yl, 1-hepten-3-yl, 3-hepten-1-yl, 2-octen-6-yl, 2-methylhept-2-en-4-yl -nonen _{1 '} 8-yl, 1-decen-1-yl, 1-undecen-5-yl,

CH ₃ - (CH ₂ ) 10 -C (H) = C (H) -C (H) = C (H) - and 2,4-dimethyl-2-decen-1-yl.

Illustrative examples of unsubstituted cycloalkenyl groups are 1-cyclopropenyl, 2-cyclobutenyl, 2-cyclopentenyl, 4-cyclohexenyl, 1-cycloheptenyl, 5-cyclooctenyl, 5-cyclononenyl and 5-cyclotetradecenyl. Substituted alkenyls are described and described below.

The term "alkynyl" means a straight or branched hydrocarbon chain having one or two unsaturated bonds having 2 to 20 carbon atoms or a cyclic hydrocarbon group having one unsaturation having 12 to 20 carbon atoms, also known as a "cycloalkynyl" group. Alkynyl groups may be unsubstituted or substituted with from 1 to 4 substituents as described below. Preferred straight or branched chain alkenyl groups have 2 to 8 carbon atoms. Preferred cycloalkynyl groups have 12 to 14 carbon atoms. Typical examples of straight or branched alkynyl chains are ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 2-propyn-1-yl, 1-butin-3-yl, 1-butadiinyl, 2-pentin-5 -yl, 1-hexin-6-yl, 1-heptin-3-yl, 3-heptin-1-yl, 2-octin-6-yl, hept-2-yn-4-yl, and 4,4-dimethyl 2-yne-l-yl. An exemplary unsubstituted cycloalkynyl group is 6-cyclotetradecinyl. Substituted alkynyls are described and described below.

It will be appreciated that double unsaturated straight or branched alkenyl and alkynyl groups may have a C = C or C = C second unsaturation.

The term "alkoxy" refers to an alkyl group bonded through an oxygen atom, alkyl-Ο-, wherein alkyl is unsubstituted alkoxy groups cyclopropyloxy, cyclopentyloxy as defined above. Exemplary examples are methoxy, isopropoxy, 2-hexyloxy, and cyclohexyloxy. Exemplary substituted alkoxy groups are set forth below.

The term "acyl" ozna_čuje R _y -C (O) R wherein _R is H, alkyl, alkenyl, alkynyl, all of the definitions given above, or aryl (including heteroaryl) as defined below. Exemplary examples are acetyl, benzoyl, 2-thienylcarbonyl and cyclopentylcarbonyl. Exemplary substituted acyls include hydroxyacetyl, 3,5-dichloro-4-nitrobenzoyl, (2-methylphenyl) propylcarbonyl, and 3-hydroxycyclopentylcarbonyl.

The term "acyloxy" refers to a R _y -C (O) -O-, wherein R _y is H, alkyl, alkenyl, alkynyl, all of the definitions given above, or aryl (including heteroaryl) as defined below. Exemplary examples are acetyloxy, benzoyloxy, 2-thienylcarbonyloxy and cyclopentylcarbonyloxy. Exemplary substituted acyloxy groups are hydroxyacetyloxy, trifluoroacetyloxy, 3,5-dichloro-4-nitrobenzoyloxy, (2-methylphenyl) propylcarbonyloxy and 3-hydroxycyclopentylcarbonyloxy.

The term "haloalkyl" refers to a halogen attached to an alkylene, which is a haloalkylene group, wherein halo and alkylene are defined below.

The terms "halo" and "halogen" are used interchangeably to mean fluorine, chlorine, bromine or iodine.

The terms "hydroxamic ester" and "hydroxamic acid ester" are synonymous and refer to a hydroxamic acid substituted on an oxygen atom attached to a nitrogen atom by the substituents described above for the group R ¹⁹ .

The term "alkylene" denotes a divalent straight or branched chain hydrocarbon group having from 1 to 20 carbon atoms or a divalent cyclic hydrocarbon group having from 3 to 20 carbon atoms. The groups may be unsubstituted or substituted by 1 to 4 substituents. Exemplary unsubstituted alkylene groups include -CH ₂ -> -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -, -C (CH ₃ ) ₂ -CH ₂ -C (H) CH ₃ - (CH ₂ ) ₁₂ -,

-CH (CH ₃₎ CH ₂ CH ₂ -, 1,4-cyclobutylene, 1,3-cyclohexylene and 1,2-cykloheptadecylén. Exemplary substituted alkylenes are given below.

The term "alkylsulfonic acid" refers to an alkyl group attached to an SO ₃ H group, also known as an alkyl-SO ₃ H group, wherein alkyl is unsubstituted alkyl as defined above. Exemplary unsubstituted alkylsulfonic acids are CH ₃ SO ₃ H, ethanesulfonic acid, tert-butylsulfonic acid and cyclohexylsulfonic acid.

Examples of fluorine substituted alkylsulfonic acids are CH2FSO3H,

CF ₂ HSO ₃ H, CF ₃ SO ₃ H and CH ₃ CF ₂ SO ₃ H.

The term "arylsulfonic acid" refers to an aryl group attached to an SO ₃ H group, also known as an aryl-SO ₃ H group, wherein aryl is unsubstituted aryl or aryl substituted with halogen or alkyl, wherein halogen and alkyl are as defined above.

The term "alkylsulfonyloxy" refers to an alkyl group attached to an SO 3 group, also known as an alkyl-SO _{3 group} , wherein alkyl is unsubstituted alkyl as defined above or substituted by fluorine. Exemplary unsubstituted groups are CH 3 SO 3, ethanesulfonate, tert-butylsulfonate, and cyclohexylsulfonate. Examples of fluoro-substituted groups are CH 2 FSO 3, CF 2 HSO 3, CF 3 SO 3 and CH 3 CF 2 SO 3.

The term "arylsulfonyloxy" refers to an aryl group attached to an SO 3 group, also known as an aryl-SO _{3 group} , wherein aryl is unsubstituted aryl as defined above or substituted with halogen.

As described above, alkyl, alkenyl, alkynyl, alkoxy and acyl may be substituted with from 1 to 4 substituents. The substituents are independently selected from:

phenyl, phenyl substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl, halogen, OH, O-C 1 -C 6 alkyl, 1,2-methylenedioxy, CN, NO 2, N ₃ , NH 2, N (H) CH 3, N (CH ₃ ) 2, C (O) CH ₃ , OC (O) -C 1 -C ₆ alkyl, C (O) -H, CO ₂ H, CO ₂ (C 1 -C ₆ alkyl) C (O) N (H) OH, C (O) NH ₂ , C (O) NHMe, C (O) N (Me) ₂ , NHC (O) CH ₃ , N (H) C (O) NH ₂ , SH, S-C 6 -C 6 alkyl, OCH, C (= NOH) -H, C (= NOH) -CH ₃ , CH ₂ OH, CH ₂ NH ₂ , CH ₂ N (H) CH ₃ , CH ₂ N (CH ₃ ) 2, C (H) F-OH, CF ₂ -oh, S (O) ₂ NH ₂ , S (O) ₂ N (H) CH ₃ , S (O) ₂ N (CH ₃ ) 2, S (O) -CH ₃ , S (O) ₂ CH ₃ , S (O) ₂ CF ₃ or NHS (O) ₂ CH ₃ , benzyl, benzyl substituted with 1 to 3 substituents selected from oxo (on methylene carbon only), C 1 -C 6 alkyl, halogen, OH, O-C 1 -C 6 alkyl, 1,2-methylenedioxy, CN, NO ₂ , N ₃ , NH ₂ , N (H) CH ₃ , N (CH ₃ ) ₂ , C (O) CH ₃ , OC (O) -C ₆ C ₆ alkyl, C (O) -H, CO ₂ H, CO ₂ - (C 1 -C ₆ alkyl), C (O) -N (H) OH, C (O) NH ₂ , C (O) NHMe, C (O) N (Me) ₂ , NHC (O) CH ₃ , N (H) C (O) NH ₂ , SH, C 1 -C ₆ alkyl, C-CH, C (= NOH) -H, C (= NOH) -CH ₃ , CH ₂ OH, CH ₂ NH ₂ , CH ₂ N (H) CH ₃ , CH ₂ N (CH ₃ ) ₂ , C (H) F-OH, CF ₂ -OH, S (O) ₂ NH ₂ , S (O) ₂ N (H) CH ₃ , S (O) ₂ N (CH ₃ ) ₂ , S ( O) -CH ₃ , S (O) ₂ CH ₃ , S (O) ₂ CF ₃ or NHS (O) ₂ CH ₃ , heteroaryl wherein heteroaryl is as defined below, heterocyclic group wherein the heterocyclic group is as defined below, oxo,

OR _z , wherein R _z is hydrogen, C 1 -C 6 alkyl, C ₃ -C 6 cycloalkyl, phenyl or benzyl, wherein the phenyl or benzyl may be substituted with 1 to 3 substituents as described below,

SR _z , wherein R _z is hydrogen, C 1 -C 6 alkyl, C ₃ -C 6 cycloalkyl, phenyl or benzyl, wherein the phenyl or benzyl may be substituted with 1 to 4 substituents as described below,

C (O) -R _z , wherein R _z is hydrogen, C 1 -C 6 alkyl, C ₃ -C 6 cycloalkyl, phenyl or benzyl, wherein the phenyl or benzyl may be substituted with 1 to 4 substituents as described below,

CO ₂ R _z , wherein R _z is hydrogen, C 1 -C 6 alkyl, C ₃ -C 6 cycloalkyl, phenyl or benzyl, wherein the phenyl or benzyl may be substituted with 1 to 4 substituents as described below,

C (O) -N (H) OR _z , wherein R _z is hydrogen, C 1 -C 6 alkyl, C ₃ -C 6 cycloalkyl, phenyl or benzyl,

C (= NOR _Z ) -H, wherein R _z is hydrogen, C 1 -C 6 alkyl, C ₃ -C 6 cycloalkyl, phenyl or benzyl,

C (= NOR _Z ) -CH ₃ , wherein R _z is hydrogen, C 1 -C 6 alkyl, C ₃ -C 8 cycloalkyl, phenyl or benzyl,

C (H) F-OH, CF ₂ -oh,

OC (O) -R _Z , wherein R _z is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or benzyl, wherein the phenyl or benzyl may be substituted with 1 to 4 substituents as described below,

C (O) -N (R _z ) R _y , wherein R _z and R _y are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or benzyl, wherein the phenyl or benzyl may be substituted with 1 to 4 substituents as described below or R ₂ and R _y together with the nitrogen atom to which they are attached form a 5-membered saturated heterocycle containing 1 nitrogen and 4 carbon atoms or a 6-membered saturated heterocycle of formula (Z), wherein (Z) ) is defined above,

N (R _z ) R _y , wherein R _z and R _y are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or benzyl, wherein the phenyl or benzyl may be substituted with 1 to 4 substituents as described below or R _z and R _y together with the nitrogen atom to which they are attached form

A 5-membered saturated heterocycle containing 1 nitrogen and 4 carbon atoms or a 6-membered saturated heterocycle of formula (Z), wherein (Z) is as defined above,

N (R _z ) -C (O) -R _y , wherein R _z and R _y are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or benzyl, wherein the phenyl or benzyl may be substituted with 1 to 4 substituents as described below,

N (H) -C (O) -N (R _z ) R _y , wherein R _z and R _y are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or benzyl, wherein the phenyl or benzyl may be substituted with 1 to 4 substituents as described below, or R ₂ and R _y together with the nitrogen atom to which they are attached form a 5-membered saturated heterocycle containing 1 nitrogen and 4 carbon atoms or a 6-membered saturated heterocycle of formula (Z) ), where (Z) is as defined above,

N (H) -C (O) -OR _Z , wherein R _z is independently hydrogen, C 1 -C 6 alkyl, C ₃ -C 6 cycloalkyl, phenyl or benzyl, wherein the phenyl or benzyl may be substituted with 1 to 4 substituents as described further,

OC (O) -N (R _z ) R _y , wherein R _z and R _y are independently hydrogen, C 1 -C 6 alkyl,

C 3 -C 6 cycloalkyl, phenyl or benzyl, wherein phenyl or benzyl may be substituted with 1 to 4 substituents as described below or R ₂ and R ₂ together with the nitrogen atom to which they are attached form a 5-membered saturated heterocycle containing 1 a nitrogen atom and 4 carbon atoms or a 6-membered saturated heterocycle of formula (Z), wherein (Z) is as defined above,

NO ₂ , n ₃

N (H) -C (NR _x ) -N (R _z ) R _y , wherein R _z and R _y are independently hydrogen, C 1 -C 6 alkyl, C ₃ -C 6 cycloalkyl, phenyl or benzyl, wherein phenyl or benzyl may be substituted with 1 to 4 substituents as described below or R ₂ and R _y together with the nitrogen atom to which they are attached form a 5-membered saturated heterocycle containing 1 nitrogen and 4 carbon atoms or a 6-membered saturated heterocycle of the formula (Z) wherein (Z) is as defined above and R _x is hydrogen, hydroxy, methoxy or CN,

CN, halogen,

S (O) - (C 1 -C ₆ alkyl),

S (O) ₂ - (C 1 -C ₆ alkyl),

S (O) ₂ -N (R _z ) R _y , wherein R _z and R _y are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or benzyl, wherein the phenyl or benzyl may be substituted with 1 to 4 or R _z and R _y together with the nitrogen atom to which they are attached form a 5-membered saturated heterocycle containing 1 nitrogen and 4 carbon atoms or a 6-membered saturated heterocycle of formula (Z), wherein ( Z) is as defined above and

N (H) -S (O) ₂ - (C 1 -C ₆ alkyl);

with the exception that alkenyl or alkynyl are not substituted by oxo on unsaturated carbon atoms.

Exemplary substituted straight or branched chain alkyl groups are CH 2 OH, CF 2 OH, CH 2 C (CH 3) 2 CO 2 CH 3, CF 3,

C (O) CF ₃ , C (O) CH _3j (CH ₂ ) 4 -S-CH ₃ , CH (CO ₂ H) CH ₂ CH ₂ C (O) NMe 2, (CH ₂ ) ₅ NHC (O) -NH ₂ , CH ₂ -CH ₂ -C (H) - (4-fluorophenyl), CH (OCH 3) CH ₂ CH ₃ , (CH ₂ ) ₉ (morpholin-4-yl), CH ₂ SO ₂ NH ₂ and CH (CH ₃ ) CH ₂ CH ₂ OC (O) CH 3.

Exemplary substituted cycloalkyl groups are 1-hydroxy-cyclopropyl, cyclobutanone-3-yl, 3- (3-phenylureido) -cyclopent-1-yl, 4-carboxycyclohexyl and 9-trifluoromethylcyclodecanyl. Exemplary substituted cycloalkyl-alkylene groups are cyclopropyldifluoromethyl,

2-cyclopropyl-1,1-difluoroethyl, cyclopropyl (methyl) methyl, 3-cyclopentyl-2-oxohexyl and 2-cyclopentyl-1,1,1-trifluorodecyl. Exemplary substituted alkyl-cycloalkylene groups are 1-trifluoromethylcyclopropyl, 3-hexyl-1-hydroxycyclopentyl and 2- (2-cyano-dec-3-yl) cyclopentyl.

Substituted alkyls are described and illustrated below.

Exemplary substituted straight or branched alkenyl chains are C (H) = C (H) CH 2 OH, CH = CF 2,

CH ₂ C (H) = C (H) - (CH ₂ ) ₂ CF ₂ OH, CH ₂ C (-CH ₂ ) CO ₂ CH ₃ , C (H) = (CH) -CF ₃ , CH ₂ -CH 2 -C ( H) = C (H) -C (O) -CH ₃ , C (H) = C (CH ₃ ) -S-CH ₃ ,

C (H) = C (H) -C (H) = C (CH ₃ ) -CO ₂ Me, (CH ₂ ) i ₂ -C (H) = C (H) -C (H) = C (H) ) phenyl,

CH ₃ -C = C-CH ₂ -CH 2 -C (H) = C (H) - and C (H) = C = C (H) OC (O) CH ₃ .

Exemplary substituted cycloalkenyl groups include 1-hydroxycyclopropenyl, 3-oxo-cyclobuten-1-yl and 9-trifluoromethylcyclodecen-1-yl.

Exemplary substituted straight or branched alkynyl chain chains are C = CCH ₂ OH, C = CF, CH 2 C = C- (CH _{2) 2} CF ₂ OH, OC-CF 3, CH ₂ -CH ₂ -C = CC (O) -CH ₃ , OC- CH 2 -S-CH 3, OC (CH ₂₎ 8-C0 ₂ Me, (CH ₂₎ i2 -C = C-phenyl, C ₃ -C C-CH ₂ -CH ₂ -C (H) = C (H ) - and OC-CH ₂ OC (O) CH ₃ .

Exemplary substituted cycloalkynyl groups include

4-trifluoromethyl-cyklododecyn-4-yl.

Exemplary substituted alkoxy groups include trifluoromethoxy, 2-carboxy-isopropoxy, 3-oxo-2-hexyloxy, (±) -2-methyl-cyclopropyloxy, (±) -3-amino-cyclopentyloxy and 1-cyano-cyclohexyloxy.

Exemplary substituted alkylenes include hydroxymethylene, 2-dimethylaminobutylene, 2-fluoro-2-hexyl-propylene, and 2,4-cyclobutanediyl.

The term "aryl" refers to phenyl, substituted phenyl, 1-naphthyl, substituted 1-naphthyl, 2-naphthyl, substituted 2-naphthyl or heteroaryl, wherein heteroaryl is as defined below. Substituted phenyl, substituted

1-naphthyl and substituted 2-naphthyl are substituted with 1 to 4 substituents described below. Exemplary substituted phenyl, substituted 1-naphthyl and substituted 2-naphthyl are given below.

The term "heteroaryl" refers to a 5-membered, monocyclic heteroaryl,

A 6-membered monocyclic heteroaryl or a 9- or 10-membered bicyclic heteroaryl as defined below and may be unsubstituted or substituted as defined below.

The term "5-membered, monocyclic heteroaryl" refers to an unsubstituted or substituted 5-membered, monocyclic, aromatic group containing carbon atoms and 1 to 4 heteroatoms selected from N, O and S, provided that O or S heteroatoms are not present as one. Exemplary unsubstituted 5-membered monocyclic heteroaryl groups include thiophen-2-yl, furan-2-yl, pyrrol-3-yl, pyrrol-1-yl, imidazol-4-yl, isoxazol-3-yl, oxazol-2- yl, thiazol-4-yl, tetrazol-1-yl, 1,2,4, -oxadiazol-3-yl,

1,2,4-triazol-1-yl and pyrazol-3-yl. A substituted 5-membered monocyclic heteroaryl is described below.

The term "6-membered, monocyclic heteroaryl" refers to an unsubstituted or substituted 6-membered, monocyclic, aromatic group containing carbon atoms and 1 to 2 nitrogen atoms. Exemplary unsubstituted 6-membered monocyclic heteroaryl include pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyridazin-4-yl and pyrazin-2-yl. A substituted 6-membered, monocyclic heteroaryl is described below.

The term "9- or 10-membered, fused-bicyclic heteroaryl" refers to an unsubstituted or substituted, 9-membered or 10-membered, fused bicyclic aromatic group containing carbon atoms and 1-4 heteroatoms selected from N, O and S, with the proviso wherein the O or S heteroatoms are not more than two, and furthermore, when two are present, they are not bound to each other. Exemplary examples of unsubstituted 9- or 10-membered fused bicyclic heteroaryl include indol-2-yl, indol-6-yl, isoindol-2-yl, benzimidazol-2-yl, benzimidazol-1-yl, benzotriazol-1-yl, benzotriazol-5-yl, quinolin-2-yl, isoquinolin-7-yl, benzopyrimidin-2-yl, benzoxazol-2-yl, benzothiophen-5-yl and benzofuran-3-yl. A substituted 9- or 10-membered, bicyclic heteroaryl is described below.

The term "substituted, 5-membered, monocyclic heteroaryl" refers to

A 5-membered monocyclic, aromatic group containing carbon atoms and 1 to 4 heteroatoms selected from N, O and S, which is substituted with 1 or 2 substituents as defined below, provided that no more than one oxygen or sulfur heteroatom is present and further that no substituent is bonded to an oxygen or sulfur atom. Exemplary substituted, five-membered, monocyclic heteroaryl are set forth below.

The term "substituted, 6-membered, monocyclic heteroaryl" refers to

A 6-membered, monocyclic, aromatic group containing carbon atoms and 1 or 2 nitrogen atoms which is substituted with 1 or 2 substituents defined below, provided that no substituent is attached to the nitrogen atom. Exemplary substituted, 6-membered, monocyclic heteroaryl are provided below.

The term "substituted 9- or 10-membered, fused bicyclic heteroaryl" refers to a 9-membered or 10-membered, fused bicyclic aromatic group containing carbon atoms and 1 to 4 heteroatoms selected from N, O and S, substituted with 1 to 3 substituents defined further, provided that the O or S heteroatoms are not more than two present; and further, when two are present, they are not bound to each other. Exemplary unsubstituted 9- or 10-membered, fused bicyclic heteroaryl are set forth below.

The term "heterocyclic group" refers, unless otherwise indicated, to heteroaryl wherein heteroaryl is as defined above or a saturated or partially saturated 3- to 14-membered, monocyclic, bicyclic or tricyclic ring containing carbon atoms and 1 to 5 heteroatoms selected from N, O and S. This ring may be unsubstituted or substituted as defined below. The nitrogen atom (s) in the ring may be unprotected or protected by suitable nitrogen protecting groups. Preferred is a 5-membered, monocyclic heterocycloalkyl, a 6-membered monocyclic heterocycloalkyl or a 9- or 10-membered linked bicyclic heterocycloalkyl, which may be unsubstituted or substituted as described below. Examples of suitable heterocyclic groups include unsubstituted or substituted acridinyl, aziridinyl, benzathiolinyl, benzimidazolyl, benzofuranyl, imidazolyl, ind-indolyl, ΙΗ-indazolyl, isoindolyl, isoquinolinyl, isothiazolyl, N-methylpiperazinyl, morpholinyl, oxadiazyl, oxadiazyl, oxazolyl, oxadiazyl, oxazolyl, oxadiazyl phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperidinyl, piperazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinil, pyrimidinil, pyrrolyl, pyrrolidinil, quinazolinyl, quinalinyl, quinoxalinyl, thiazolyl, 1,3,4-thiadiazolyl, thi thiaziazolyl, thiiazolyl, 3,5-triazinyl, 1,2,3-triazolyl and the like.

The term "5-membered, monocyclic heterocycloalkyl" refers to a 5-membered, monocyclic non-aromatic group containing carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur and any 1 double bond, optionally substituted with 1 to 2 substituents defined below, with the proviso wherein the O and / or S heteroatoms are not more than two, and further, when two heteroatoms are present, they are not bound to each other. Preferred 5-membered, monocyclic heterocycloalkyl groups contain no double bond. Exemplary unsubstituted, 5-membered, monocyclic heteroalkyls include 2,3-dihydrofuran-2-yl, tetrahydrofuran-3-yl and tetrahydroimidazol-1-yl. Substituted 5-membered, monocyclic heterocycloalkyls are listed and described below.

The term "6-membered, monocyclic heterocycloalkyl" refers to a 6-membered, monocyclic non-aromatic group containing carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur and any 1 double bond, optionally substituted with 1 to 2 substituents defined below, with the proviso wherein the O and / or S heteroatoms are not more than two, and further, when two O and / or S heteroatoms are present, they are not bound to each other. Preferred 6-membered, monocyclic heterocycloalkyl groups contain no double bond. Exemplary unsubstituted, 6-membered, monocyclic heterocycloalkyls include 1,2,5,6-tetrahydropyridin-2-yl, piperidin-4-yl, piperazin-1-yl, morpholin-1-yl, and thiomorpholine-

2-yl.

The term "9- or 10-membered, fused bicyclic heterocycloalkyl" refers to a 9- or 10-membered, fused bicyclic group containing carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the first cycle is 5- or 6 a membered aromatic ring containing carbon atoms and 0 to 2 heteroatoms selected from nitrogen, oxygen and sulfur, and the second cycle is a 5- or 6-membered non-aromatic ring containing carbon atoms and 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, and wherein the first and second cycles are joined by sharing one double bond (i.e., the second cycle is dihydroaromatic) and optionally substituted with 1 to 3 substituents defined below, provided that the O and / or S heteroatoms are not present for more than three and beyond, if present two or three O and / or S heteroatoms are not attached to each other. Preferred 9- or 10-membered, fused bicyclic heterocycloalkyl groups have a 6-membered ring fused to a 5-membered ring. Exemplary unsubstituted 9- or 10-membered fused bicyclic heterocycloalkyl are 2,3-dihydrobenzofuran-2-yl and 2,3-dihydroindol-5-yl.

Substituents for substituted aryl, which is as defined above, substituted phenyl, substituted 1-naphthyl and substituted 2-naphthyl, for substituted heteroaryl, which, as above, is substituted 5-membered, monocyclic heteroaryl, substituted 6-membered, monocyclic heteroaryl or substituted 9- or 10-membered fused bicyclic heteroaryl or substituted heterocycloalkyl, as defined above, means substituted 5-membered, monocyclic heterocycloalkyl, substituted 6-membered, monocyclic heterocycloalkyl or substituted 9- or 10-membered, fused, bicyclic heterocycloalkyl, are independently selected from:

C 1 -C 6 alkyl,

C ₂ -C 6 alkenyl,

C2-C6 alkynyl,

C 3 -C 6 cycloalkyl, phenyl, phenyl substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl, halogen, OH, O-C 1 -C 6 alkyl, 1,2-methylenedioxy, CN, NO ₂ , N ₃ , NH ₂ , N ( H) CH ₃ , N (CH ₃ ) ₂ , C (O) CH ₃ , OC (O) -C 1 -C 6 alkyl, C (O) -H, CO ₂ H, CO ₂ - (C 1 -C ₆ alkyl) , C (O) -N (H) OH, C (O) _NH2, C (O) NHMe, C (O) N (Me) _2, NHC (O) CH _3, (NHC (O) CH _3, N (H) C (O) NH ₂ , SH, C 1 -C 6 alkyl, C 1 CH, C (= NOH) -H, C (= NOH) -CH ₃ , CH ₂ OH, CH 2 NH 2, CH ₂ N (H) CH ₃ , CH ₂ N (H) CH ₃ , CH ₂ N (CH ₃ ) ₂ ,

C (H) F-OH, CF ₂ -OH, S (O) ₂ NH ₂ , S (O) ₂ N (H) CH ₃ , S (O) ₂ N (CH ₃ ) ₂ , S (O) - CH ₃ , S (O) ₂ CH ₃ , S (O) ₂ CF ₃ or NHS (O) ₂ CH ₃ , benzyl, benzyl substituted with 1 to 3 substituents selected from oxo (on methylene carbon only), C 1 -C 6 alkyl, halogen, OH, O-C 1 -C 6 alkyl,

1,2-methylenedioxy, CN, NO ₂ , N ₃ , NH ₂ , N (H) CH ₃ , N (CH ₃ ) ₂ , C (O) CH ₃ , OC (O) -C 1 -C ₆ alkyl, C (O) -H, CO ₂ H, CO ₂ - (C 1 -C ₆ alkyl), C (O) -N (H) OH, C (O) NH ₂ , C (O) NHMe, C (O) N (Me) _2, NHC (O) CH _3, (NHC (O) _CH3, N (H) C (O) _NH2, SH,

S-C 1 -C 6 alkyl, OCH, C (= NOH) -H, C (= NOH) -CH ₃ , CH ₂ OH, CH ₂ NH ₂ , CH ₂ N (H) CH ₃ , CH ₂ N (H) CH ₃ , CH ₂ N (CH ₃ ) ₂ , C (H) F-OH, CF ₂ -OH, S (O) ₂ NH ₂ , S (O) ₂ N (H) CH ₃ , S (O) ₂ N (CH ₃ ) ₂ , S (O) -CH ₃ , S (O) ₂ CH ₃ , S (O) ₂ CF _3, or NHS (O) ₂ CH ₃ , (CH ₂ ) ₂ . ₄ - (phenyl), _{(CH2) 2} .4- (substituted phenyl) wherein phenyl is substituted as defined immediately above,

OR _z , where R _z is hydrogen, C 1 -C 6 alkyl, phenyl or benzyl,

SR _z , wherein R _z is hydrogen, C 1 -C 6 alkyl, phenyl or benzyl,

1,2-methylenedioxy,

C (O) -R _Z , where R _z is hydrogen, C 1 -C 6 alkyl, phenyl or benzyl, CO ₂ R _z , wherein R _z is hydrogen, C 1 -C 6 alkyl, phenyl or benzyl, C (O) -N ( H) OR _Z wherein R _z is hydrogen, C 1 -C 6 alkyl, phenyl or benzyl, C (= NOR _Z ) -H, where R _z is hydrogen, C 1 -C 6 alkyl, phenyl or benzyl, C (= NOR _Z ) -CH ₃ , where R _z is hydrogen, C 1 -C 6 alkyl, phenyl or benzyl, CH ₂ OR _z , where R _z is hydrogen, C 1 -C 6 alkyl, phenyl or benzyl, CH ₂ N (R _z ) R _y , wherein R ₂ and R _y are independently hydrogen, C 1 -C 6 alkyl, phenyl or benzyl, or together with the nitrogen atom to which they are attached form a 5-membered, saturated heterocycle with one nitrogen and 4 carbon atoms or a 6-membered, saturated heterocycle of formula (Z), wherein (Z) is as defined above,

C (H) F-OH,

CF 2 -OH,

OC (O) -R _Z , wherein R _z is hydrogen, C 1 -C 8 alkyl, phenyl or benzyl, CO-N (R _z ) R _y , wherein R _z and R _y are independently hydrogen, C 1 -C 8 alkyl, phenyl or benzyl or together with the nitrogen atom to which they are attached form a 5-membered, saturated heterocycle with one nitrogen and 4 carbon atoms or a 6-membered, saturated heterocycle of formula (Z), wherein (Z) is as defined above,

N (R _z ) R _y , wherein R _z and R _y are independently hydrogen, C 1 -C 8 alkyl, phenyl or benzyl, or together with the nitrogen atom to which they are attached form a 5-membered, saturated heterocycle with one nitrogen atom and 4 or a 6-membered, saturated heterocycle of formula (Z), wherein (Z) is as defined above,

N (R 2) -C (O) -R y, wherein R _z and R _y are independently hydrogen, C 1 -C 8 alkyl, phenyl or benzyl,

N (H) -C (O) -N (R _z ) R _y , wherein R _z and R _y are independently hydrogen, C 1 -C 8 alkyl, phenyl or benzyl, or R 2 and R y together with the nitrogen atom to which they are attached form attached, 5-membered, saturated heterocycle with one nitrogen and 4 carbon atoms, or a 6-membered, saturated heterocycle of formula (Z) wherein (Z) is as defined above, N (H) -C (O) -OR 2, wherein R 2 is independently hydrogen, C 1 -C 8 alkyl, phenyl or benzyl,

N (H) -S (O ₂ ) - (C 1 -C ₆ alkyl),

OC (O) -N (R _z ) R _y , where R _z and R _y are independently hydrogen, C 1 -C 8 alkyl, phenyl or benzyl, or together with the nitrogen atom to which they are attached form a 5-membered, saturated heterocycle with one nitrogen and 4 carbon atoms or a 6-membered, saturated heterocycle of formula (Z), wherein (Z) is as defined above,

NO ₂ , n ₃

N (H) -C (NR _x ) -N (R _z ) R _y , wherein R _z and R _y are independently hydrogen, C 1 -C 8 alkyl, phenyl or benzyl, or together with the nitrogen atom to which they are attached form 5 - a membered, saturated heterocycle of one nitrogen and 4 carbon atoms or a 6-membered, saturated heterocycle of formula (Z), wherein (Z) is as defined above and R _x is hydrogen, hydroxy, methoxy or CN,

CN, halogen,

SCOXQ-C6 alkyl),

(COOH-C 1 -C 6 alkyl),

S (O) 2 -N (R _z ) - (R _y ), wherein R _z and R _y are independently hydrogen, C 1 -C 6 alkyl, phenyl or benzyl, or together with the nitrogen atom to which they are attached form a 5-membered , a saturated heterocycle of one nitrogen and 4 carbon atoms or a 6-membered, saturated heterocycle of formula (Z), wherein (Z) is as defined above, and

S (O) ₂ CF ₃ .

Preferred substituents for substituted aryl and preferred substituents on carbon atoms for substituted, 5-membered, monocyclic heteroaryl, substituted, 6-membered, monocyclic heteroaryl, substituted, 9- or 10-membered, linked bicyclic heteroaryl, substituted, 5-membered, monocyclic heterocycloaryl, substituted, 6-membered, monocyclic heterocycloaryl and substituted, 9- or 10-membered, bicyclic heterocycloaryl are C 1 -C 6 alkyl, halogen, OH, O-C 1 -C 6 alkyl, 1,2-methylenedioxy, CN, NO ₂ , N ₃ , NH ₂ , N (H) CH ₃ , N (CH ₃ ) ₂ , C (O) CH ₃ , OC (O) C _1-6 alkyl), C (O) -N (H) OH, C ( O) NH ₂ , C (O) NHMe, C (O) N (Me) ₂ , NHC (O) CH ₃ , N (H) C (O) NH ₂ , SH, S-C 1 -C 6 alkyl, C 1-6 CH, C (= NOH) -H, C (= NOH) -CH ₃ , CH ₂ OH, CH ₂ NH ₂ , CH ₂ N (H) CH ₃ , CH ₂ N (CH ₃ ) ₂ , C (H) F-OH, CF ₂ -OH,

S (O) ₂ NH ₂ , S (O) ₂ N (H) CH ₃ , S (O) ₂ N (CH ₃ ) ₂ , S (O) -CH ₃ , S (O) ₂ CH ₃ , S ( O) ₂ CF ₃ or NHS (O) ₂ CH ₃ .

Further, as noted above, substituted 5-membered, monocyclic heteroaryl, substituted 9- or 10-membered, fused bicyclic heteroaryl, substituted 5-membered, monocyclic heterocycloaryl, substituted 6-membered, monocyclic heterocycloaryl, and substituted 9- or 10-membered, fused the bicyclic heterocycloaryl may be optionally substituted on a nitrogen atom instead of on a carbon atom by one of the above 1 to possible. Substitution on the nitrogen atom is possible when the -N (H) - diradical is present. The substituent replaces the hydrogen atom in this radical and is selected from:

C 1 -C 6 alkyl, which may be straight or branched,

C 2 -C 6 alkenyl, which may be straight or branched,

C 2 -C 6 alkynyl, which may be straight or branched,

C3-C6 cycloalkyl a

CN.

Further, there remains a substituted 5-membered, monocyclic heterocycloalkyl, substituted 6-membered, monocyclic heterocycloalkyl and substituted 9- or 10-membered, bicyclic heterocycloalkyl, which may be substituted on saturated carbon by an oxo group (= O) to form C = O.

As described above, substituted aryl refers to substituted phenyl, substituted 1-naphthyl or substituted 2-naphthyl. Examples:

(i) substituted phenyl includes 4-methoxyphenyl, 2,6-difluorophenyl,

3-hydroxy-4-methylphenyl, 2-hydroxymethyl-3,4-dichlorophenyl, 1,3-benzoxazol-5-yl and 2-methoxy-4-nitrophenyl;

(ii) substituted 1-naphthyl includes 5-trifluoromethanesulfonylamino-naphthyl-

1-yl and (2- (N-hydroxycarboxyamido) -naphth-1-yl; and (iii) substituted 2-naphthyl includes 5-trifluoromethanesulfonylamino-naphthyl-

2-yl and (2- (N-hydroxy-carboxyamido) naphth-2-yl).

As noted above, substituted heteroaryl refers to substituted, 5-membered, monocyclic heteroaryl, substituted 6-membered, monocyclic heteroaryl or substituted 9- or 10-membered bicyclic heteroaryl. Examples:

(i) substituted 5-membered, monocyclic heteroaryl includes 3-chlorothiophen-2-yl, 5-hexyl-furan-2-yl, 1-methyl-pyrrol-3-yl, 2-carboxypyrol-1-yl, 1,2 -dimethyl-imidazol-4-yl, 5- (4-carboethoxy-7-fluoroheptyl) -isoxazol-3-yl, 4-trifluoromethyl-oxazol-2-yl, 2-hydroxy-thiazol-4-yl, 5-acetylamino-tetrazole -1-yl, 5- (tert-butyl) -1,2,4-oxadiazol-3-yl, 3-cyano-1,2,4-triazol-1-yl and 5-acetyl-pyrazol-3-yl;

(ii) substituted 6-membered, monocyclic heteroaryl includes 4,6-difluoropyridin-2-yl, 2-methyl-pyridin-4-yl, 4-azido-pyrimidin-2-yl,

6-ureido-pyridazin-4-yl and 5-methylthiopyrazin-2-yl; and (iii) a 9- or 10-membered, bicyclic heteroaryl includes 6,7-dimethoxyindol-2-yl, 1-propyl-indol-6-yl, 7-nitro-isoindol-2-yl, 1-benzylbenzimidazol-2- yl, 4-chloro-benzimidazol-1-yl, 7- (2-propyl) benzotriazol-1-yl, 1- (2-hydroxyethyl) benzotriazol-5-yl, 4-iodoquinolin-2-yl, 1-nitro -isoquinolin-7-yl, 4-cyano-benzopyrimidine-

2-yl, 4,5,6-trifluoro-benzoxazol-2-yl, 2-carboxy-benzothiophen-5-yl and 4-methylsulfinyl-benzofuran-3-yl.

As noted above, substituted heterocycloalkyl refers to substituted, 5-membered, monocyclic heterocycloalkyl, substituted 6-membered, monocyclic heterocycloalkyl, or substituted 9- or 10-membered fused bicyclic heterocycloalkyl. Examples:

(i) substituted 5-membered, monocyclic heterocycloalkyl includes 5-chloro-2,3-dihydrofuran-2-yl, 2,2-dimethyl-tetrahydrofuran-3-yl, 1- (3,4-dichlorophenyl) - 2,5-dihydro-1H-pyrrole-3,4-diyl (i.e. 1-substituted, 2,5-dihydropyrrole linked to the benzo group at the 3,4-position) and 2-oxo-tetrahydroimidazol-1-yl;

(ii) a substituted 6-membered, monocyclic heterocycloalkyl includes

4-acetyl-1,2,5,6-tetrahydropyridin-2-yl, 1-methylpiperidin-4-yl,

4-benzyl-piperazin-1-yl, 3-fluoro-morpholin-1-yl and 2-methyl-thiomorpholin-2-yl; and (iii) a 9- or 10-membered, bicyclic heterocycloalkyl includes

4-nitro-2,3-dihydrobenzofuran-2-yl, 1,3-benzoxazol-5-yl and 2-oxo-

2,3-dihydro-indol-5-yl.

The term "heteroatom" refers to N, O or S unless otherwise indicated.

The term "oxo" refers to = 0. Oxo together with the carbon atom to which it is attached form a carbonyl group (i.e., C = O).

The term "amino" refers to NH 2.

The term "alkali metal cation" refers to Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ or Fr ⁺ .

The term "alkaline earth metal cation" refers to Be ⁺² , Mg ⁺² , Ca ⁺² , Sr ⁺² , Ba ⁺² or Ra ⁺² .

The term "alkali metal amide" refers to a base consisting of NH 2 'and a cation that is Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ or Fr ⁺ .

The term "alkaline earth metal amide" refers to a base consisting of NH 2 'and a cation that is Be ⁺² , Mg ⁺² , Ca ⁺² , Sr ⁺² , Ba ⁺² or Ra ⁺² .

The term "alkali metal dialkylamide" refers to a base containing two independent alkyl groups, each of which is attached to an N 'group, giving an alkyl-N (') alkyl group, wherein alkyl is unsubstituted alkyl as defined above, and a cation by which is Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ or Fr ⁺ . An exemplary alkali metal dialkylamide is lithium diisopropylamide ("LDA").

The term "alkaline earth metal dialkylamide" refers to a base containing two independent alkyl groups, each of which is attached to an N 'group, giving an alkyl-N (') alkyl group wherein alkyl is an unsubstituted alkyl as defined above, and a cation, which is Be ⁺² , Mg ⁺² , Ca ⁺² , Sr ⁺² , Ba ⁺² or Ra ⁺² . An exemplary alkaline earth metal dialkylamide is magnesium bis (diisopropylamide).

The term "alkali metal bis (trialkylsilyl) amide" refers to a base containing two independent trialkylsilyl groups, each of which is attached to an N 'group, giving a (alkyl) 3 Si-N (') - Si- (alkyl) 3 group, wherein alkyl is unsubstituted alkyl as defined above, and a cation which is Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ or Fr ⁺ . An exemplary alkali metal bis (trialkylsilyl) amide is lithium bis (trimethylsilyl) amide ("LiHDMS" or "lithium hexamethyldisilazane").

The term "alkaline earth metal bis (trialkylsilyl) amide" refers to a base containing two independent trialkylsilyl groups, each of which is attached to an N 'group, to give (alkyl) ₃ Si-N (') - Si- (alkyl) 3 a group wherein alkyl is unsubstituted alkyl as defined above, and a cation which is Be ⁺² , Mg ⁺² , Ca ⁺² , Sr ⁺² , Ba ⁺² or Ra ⁺² . An exemplary alkaline earth metal bis (trialkylsilyl) amide is magnesium di [bis (trimethylsilyl) amide].

The term "alkali metal alkoxide" refers to a base that contains an alkyl attached to an O 'group, giving an alkyl-θ' group, wherein alkyl is unsubstituted alkyl as defined above, and a cation which is Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ or Fr ⁺ . Exemplary alkali metal alkoxides are lithium methoxide, sodium ethoxide, and potassium tert-butoxide.

The term "alkaline earth metal alkoxide" refers to a base that contains an alkyl attached to the O 'group, giving an alkyl-θ' group, wherein alkyl is unsubstituted alkyl as defined above, and a cation being Be, Mg, Ca, Sr ⁺² , Ba ⁺² or Ra ⁺² . Exemplary alkali metal alkoxides are magnesium bismetoxide and calcium bisetoxide.

Of the aforementioned bases, those containing an alkali metal cation salt are preferred. More preferred are those containing a salt of Li ⁺ , Na ⁺ and K ⁺ . Even more preferred are bases which contain a Li ⁺ salt. However, any base whose associated acidity has a pK a> 16 will work within the scope of the invention.

The term "carboxylic acid activating agent" refers to an agent that activates a -C (= O) OH group or a corresponding conjugate base (i.e., -C (= O) O ') toward a coupling reaction that includes OH and O' replacement, respectively. Examples of carboxylic acid activators are lipase enzymes, an inorganic acid including HCl and sulfuric acid, 2,4,6-trichloro-1,3,5-triazine, 3-nitro-2-pyridinesulfonyl chloride, trifluoroacetic anhydride, mesyl chloride, S (O) C12, S (O) 2C12, P (O) C13, oxalyl chloride, (phenyl) ₂ P (= O) Cl ("DPPC1"), 1,1'-carbonyldiimidazole ("CDI"), triphenylphosphine / diethyl azocarboxylate Ν, Ν'-docyclohexylcarbodiimide ("DCC"), water-soluble carbodiimides, including 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ("EDC") and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide methiodide, 2- ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline ("EEDQ"), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate ("BOP"), and bromotri-tris (pyrrolidino) phosphonium hexafluorophosphate ("PyBrOP"). Other carboxylic acid activating agents can be found in Comprehensive Organic Transformations, Richard C. Larock, VCH Publishers, Inc., New York, 1989.

Preferred carboxylic acid activators are selected from: (COCl) 2, S (O) C12, S (O) 2Cl2, P (O) C13, (phenyl) 2P (= O) Cl, 1,1'-carbonyldiimidazole, triphenylphosphine diethyl azodicarboxylate, EDC, EDCI and N, N'-dicyclohexylcarbodiimide.

The term "organopalladium catalyst" refers to a catalyst comprising palladium and an organic ligand. Exemplary organopalladium catalysts are palladium acetate, palladium tetrakis (triphenylphosphine) and palladium (bis (diphenylphosphino) ferrocene) chloride. Other organo-palladium catalysts are known and can be found in Comprehensive Organic Transformations, Richard C. Larock, VCH Publishers, Inc., New York, 1989.

The term "reaction functional group" refers to a group that is responsible for reaction with certain solvents, reagents, catalysts, reaction starting materials, reaction intermediates or reaction products under certain reaction conditions used. Non-limiting examples of reaction functional groups are NH ₂ , OH, SH, COOH, N = C = O, C (O) Cl, and the like.

The term "non-nucleophilic base" refers to a base that acts as a nucleophile slowly in substitution reactions per se, such as in nucleophilic aromatic substitution reactions. Examples of non-nucleophilic bases include tertiary organic amines as defined below, alkali metal hydrides, alkaline earth metal hydrides, alkali metal dialkylamides, alkaline earth metal dialkylamides, alkali metal bis (trialkylsilyl) amides, alkaline earth metal bis (trialkylsilyl) amides, tertiary alkoxides alkali metals, tertiary alkoxides of alkaline earth metals.

The term "acid catalyst" refers to Bronsted or Lewis acid, which may be present in a catalytic, stoichiometric or greater than stoichiometric amount.

The term "aprotic solvent" refers to a solvent that, under certain conditions of use, does not yield a proton (i.e., acts as a Bronsted acid). That is, the pKa (relative to water or optionally relative to DMSO) of the aprotic solvent is greater than the pKa of the conjugated acid of the strongest base used. Typical high pKA aprotic solvents (i.e., &gt; 30) include diethyl ether, tetrahydrofuran, dioxane, dimethylsulfoxide, hexane, heptane, dimethylformamide, toluene and benzene. Typical aprotic solvents with lower pKa (i.e., 19 <pKa <30) include ethyl acetate, acetone, and acetonitrile. Solvents with a pK a lower than 19, such as tert-butanol, are generally not aprotic, although nitromethane is aprotic. Solvents containing OH, NH and SH functional groups are typically not aprotic.

The term "protic solvents" or "protic admixture" refers to a solvent or admixture that provides protons under certain conditions of use.

The term "tertiary organic amine" refers to a triple substituted nitrogen group in which three substituents are selected from C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl and benzyl, or wherein two of the three substituents together with the nitrogen atom to which they are attached form a 5-membered or a 6-membered monocyclic heterocycle containing the nitrogen and carbon atoms and the third substituent is selected from C1-C12 alkyl, C3-C12 cycloalkyl and benzyl, or wherein the three substituents together with the nitrogen atom to which they are attached form

7-membered to 12-membered bicyclic heterocycle containing 1 or 2 nitrogen atoms and carbon atoms and optionally containing a carbon-nitrogen double bond ("C = N") when two nitrogen atoms are present. Exemplary tertiary organic amines include triethylamine, diisopropylethylamine, dicyclohexylmethyl-amine, 1,8-diazabicyclo [5.4.0] undec-7-ene ("DBU"), 1,4-diazabicyclo [2.2.2] octane ("TED") ) and 1,5-diazabicyclo [4.3.0] non-5-ene.

The term "purification" means separation of the desired compound from the undesirable components of the mixture, including distillation, chromatography, including column chromatography, thin layer chromatography, reverse phase chromatography, gas chromatography and ion exchange chromatography, precipitation, extraction, rotary evaporation, chemical separation of reactions with incompatible functional groups, including quenching, filtration, centrifugation, physical separation and fractional crystallization.

The term "carry out on an industrial scale" means a process that utilizes more than 1 kilogram of a compound of formula (A) or a compound of formula (B), wherein the compound of formula (A) and the compound of formula (B) are as defined above.

Certain compounds prepared according to the process of the invention are capable of further forming pharmaceutically acceptable salts, including, but not limited to, acid and base addition salts. Acid addition salts are formed from basic compounds, while base addition salts are formed from acidic compounds. All of these forms are included within the scope of the compounds prepared by the process of the invention.

Pharmaceutically acceptable acid addition salts of the basic compounds prepared by the methods of the invention include non-toxic salts derived from inorganic acids such as hydrochloric, nitric, phosphorous, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphoric and the like, as well as non-toxic salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Thus, these salts include sulfates, disulfates, hydrogen sulfates, sulfites, hydrogen sulfites, nitrates, phosphates, hydrogen phosphates, dihydrogen phosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalate, fumarate, oxalate, fumarate, oxalate, oxalate, fumarate, oxalate, fumarate, oxalate, molonate, fumarate maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malate, succinates, methanesulfonates and the like. Salts of amino acids such as arginate and the like and gluconate, galacturonate are also contemplated (see, for example, Berge

S.M. et al., "Pharmaceutical Salts", J. of Pharma. Sci., 1977; 66: 1).

The acid addition salts of the basic compounds prepared by the process of the present invention are prepared by contacting the free base compound with a sufficient amount of the desired acid to form a non-toxic salt in a conventional manner. The free base compound can be regenerated by contacting the thus formed salt with a base and isolating the free base compound in a conventional manner. The free base form of the compounds of the present invention differs somewhat from their acid addition salts in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but for the purpose of the present invention, the free base form is also in the salt form acid addition equivalent.

The pharmaceutically acceptable base addition salts of the acidic compounds prepared by the process of the present invention are prepared by contacting the free acid compound with a nontoxic metal cation such as an alkali metal or alkaline earth metal cation or an amine, especially an organic amine. Examples of suitable metal cations include sodium cation (Na ⁺ ), potassium cation (K ⁺ ), magnesium cation (Mg ⁺² ), calcium cation (Ca ⁺² ) and the like. Examples of suitable amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohaxylamine, ethylenediamine, N-methylglucamine and procaine (see, e.g., Berge, supra, 1977).

The base addition salts of acidic compounds prepared by the process of the present invention are prepared by contacting the free acid compound with a sufficient amount of the desired base to form a non-toxic salt in a conventional manner. The free acid compound can be regenerated by contacting the salt thus formed with an acid and isolating the free acid in a conventional manner. The free acid form of the compounds of the present invention differs somewhat from their base addition salts in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but for the purpose of the present invention the free acid form is also in the form base addition salts equivalent.

Some compounds prepared by the process of the invention have one or more chiral centers, and each center may exist in the R or S configuration. The process of the invention prepares all diastereomeric, enantiomeric and epimeric forms of the compounds as well as mixtures thereof.

In addition, some of the compounds prepared by the process of the invention may exist as geometric isomers such as the "entgegen" (E) and the "zusammen" (Z) isomers of alkenyl groups. The process of the invention prepares all cis, trans, syn, anti and entgegen (E) and zusammen (Z) isomers as well as mixtures thereof.

Certain compounds prepared by the process of the invention may exist as two or more tautomeric forms. Tautomeric forms of the compounds may be varied from one another, for example, by enolization / deenolization, and the like. The process of the invention prepares all tautomeric forms of the compounds of formula I.

Intermediates and synthesis auxiliaries of the compounds of formula I and their pharmaceutically acceptable salts can be prepared by one of the syntheses customary in the art of organic chemistry by adapting synthetic procedures well known in the art. These procedures can be found in the literature, for example, Reagents for Organic Synthesis, Fieser and Fieser, John Wiley & Sons, Inc., New York, 2000; Comprehensive Organic Transformations, Richard C. Larock, VCH Publishers, Inc., New York, 1989; edition of Compendium of Organic Synthetic Metods (1989) by Wiley-Interscience; Advanced Organic Chemistry textbook, 4th edition, Jerry March, WileyInterscience, New York (1992) or Handbook of Heterocyclic Chemistry, Alan R. Katritzky, Pergamon Press Ltd, London, 1985, to mention just a few. Alternatively, skilled artisans may find suitable methods for preparing intermediates in generally available databases such as Chemical Abstracts Service, Columbus, Ohio, or MDL Information Systems GmbH (formerly Beilstein Information Systems GmbH), Frankfurt, Germany.

Preparations of the compounds of this invention may use starting materials, reagents, solvents and catalysts, which may be purchased from commercial sources or may be prepared by adapting the procedures of the references and sources cited above. Commercial sources of starting materials, reagents, solvents and catalysts suitable for the preparation of the compounds of this invention include, for example, The Aldrich Chemical Company and other branches of Sigma-Aldrich Corporation, St. Petersburg. Louis, Missouri, BACHEM, BACHEM A.G., Switzerland, or Lancaster Synthesis Ltd, United Kingdom.

The syntheses of some of the compounds of this invention may employ starting materials, excipients, intermediates, or reaction products that contain reactive functional groups. During chemical reactions, the reactive functional groups may be protected by protecting groups which render the reactive functional group substantially inert under the reaction conditions. The protecting group is introduced into the starting material before carrying out the reaction step during which the protecting group is needed. If the protecting group is no longer needed, it can be removed. The deprotection and subsequent deprotection should be a conventional technique during the synthesis of a compound of formula I. The deprotection and deprotection procedures are known and reported in the literature, such as in Protective Groups in Organic Synthesis, 2nd Edition, Greene T.W. and Wuts P.G., John Wiley & Sons, New York: New York, 1991, incorporated herein by reference. For example, the following protecting groups may be used to protect amino, hydroxy and other groups: carboxylic acyl groups such as formyl, acetyl, and trifluoroacetyl; alkoxycarbonyl groups such as ethoxycarbonyl, tert-butoxycarbonyl (BOC), β, β, β-trichloroethoxycarbonyl (TCEC) and β-iodoethoxycarbonyl; aralkyloxycarbonyl groups such as benzyloxycarbonyl (CBZ), para-methoxybenzyloxycarbonyl and 9-fluorenylmethyloxycarbonyl (FMOC); trialkylsilyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS) and other groups such as triphenylmethyl (trityl), tetrahydropyranyl, vinyloxycarbonyl, ortho-nitrophenylsulfenyl, diphenylphosphinyl, para-toluenesulfonyl (Ts), mesyl, trifluoromethanes. Examples of deprotection procedures include hydrogenolysis of CBZ groups using, for example, hydrogen gas at 50 psi in the presence of a hydrogenation catalyst such as 10% palladium on carbon, acidolysis of BOC groups using, for example, hydrogen chloride in dichloromethane, trifluoroacetic acid (TFA) in dichloromethane and the like, reaction of silyl groups with fluoride ions, and reductive cleavage of TCEC groups with zinc metal.

General methods of the invention are illustrated in the schemes below.

The process of the invention for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof by reacting a compound of formula (A) with a compound of formula (B) supported by a base wherein R ¹ to R ¹⁰ , X and Z are as defined above is outlined below first

Scheme 1

In Scheme 1, the amount of molar equivalents ("mol equivalents") of the base used in the method of the present invention is preferably greater than about 2 compared to the lower number of moles of the compound of formula (A) or the compound of formula (B) used in the method of the invention more preferably greater than about 2.5, even more preferably greater than about 2.75, and most preferably between 3 and 3.5. Reducing the number of equivalents below 3 reduces the yield, except when a compound of formula (B) in which Z is COOM is used as the starting material, where M is an alkali or alkaline earth metal cation. In these cases, an amount of between 2 and 2.5 equivalents of base added is preferred. The use of more than 3.5 equivalents of base increases the reaction yields when the reagents contain a protic solvent or protic admixture (see Table I, items 1-4 below).

Generally speaking, the reaction of the invention is carried out by mixing a compound of formula (A) with a compound of formula (B), preferably in an aprotic solvent, which is preferably tetrahydrofuran or acetonitrile together with a base. The reaction is generally conducted at a temperature of about -78 ° C to about 150 ° C (preferably about -70 ° C to 120 ° C) and is normally complete in about 2 hours to about 4 days. The compound of formula I prepared by the process of the invention can be isolated by removing the solvent, for example, by rotary evaporator under reduced pressure, followed by purification, if necessary, by standard methods such as chromatography, crystallization or distillation. Other standard purification methods have been mentioned above.

The base used in the process of the invention can be added to the reaction in several ways. Four methods, namely A-D methods, are described below.

Method A - A base can be added by the "two-pot method" when a base is added to a first flask to a solution or suspension of a compound of formula (B) (11 mol equiv); to a second flask was added a base to a solution or suspension of the compound of formula (A) (~ 1 mol equiv). The contents may be mixed and the resulting mixture heated, if necessary or desired, to react.

Method B - The base can be added by the "single-pot method" when both compounds of formula (A) and (B) are dissolved or suspended in a solvent and cooled. A base is added and the mixture is heated, if necessary or desired, to react.

Method C - The base can be added by the alternative "two-pot method" when the first flask contains a solution or suspension of the compound of formula (B) (11 mol equiv); in a second flask, mix the base and the compound of formula (A) (ekv1 mol equiv). The contents of the first container are transferred to the second container or, optionally, the contents of the second container are transferred to the first container and the resulting mixture is heated, if necessary or desired, to react.

Method D - A solution or suspension of a compound of formula (B) (~ 1 eq) and a compound of formula (A) is formed and the contents are transferred to a flask containing a base or, optionally, the contents of the flask containing a base are transferred to a flask containing compounds of formulas (A). ) and (B). The resulting mixture is heated, if necessary or desired, to react.

When Z is -COOH, the compound of formula I may be reacted with an alcohol (optionally in the presence of a coupling agent) to form an ester.

When Z is -COOH or -COOM, the compound of formula I may be reacted with NH ₃ , a primary or secondary amine, hydroxylamine or hydroxylamine substituted on O to form an amide, hydroxamic acid or hydroxamic acid ester.

If the compound of formula I is to be intentionally further reacted with an alcohol, amine or hydroxylamine derivatives to form pharmaceutical esters, amides (such as those described in WO 99/01421 and

WO 99/01426) or hydroxamic acid or hydroxamic acid ester, then it is preferred to activate the compound of formula I wherein Z is

COOM, where M is as defined above, in a manner that avoids the need for isolation. In these cases, it is preferable to use the method shown in Scheme 2 below:

O 1 ktorej in which M and R to R are as defined above and

Z is COOR ' ⁵ , C (O) N (R ¹⁶ ) R ¹⁷ or C (O) N (R ¹⁸ ) R ¹⁹ , wherein R ¹⁵ to R ¹⁹ are as defined above.

In step (a) of Scheme 2, 1 eq. acids such as MeSCUH at a temperature and for a time sufficient to monoprotonize the compound of Formula I to form the carboxylic acid salt as an intermediate. Typically, the temperature is about -78 ° C to about 0 ° C (preferably about -20 ° C, and the reaction is complete in about 30 minutes. The resulting mixture is warmed if necessary or desired to react.

Then, in step (b), the carboxylic salt is converted to the corresponding acid chloride intermediate using, for example, thionyl chloride (SOCl 2). Subsequently, the acid chloride is reacted with an alcohol, amine or hydroxylamine derivative to form an ester, amide or hydroxamic acid or hydroxamic acid ester, wherein Z is as defined immediately above.

In another embodiment of the present invention, higher yields of the compound of formula I from the reaction of a compound of formula (A) with a compound of formula (B) can be achieved by successive addition of a base. One such sequence method consists in (a) dissolving or suspending a compound of formula (A) and a compound of formula (B) in a solvent, more preferably in an aprotic solvent;

(b) adding a base to the mixture of step (a), preferably at a temperature of from about -70 ° C to about 30 ° C, and allowing the compound of formula (A) and the compound of formula (B) to react long enough to increase the amount of the compound of formula I;

(c) optionally heating the reaction mixture of step (b) for a time sufficient to increase the amount of the compound of Formula I or reduce the time required to produce the amount of the compound of Formula I;

(d) adding a base to the mixture of step (b), at a temperature preferably from about -70 ° C to about 30 ° C and allowing the compound of formula (A) and the compound of formula (B) to react long enough to increase the amount of compound of formula I; or cooling the mixture of step (c) to a temperature of from about -70 ° C to about 30 ° C, adding a base to cool the mixture and allowing it to react for a sufficient time to increase the amount of the compound of formula i;

(e) optionally heating the reaction mixture of step (d) long enough to increase the amount of the compound of formula I; and (f) optionally repeating steps (d) and (e).

The number of repetitions of step (d) or steps (d) and (e) according to step (f) is preferably less than 10 and most preferably from 0 to 7.

The amount of base added in step (b) is preferably about 2 mol equiv, except when a compound of formula (B) wherein Z is COOM is used, where M is as defined above. In this case, the amount of base is preferably about 1 mol eq.

The amount of base added in steps (b) and (d) above may be the same or different. Suitable bases include lithium diisopropylamide (LDA), lithium hydride, lithium amide, lithium diethylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide or potassium bis (trimethylsilyl) amide.

LDA is preferably used in the process of the invention in industrial (i.e., scale) operation, but more preferably the bases are LiHMDS, LiH or LiNH ₂ .

It should be appreciated that the process of the invention can be carried out in a vessel or reactor of any size.

The following examples are provided so much to illustrate the invention. The scope of the invention is not limited thereto.

DETAILED DESCRIPTION OF THE INVENTION

EXAMPLE 1

2- (2-Chloro-4-iodophenylamino) -3,4-difluorobenzoic acid

Sequential addition procedure using diisopropylamide (LDA) as a base Method B

To a 3 L flask equipped with a mechanical stirrer was added 58 g (0.33 mol) of 2,3,4-trifluorobenzoic acid, 76 g (0.30 mol) of 2-chloro-4-iodoaniline and 500 ml of TF. The mixture was cooled to about -20 ° C and 400 mL of a 1.5 M solution of lithium diisopropylamide ("LDA") in hexane / THF was added. The reaction mixture was then allowed to warm to room temperature and stirred for at least 1 hour. It was then cooled to about -20 ° C and 100 mL of a 1.5 M LDA in hexane / THF solution was added. The reaction mixture was then allowed to warm to room temperature and stirred for at least 1 hour. It was then cooled to about -20 ° C and 50 mL of a 1.5 M LDA in hexane / THF solution was added. The reaction mixture was then allowed to warm to room temperature and stirred for at least 1 hour. It was then cooled to about -20 ° C and 25 mL of a 1.5 M LDA in hexane / THF solution was added. The reaction mixture was then allowed to warm to room temperature and stirred for at least 1 hour. It was then cooled to about -20 ° C and 12 ml of a 1.5 M solution of LDA in hexane / THF was added. The reaction mixture was then allowed to warm to room temperature and stirred for at least 1 hour. It was then cooled to about -20 ° C and 6 mL of a 1.5 M LDA in hexane / THF solution was added. The reaction mixture was then allowed to warm to room temperature and stirred for at least 1 hour. It was then cooled to about -40 ° C and 600 mL of a 4 M aqueous HCl solution was added. The reaction mixture was then allowed to warm to room temperature and stirred for at least 10 minutes, and the phases were allowed to separate for at least 1 hour. The lower phase was drained and the upper phase was concentrated to a slurry by vacuum distillation. This was dissolved in hot acetone and the solution was diluted with water and cooled to crystallize. The product was isolated by filtration and dried in a vacuum oven to give 96 g (78%) of 2- (2-chloro-4-iodophenylamino) -3,4-difluorobenzoic acid as an off-white solid.

Table 1 shows the intermediate results of high-resolution liquid chromatography ("HPLC") obtained during the preparation described in Example 1. The percentages of 2- (2-chloro-4-iodophenylamino) -3,4-difluorobenzoic acid were determined using ultraviolet (" UV ”) of the detector.

Table 1

mole 0.5 equiv. 0.25 equiv. 0.13 equiv. 0.06 equiv. 0.03 equiv. 0,015 equiv. eq LDA 2 equiv. Percentage of product 40% 66% 82% 89% 93% 96% 97%

Further examples 2-10, indicated by their numbers in the column labeled "Pr. C. ", are shown in Table 2 below. The reactants are a compound of formula (A) and a compound of formula (B), which are indicated in the columns marked "(A)" and "(B)". The bases and method used are listed in the columns labeled "Base" and "Method". Three (3) molar equivalents of base were used unless otherwise stated.

Table 2

Pr. (A) (A)

no.

Base Method Yield (%)

CN NH ₂

HsCO ^Fr & ₃

LiHMDS A 33 LiHMDS B 6 LiHMDS B and LiHMDS B 6 LiHMDS B and LiHMDS B NU ^b

och ₃

F

och ₃ coch ₃

The same

LiHMDS

LiHMDS

LiHMDS

A ^c

NU

Amide formation was observed

NU means that the amount of product has not been determined

1.3 eq. compounds of formula (A)

EXAMPLE 11

Sequential addition procedure Using lithium amide as a base (solid addition)

Lithium amide process for the formation of 2- (2-chloro-4-iodophenylamino) -3,4-difluorobenzoic acid

To an "inert" flask equipped with a magnetic stirrer was added 8 g (31.6 mmol) of 2-chloro-4-iodoaniline, 6 g (34 mmol) of 2,3,4-trifluorobenzoic acid and 50 ml of acetonitrile. Lithium amide (2.7 g, 117 mmol) was added portionwise at room temperature over two days. The reaction mixture was heated to 60 ° C for about 1 hour, then cooled to room temperature and quenched with dilute hydrochloric acid. After cooling to 0 ° C to -15 ° C, the reaction mixture was filtered and the filter cake was washed with acetonotril / water. The wet cake was dried in a vacuum oven to give 12.8 g (98%) of 2- (2-chloro-4-iodophenylamino) -3,4-difluorobenzoic acid (CIPFA).

EXAMPLE 12

Lithium amide process for the formation of 2- (2-chloro-4-iodophenylamino) -3,4-difluorobenzoic acid using 2,3,4-trifluorobenzoic acid sodium salt

To an "inert" flask equipped with a magnetic stirrer was added 5 g (20 mmol) of 2-chloro-4-iodoaniline, 4.3 g (22 mmol) of sodium 2,3,4-trifluorobenzoic acid, 2.0 g of lithium amide powder and 50 g of sodium amide. ml of acetonitrile. The reaction mixture was stirred at room temperature for 16 hours, then 35 mL of dilute hydrochloric acid was added and the pellet cooled to -5 ° C. The product was isolated by filtration and dried in a vacuum oven to give 7.5 g (93%) of 2- (2-chloro-4-iodophenylamino) -3,4-difluorobenzoic acid (CIPFA).

Alternative methods of addition using lithium hydride and / or lithium amide

EXAMPLE 13

Pairing of lithium hydride to form 2- (2-chloro-4-iodophenylamino) -3,4-difluorobenzoic acid

To an "inert" three-necked flask equipped with a condenser, mechanical stirrer, thermo jacket, and dispenser was added 85 g (10.6 mol) of lithium hydride, 823 g (3.25 mol) of 2-chloro-4-iodoaniline and 6 L of acetonitrile. 630 g (3.58 mol) of 2,3,4-trifluorobenzoic acid in 7 L of acetonitrile was added causing the temperature to rise to 60 ° C. The pellet was stirred at 60 ° C to 70 ° C for 44 hours. After this time a solution formed. To this solution was added a mixture of 1.75 L (21 mol) of 37% hydrochloric acid and 4.5 L of water. The resulting product pellet was cooled to 0 ° C to -15 ° C and after stirring for about 1 hour, the product was filtered and the filter cake was washed with 8 L of 1: 1 acetonitrile / water. The wet cake was dried under vacuum to give 1.2 kg (90%) of 2- (2-chloro-4-iodophenylamino) -3,4-difluorobenzoyl acid.

EXAMPLE 14

Pairing of lithium hydride to form 2- (2-chloro-4-iodophenylamino) -3,4-difluorobenzoic acid using 2,3,4-trifluorobenzoic acid sodium salt

To an "inert" 121 flask equipped with a mechanical stirrer was added 580 g (23 mol) of 2-chloro-4-iodoaniline, 500 g (2.53 mol) of sodium acid salt

2,3,4-trifluorobenzoic acid, 50 g of lithium hydride powder (size 30) and 6 L of anhydrous acetonitrile. The reaction mixture was heated to 57 ° C and stirred for 16 hours, then cooled to about 40 ° C and 3.5 L of 12% hydrochloric acid (exothermic to 55 ° C) was added. The pellet was cooled to 0 ° C and the product collected by filtration. The filter cake was washed with aqueous acetonitrile and dried in a vacuum oven to give 860 g (91%) of 2- (2-chloro-4-iodophenylamino) -3,4-difluorobenzoic acid.

EXAMPLE 15

Preparation of compound (1) using acid chloride and HCl salt of amine with aqueous sodium hydroxide

CIPFA (70 g, 171 mmol), dimethylformamide ("DMF") (0.66 mL,

8.6 mmol) and toluene (560 mL). The reaction vessel was sealed and a vacuum of ~ 50 cm Hg was applied. Thionyl chloride (15.0 mL, 205 mmol) was added under vacuum, followed by rinsing with toluene (10 mL). The reaction mixture was stirred and gradually warmed to 60 ° C. After about 4 hours, the reaction mixture changed from an off-white deposit to a yellow solution, and the pressure inside the vessel increased from about 20 inches Hg to 12 pounds / inch (0.08370 MPa). The toluene solution was washed with cold water (250 mL) and the organic layer was used directly in the next step.

O-Cyclopropylmethylhydroxylamine hydrochloride CPMON.HCl (25.4 g, 205 mmol) and 5 M NaOH (164 mL, 820 mmol) were added to a 1000 mL three-necked, oval bottom flask. The mixture was stirred at room temperature until CPMON.HCl was dissolved. To this vigorously stirred solution was added a solution of CIPFA chloride (171 mmol, 0.3 M in toluene) prepared separately dropwise while maintaining the temperature below 35 ° C. A white deposit formed during the addition. This was stirred for 1 hour at room temperature and quenched with concentrated HCl solution (35 mL), EtOAc (400 mL) and water (150 mL). This mixture was heated to 45 ° C to dissolve the solids and the lower aqueous layer was drained. The organic layer was washed with water at 40 ° C to 45 ° C (2 x 250 mL). After distilling about 400 mL of solvent, the organic layer was allowed to crystallize overnight. The pellet was cooled in an ice / acetone bath for about 2 hours and then vacuum filtered. The cake was washed with toluene (2 x 100 mL) and water (100 mL) and dried in a vacuum oven. 71.3 g of white solid remained (87% yield, 99.8% purity measured by HPLC).

EXAMPLE 16

Preparation of Compound (1) Using Dianion Monoprotonization followed by Reaction with Thionyl Chloride and Amine Free Base

To a solution of 8 g of 2-chloro-4-iodoaniline and 6 g of 2,3,4-trifluorobenzoic acid in 50 ml of THF was added 2.3 g of lithium amide in portions over 2 days. The reaction mixture was stirred at 20 ° C to 40 ° C for a further 16 hours, then heated to reflux and allowed to cool to room temperature. This dianion solution (31 mmol) was cooled to 0 ° C and methanesulfonic acid (3.0 g, 31 mmol) was added. The solution was stirred at 0 ° C for 30 minutes. Thionyl chloride (7.3 g, 62 mmol) was added and the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0 ° C and o-cyclopropylmethylhydroxylamine (5.9 g, 68 mmol) was added followed by triethylamine (9.4 g, 93 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. After addition of 50 ml of water, the mixture was acidified to about pH 1 and extracted with ethyl acetate. Following three water washes, the organic layer was evaporated to dryness and then recrystallized from toluene to give 12.0 g of compound (1) (81%).

EXAMPLE 17

Preparation of Compound (1) Using Acid Chloride

2 (2-Chloro-4-iodophenylamino) -3,4-difluorobenzoic acid (6.0 g, 14.6 mmol) was added to a 250 mL oval bottom three-necked flask and the flask was vented with N ₂ . Toluene (70 mL) was added followed by DMF (3 drops) and the thick slurry was heated to 60 ° C under a slow stream of N ₂ . Thionyl chloride (1.6 mL, 22.1 mmol) was added slowly and the temperature was maintained at 60 ° C for 4 hours. At this time, the reaction mixture became a homogeneous solution. After cooling to about 30 ° C, the contents of the flask were vacuum distilled to a volume of about 50 ml. The temperature of the flask was kept very carefully below 55 ° C. The reaction mixture was cooled to -5 ° C and o-cyclopropylmethylhydroxylamine (1.5 g, 16.9 mmol) and triethylamine (4.5 g, 44.1 mmol) were then added to this orange solution while keeping the temperature below 50 ° C. Low: 14 ° C. After the addition was complete, the contents of the flask were stirred at -5 ° C for 30 minutes, then warmed to room temperature and stirred overnight. The reaction was quenched by addition of ethyl acetate (40 mL), water (25 mL) and concentrated HCl (7 mL) _. The mixture was heated to 40 ° C to 45 ° C for 15 minutes and then stirring was stopped. The lower aqueous layer was drained and the organic layer was washed twice with water (25 mL) at 40 ° C to 45 ° C. The organic layer was then distilled to a volume of about 50 mL and allowed to cool slowly to room temperature. After cooling in an ice / acetone bath for 2 hours, the precipitate was vacuum filtered and washed twice with toluene (10 mL) and once with water (10 mL). After drying in a vacuum oven, compound (1) was obtained as an off-white solid (6.2 g, 88%).

EXAMPLE 18

Preparation of compound (1) using N, N-carbonyldiimidazole

2.75 kg of 2- (2-chloro-4-iodophenylamino) -3,4-difluorobenzoic acid was added to a 0 L glass reactor followed by 18 L of anhydrous acetonitrile. After stirring for 90 minutes at room temperature, 0.7 kg of o-cyclopropylmethylhydroxylamine was added and the reaction mixture was stirred at room temperature for 16 hours. The pellet was heated to 65 ° C to dissolve again, then filtered through a glass frit and diluted with 3 L of hot water. The resulting pellet was cooled to -15 ° C and the product was filtered off, washed with 14 L of acetonitrile / water and dried in a vacuum oven to give 2.72 kg (86%) of compound (1).

EXAMPLE 19

Preparation of Compound (1) Using BOP

To a suspension of 2- (2-chloro-4-iodophenylamino) -3,4-difluorobenzoic acid (25.1, 61.3 mmol) in THF (300 mL) and CH 2 Cl 2 (300 mL) was added o-cyclopropylmethylhydroxylamine hydrochloride (9, 1 g, 73.5 mmol) and then the mixture was cooled in an ice bath. Diisopropylethylamine (37.4 mL, 0.214 mol) was added followed by slow addition of benzotriazol-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP, 32.5 g, 73.54 mmol). The solution was stirred at ambient temperature overnight (20 hours). The mixture was concentrated and partitioned between tBuOMe and 1N HCl. The organic layer was washed with 1N HCl, brine, saturated NaHCO 3 solution and dried (MgSO 4). The crude product was recrystallized from heptane-acetone to give compound (1) as a white solid 26.4 g, 90.2%, m.p. 177.5-178.5 ° C.

EXAMPLE 20

Preparation of compound (2) using lithium amide followed by CDI

To an "inert" flask containing a solution of 24 g (95 mmol) of 2-chloro-4-iodoaniline and 15 g (95 mmol) of 2,4-difluorobenzoic acid in 150 ml of acetonitrile was added portionwise 7.6 g (330 mmol) of lithium amide 4. days.

The reaction mixture was stirred at room temperature for an additional day, then quenched by addition of 100 mL of dilute HCl. The resulting slurry was cooled to 5 ° C and the product collected by filtration, washed with acetonitrile / water and dried in a vacuum oven to give 29 g (78%) of the acid product.

To the glass flask was added 21.2 g of 2- (2-chloro-4-iodophenylamino) -4-fluorobenzoic acid and 10 g of ld, Ν-carbonyldiimidazole followed by 170 ml of anhydrous acetonitrile. After stirring at room temperature for 60 minutes, 8 g of o-cyclopropylmethylhydroxylamine was added and the reaction mixture was stirred at room temperature for 20 hours. The solution was diluted with 15 mL of water, the resulting slurry was cooled to -5 ° C and the product collected by filtration, washed with acetonitrile / water and dried in a vacuum oven to give 13.5 g (55%) of compound (2). .

EXAMPLE 21

Preparation of compound (2) using lithium amide in THF

To a solution of 2,4-difluorobenzoic acid (0.69 g, 4.34 mmol, 1.1 eq) and 2-chloro-4-iodoaniline (1.0 g, 3.95 mmol) in dry THF (60 mL) LiNH ₂ (0.32 g, 13.81 mmol, 3.5 eq) was added at ambient temperature. The mixture was stirred at ambient temperature overnight (18 hours). TF was evaporated on a rotary evaporator. The residue was dissolved in tBuOMe, washed with 2N HCl, H 2 O (2x) and brine, and dried over MgSO 4. Evaporation gave a brown solid, which was stirred in hexane-CFUCl (4: 1) for 30 minutes. The solid was filtered off, washed with hexane and dried at 40 ° C under vacuum overnight to give 2- (2-chloro-4-iodophenylamino) -4-fluorobenzoic acid, 1.46 g, 85.9%, bt 238- 239

To a solution of 2- (2-chloro-4-iodophenylamino) -4-fluorobenzoic acid (1.0 g, 2.55 mmol) in dry THF (40 mL) cooled in an ice bath was added N-methylmorpholine (0.7 mL). , 6.38 mmol) followed by diphenylphosphonic acid chloride (0.78 g, 3.32 mmol). The mixture was stirred for 30 minutes and o-cyclopropylmethylhydroxylamine (0.31 g, 3.58 mmol) was added. The ice bath was removed and the mixture was stirred at ambient temperature overnight (18 hours). The mixture was concentrated and tBuOMe was added. The organic solution was washed with saturated NaHCO 3 solution and water and dried over MgSO 4. The crude solid was triturated with hexane-CH 2 Cl 2 (4: 1) to give compound (2) as an off-white solid, 1.14 g, (97%), m.p. 141-142 ° C.

EXAMPLE 22

Preparation of compound (3) using lithium amide

I (3)

Step (a): Dissolve 2,3,4,5-tetrafluorobenzoic acid (30.00 g, 154.6 mmol, 1 eq.) And 4-iodo- 2-methylaniline (36.15 g, 154.6 mmol, 1 eq) in a mixture of THF (220 mL) and acetonitrile (220 mL). The flask was placed in a water bath and L1NH2 (11.1 g, 479.2 mmol, 3.1 eq) was added over 20 min. The temperature was kept below 30 ° C during the addition. After 30 minutes, 1.79 g (0.5 eq.) Of L1NH2 was added in one portion and the same operation was repeated for another 10 minutes to move the reaction to completion. The dark green mixture was quenched with 1N HCl to acidic pH and extracted with diethyl ether (3x). The combined organic extracts were washed with brine and dried over MgSO 4. The solvent was removed in vacuo and the crude solid thus obtained was triturated with CH 2 Cl 2 to give 34.33 g (54%, mp 2.6-210 ° C) of 2- (4-iodo-2-methylphenylamino) -3,4 acid. , 5-trifluorobenzoate as a bright green solid.

Step (b): To an "inert" three-necked, oval-bottom flask containing a solution of 2- (4-iodo-2-methylphenylamino) -3,4,5-trifluorobenzoic acid (30.00 g)

73.7 mmol, 1 eq) in dry THF (150 mL) was added 4-methylmorpholine (20.3 mL,

184.2 mmol, 2.5 eq). After cooling the mixture to -20 ° C, a solution of diphenylphosphine chloride (18.3 mL, 95.8 mmol, 1.3 eq.) In dry THF (30 mL) cooled to -20 ° C was added via cannula. The resulting mixture was stirred at this temperature for 30 minutes and then a solution of o-cyclopropylmethylhydroxylamine (8.99 g,

103.2 mmol, 1.4 eq) in dry THF (30 mL) cooled to -20 ° C. The mixture was stirred at -20 ° C for 1.5 hours and then allowed to warm to ambient temperature overnight (18 hours). The reaction mixture was concentrated under reduced pressure to a paste and this was dissolved in ethyl acetate. The organic layer was washed with brine, 1M KHSO 4 (2x), saturated NaHCO 3 solution and brine again, and dried over MgSO ₄ . The solvent was removed in vacuo to give a foamed product which was passed through a pad of silica gel with CH 2 Cl 2 as eluent to give 31.68 g (90% yield, mp 137-139 ° C) of compound (3) as an off-white solid.

EXAMPLE 23

Preparation of compound (4) using lithium hydride

Compound (4)

To a 100 ml flask was added 3 g of 2-fluorobenzoic acid, 4 g of 2,6-dichloro-3-methylaniline, 0.5 g of lithium hydride and 35 ml of diethoxyethane. The mixture was heated at 80 ° C for 130 hours, allowed to cool to 45 ° C and diluted with 20 mL of 20% HCl. After cooling to -10 ° C, the product was collected by filtration, washed with aqueous acetonitrile, and dried in a vacuum oven to give 4 g of an off-white 2- (2-6-dichloro-3-methylphenylamino) benzoic acid product (4).

EXAMPLE 24

Preparation of 2- {4- [2- (3,4-dichlorophenyl) ethyl] phenylamino} benzoic acid compound (5)

Compound (5) An "Inert" flask was charged with lithium amide powder (9.4 mg) and 25 mL tetrahydrofuran. To this slurry was added a solution containing 4- (2- (3,4-dichlorophenyl) ethyl] benzenamine (22 g), 2-fluorobenzoic acid (11.5 g), and tetrahydrofuran (75 mL), then heated to 50-65. ° C for several hours and monitored (HPLC) loss of starting material Upon completion, the reaction was quenched with dilute HCl, the aqueous layer was removed and the organic layer was washed with water, treated with charcoal, filtered and the product precipitated by adding 150 mL of methanol followed by 20 mL of water The thick slurry was cooled to 0 ° C overnight and the product collected by filtration, washed with 100 mL of methanol / water 80:20, then dried in a vacuum oven to give 22.7 g (71.4%). compound (5) as a pale yellow solid.

EXAMPLE 25

Preparation of 2- (indolin-1-yl) benzoic acid

COOH

To a 250 mL flask was added indoline (5 g, 42.0 mmol), 2-fluorobenzoic acid (6.2 g, 44.1 mmol) and THF (140 mL). To this solution was added lithium amide (2.0 g, 88.2 mmol) in two portions over 5 minutes. The mixture was heated under nitrogen at 50 ° C for 4 hours, then cooled to room temperature. The reaction was quenched with water (25 mL), concentrated HCl (10 mL) and tBUOMe (25 mL). The aqueous layer was removed and the organic layer was washed with water (25 mL). The solvent was removed in vacuo. The resulting yellow solid was dissolved in isopropyl alcohol ("IPA") (40 mL) at 65 ° C and water (48 mL) was added slowly. The mixture was slowly cooled to 3 ° C, the product was filtered and washed with 40% IPA in water (2 x 10 mL). The off-white solid was dried in a vacuum oven at about 50 ° C to give 7.9 g (79% yield) of 2- (indolin-1-yl) benzoic acid.

EXAMPLE 26

Preparation of 2- (diphenylamino) benzoic acid

To a 250 mL flask was added diphenylamine (5 g, 29.5 mmol), 2-fluorobenzoic acid (4.3 g, 30.7 mmol) and THF (100 mL). To this solution was added lithium amide (1.4 g, 61.0 mmol) in two portions over 5 minutes. This mixture was heated under nitrogen at 60 ° C for about 72 hours, then cooled to room temperature. The reaction was quenched with water (25 mL), concentrated HCl (5 mL) and tBUOMe (25 mL). The aqueous layer was removed and the organic layer was washed with water (25 mL). The solvent was removed in vacuo. The product was dissolved in ethyl acetate (100 mL) and the remaining aqueous layer was removed. The solvent was removed in vacuo and the wet solid was dissolved in IPA (70 mL) at 70 ° C. The mixture was slowly cooled to -10 ° C, the product was filtered and washed in IPA (10 mL). The light yellow solid was dried in a vacuum oven at about 50 ° C to give 5.8 g (68% yield) of 2- (diphenylamino) benzoic acid.

EXAMPLE 27

Preparation of N-cyclopropylmethyloxy-2- (4-iodo-2-methylamino) -3,4,5-trifluorobenzamide

Η

In a three-necked, oval bottom flask equipped with a magnetic stirrer and a low temperature thermometer, 2- (4-iodo-2-methylamino) -3,4,5-trifluorobenzoic acid (2.00 g, 4.91 mmol) was dissolved in dry TF ( 10 ml). N-methylmorpholine ("NMM", 1.1 mL, 9.82 mmol) was added and the contents of the flask were cooled to -20 ° C. In a second oval-bottom flask equipped with a magnetic stirrer and low temperature thermometer, a solution of diphenylphosphine chloride ("DPPC1", 1.03 mL, 5.40 mmol) in dry THF (2 mL) cooled to -20 ° C was prepared under nitrogen. cannula into the first bank. The mixture was stirred at this temperature for 15 minutes and then a solution of o-cyclopropylmethylhydroxylamine (0.47 g, 5.40 mmol) in dry THF (2 mL) was added. The mixture was stirred at -20 ° C for 1.5 hours and then allowed to warm to ambient temperature overnight. The solvent was removed in vacuo and the residue was taken up in ethyl acetate (50 mL). The organic phase was washed with brine (20 mL), 1 M aqueous KHSO4 (20 mL), saturated NaHCO3 (2 x 20 mL), brine (20 mL) and dried over MgSO4. The solvent was removed in vacuo and the residue was Purified by silica gel chromatography (eluent: CH 2 Cl 2) to give 2.15 g (92%) of N-cyclopropylmethyloxy-2- (4-iodo-2-methylamino) -3,4,5-trifluorobenzamide as a yellow solid.

EXAMPLE 28

2- (2-Fluoro-4-iodophenylamino) -3,4-difluorobenzoic acid

2,3,4-Trifluorobenzoic acid (37.57 g, 213.4 mmol) and 2-fluoro-4-iodoaniline (50.57 g) were dissolved in an "inert" three-necked, oval bottom flask equipped with a mechanical stirrer and reflux condenser. 213.4 mmol) in dry acetonitrile (740 mL). Lithium amide (19.59 g, 853.46 mmol) was then added in small portions over 15 minutes and the resulting suspension was heated under reflux for 1 hour. During this hour, the color changed from gray-pink to dark blue. The flask was placed in an ice bath and the reaction was quenched with concentrated HCl at pH 1. Water (2 L) was then added and the resulting solid was filtered, washed with water (2 x 500 mL) and dried in a vacuum oven at 50 ° C. 18 hours. The solid so obtained was triturated with CH 2 Cl 2 (500 mL), filtered, washed with fresh CH ₂ Cl ₂ (2 x 100 mL) and dried in a vacuum oven at 50 ° C for 24 hours to give 55.8 g (66%) 2- (2-fluoro-4-iodophenylamino) -3,4-difluorobenzoic acid as a light brown solid; mp 199-201 ° C.

The results of Examples 11-28 expressed as percent yield are shown in the Examples themselves.

The other three arrangements of Method A, Method B or Method C, namely Method A1, Methods B1 and B2, and Method C1 were used in the preparation of Examples 25-39 and Preparations 3-8. In method A1, the "two-vessel method", a base (1 mol equivalent) was added to a first flask to a solution of a compound of formula (B) in which Z is COOH (1 mol equivalent) in an aprotic solvent such as tetrahydrofuran ("TF"). ") At about -78 ° C. In a second flask, the base (2 mol equivalents) was added to a solution of the compound of formula (A) (1 mol equivalents) in an aprotic solvent such as TF at about -78 ° C. The contents of the first flask were transferred to the second flask and the resulting mixture was allowed to warm or warmed overnight to, for example, ambient temperature such that the reaction progressed satisfactorily before it developed.

In method B1, the "one-pot method", both compounds, a compound of formula (B) in which Z is COOH (1 mol equivalent), and a compound of formula (A) (1 mol equivalent) were dissolved in an aprotic solvent such as TF The mixture was cooled to about -78 ° C and a base was added. The mixture was allowed to warm

100 or warmed overnight to, for example, ambient temperature to progress satisfactorily before it evolved.

In Method B2, both the compound of formula (B) in which Z is COOH (1 mol equivalent) and the compound of formula (A) (1 mol equivalent) were dissolved in an aprotic solvent such as THF, cooled to about - 20 ° C to 0 ° C and a base (3 mol equivalent) was added. The mixture was heated overnight at a temperature of, for example, 40 ° C-50 ° C to allow the reaction to proceed satisfactorily before it evolved.

In the Cl method, which is also a two-pot method, a first flask formed a solution of a compound of formula (B) in which Z is COOH (1 mol equivalent) in an aprotic solvent such as TF at about -78 ° C. In a second flask, base (3 mol equivalents) was added to a solution of the compound of formula (A) (1 mol equivalents) in an aprotic solvent such as THF at about -78 ° C. The contents of the first flask were transferred to the second flask and the resulting mixture was allowed to warm or warmed overnight to, for example, ambient temperature such that the reaction progressed satisfactorily before it developed.

Further examples 29 and 30, indicated by their example numbers in the column labeled "Ex. The results are reported as a percentage of the yield of the compound of formula I in the column labeled "Yield (%)". The reactants are the compound of formula (A) and the compound of formula (B), which are indicated in the columns marked ₃ , (A) 'and' (B) '. The bases and method used are listed in the columns labeled "Base" and "Method". Three (3) molar equivalents of base were used unless otherwise stated.

101

Table 3

Pr. (B) (A) Base Method Yield

No. (%)

F

2- (N-Methyl-N-phenylamino) benzoic acid

To a 250 mL flask was added N-methylaniline (3.75 g, 35.0 mmol), 2-fluorobenzoic acid (5.1 g, 36.8 mmol), and THF (115 mL). To this solution was added lithium amide (1.7 g, 73.5 mmol) in two portions over 5 minutes. This mixture was heated to 50 ° C under nitrogen for about 3.5 hours and then cooled to room temperature. The reaction was quenched with water (25 mL), concentrated HCl (10 mL) and MTBE (25 mL). The aqueous layer was removed and the organic layer was washed with water (25 mL). The solvent was removed in vacuo and the product was dissolved in IPA (25 mL) at 70 ° C. Water (10 mL) was added and the mixture was slowly cooled to -10 ° C. The resulting product was filtered and washed with IPA:

102 water 4: 6 (10 mL). The resulting yellow solid was dried in a vacuum oven at about 50 ° C to give 6.9 g (87% yield) of 2- (N-methyl-N-phenylamino) benzoic acid; mp 105-106 ° C.

EXAMPLE 32

2- {4- [3- (3,4-Dichlorophenyl) propyl] phenylamino} benzoic acid

To an "inert" flask containing 701 g (25 mmol) of 4- (3- (3,4-dichlorophenyl) propyl] aniline, 3.6 g (26 mmol) of 2-fluorobenzoic acid and 70 mL of TF was added 2.0 g (87%). The reaction mixture was heated at 55 ° C for 6 hours, then cooled to room temperature and quenched by the addition of water and dilute hydrochloric acid The layers were separated, the upper layer was concentrated in vacuo and the solid crystallized from acetone. The solid was filtered and the filter cake was washed with acetone / water and dried in a vacuum oven to give 7 g (70%) of 2- (4- (3- (3,4-dichlorophenyl) propyl) phenylamino} benzoic acid). mp 133 ° C.

Further examples 33 to 35, indicated by their example numbers in the column labeled "Ex. No. ", are shown in Table 4 below. Results are reported as a percentage of the yield of the compound of Formula I in the column labeled" Yield (%) ". The reactants are a compound of formula (A) and a compound of formula (B), which are indicated in the columns labeled "(A)" and "(B)". The bases and method used are listed in the columns labeled "Base" and "Method". Three (3) molar equivalents of base were used unless otherwise stated.

103

Table 4

Pr. (B) No.

(A)

base

Method Yield

COOH

LiHMDS

COOH

LiHMDS

COOH

LiHMDS

B2

B2

C1

76 ^c

99 ^d

The data in Tables 1-4 were collected from non-optimized experiments. The amount of product would increase if the reaction conditions were optimized. "NU" indicates that the product has not been identified. This does not mean that the product could not be obtained by the process of the present invention. More likely

This indicates that under the specific reaction conditions used, the amount of product was below the detection limit or simply was not determined.

The above examples show that the sequential addition method in Example 1 and the use of lithium amide in Examples 11 and 12 surprisingly increase the yield of the process of the invention.

Although the method of the invention typically provides high selectivity of ortho substitution over para substitution, the preparation of 2- (4-iodo-2-methylphenylamino) -3,4,5-trifluorobenzoic acid from 4-iodo-2-methylaniline and acid

2,3,4,5-tetrafluorobenzoic acid in TF typically provided mixtures of the desired compound and the para-substituted spatial isomer, namely 4- (4-iodo-2-methylphenylamino) -2,3,5-trifluorobenzoic acid. These mixtures were very difficult to purify. As shown in Example 22, in step (a) the use of a mixture of about 1 part TF and about 1 part acetonitrile provides the desired ortho-substituted product without contamination with the corresponding para-space isomers.

In the process of the present invention, alkali metal hydrides and amides are preferred as bases in the preparation of the compound of formula I over alkali metal and alkaline earth metal bis (trialkyl) amides, wherein compound I is as defined above, except that Z is COOH or COOM, wherein M is an alkali metal or alkaline earth metal cation. Bases such as hexamethyldisilazide must be used for best results, as these bases are degraded more slowly over time and commercially available substances are usually contaminated. More importantly, bases such as lithium hexamethyldisilazide should be added sequentially in order to avoid the formation of reactive benzyne (ΌόΗ ₄ ) intermediates. These intermediates are observed when, for example, 3 equivalents of mol of LiHMDS are added simultaneously to the reaction of the process of the invention.

105

Alkali metal hydrides and alkali metal amides as bases are solids that can be added to the reaction at once and also give the best results. Since these bases are solids, the amount of base in contact with the reactants is controlled by the degree of solubility of the base and / or by the limited surface area of the reactants' contact with the solid base particles. In addition, alkali metal hydrides and alkali metal amides need not be treated prior to use. Advantages of alkali metal hydrides and alkali metal amides over alkali metal and alkaline earth metal bis (trialkylsilyl) amides in the preparation of a compound of formula I wherein the compound of formula I is defined as above except Z is COOH or COOM where M is a cation alkali metal or alkaline earth metal cation are important for satisfactory industrial scale production.

A further advantage of the process according to the invention resides in finding excellent carbyloxy acid activating agents in the coupling of a compound of formula I, defined as above, except that Z is COOH or COOM, where M is an alkali metal or alkaline earth metal cation with a compound of the formula II, III or IV, each of which is as defined above, to give a product which is a compound of formula I wherein Z is COOR ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ or -C (O) N (R ¹⁸ ) R ¹⁹ , wherein R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are as defined above. Pairing using PyBOP typically provides products with low yields and cleaning of the resulting products is difficult. The process of the present invention utilizes carboxylic acid activators such as thionyl chloride, DPPCl, or EDC. These reagents provide higher yield products. In addition, the products are easier to clean. In addition, the cost of carbyloxy acid activating agents used in the method of the invention is usually lower than the cost of PyBOP. These advantages are important in industrial applications.

Claims (90)

1 O 1 Q i i o R and R are independently hydrogen or alkyl or R and R together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl; 138 m is 0 or 1; n is 0, 1, 2, 3, 4; R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently hydrogen, alkyl, alkenyl, phenyl and benzyl; A process for the synthesis of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hydrogen, alkyl, alkoxy or aryl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro . CN, - (O) _m - (CH ₂ ) _n -R ¹¹ or - [N (H)] _m -CH ₂ ) _n -R ¹¹ , wherein m, on R ¹¹ are defined below or any two substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , which are bonded to adjacent carbon atoms of the ring and may together form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom, to which R ¹ is attached and the carbon atom to which R ⁶ is attached and the carbon atom is attached 107 adjacent to said nitrogen atom to which R ¹ is attached form a 5-membered or 6-membered aromatic or dihydrogenaromatic cycle containing carbon atoms and 1 or 2 nitrogen atoms; R ¹¹ is hydrogen, hydroxy, -CO ₂ H or N (R ¹² ) R ¹³ , 1011 1011 R and R are independently hydrogen or alkyl or R and R together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl; m is 0 or 1; n is 0, 1, 2, 3, 4; Z is COOH, COOM, COOR ^15, C (O) R ^15, -C (O) N ^{(R16) R17,} -C (O (N (R ¹⁸ ) OR ¹⁹ , NO _2, or CN) wherein M is an alkali metal or alkaline earth metal cation; and R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are, independently of one another, hydrogen, alkyl, alkenyl, phenyl and benzyl or R and R together with the nitrogen atom to which they are attached a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl; comprising reacting a compound of formula (A) wherein R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above with a compound of formula (B) 108 wherein Z, R ² , R ³ , R ⁴ and R ⁷ are as defined above and X is halogen or O-LG, wherein LG is SO ₂ R ²⁰ or P (= O) (OR ²⁰ ) ₂ , wherein R ²⁰ is alkyl or aryl, optionally in a solvent and in the presence of an equivalent of from about 1 mole to about 10 moles of a base, wherein the base is selected from; an alkali metal or alkaline earth metal hydride, including lithium hydride, sodium hydride, potassium hydride and calcium hydride, from an alkali metal or alkaline earth metal dialkylamide, including lithium diisopropylamide, an alkali metal or alkaline earth metal amide, including lithium amide, sodium amide, potassium amide, and an alkali metal or alkaline earth metal alkoxide, including sodium ethoxide, potassium tert-butoxide, and magnesium ethoxide over time and at a temperature sufficient to provide a compound of formula I. The process according to claim 1, wherein the base is selected from: lithium diisopropylamide, lithium hydride, sodium hydride, potassium hydride, lithium amide, sodium amide, potassium amide, sodium methoxide, sodium ethoxide and potassium tert-butoxide. The method of claim 1, wherein the base is selected from: lithium hydride, sodium hydride and potassium hydride. 109 4. The process of claim 1 wherein the base is lithium hydride. The process of claim 1, wherein the base is selected from: lithium amide, sodium amide and potassium amide. 6. The process of claim 1 wherein the base is lithium amide. 7. The process of claim 1 wherein the base is lithium diisopropylamide. The process of claim 1, wherein the base is selected from: sodium methoxide, sodium ethoxide and potassium tert-butoxide. A process according to claim 1, characterized in that an equivalent of 1 to 5 moles of base is used initially and optionally an equivalent of 0.5 to 4 moles of base is added to the reaction over time, either in one batch and / or sequentially in the same. or different doses at the same or different time intervals. A 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl; m is 0 or 1; n is 0, 1, 2, 3, 4; Z is COOH or COOM; involving the reaction of a compound of formula (A) 150 (A) wherein R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above, with a compound of formula (B) R ² R ³ (B) wherein Z, R ² , R ³ , R ⁴ and R ⁵ are as defined above, X is halogen or O-LG, wherein LG is SO ² R ²⁰ or P (= O) (OR ²⁰ ) 2, wherein R ²⁰ is alkyl or aryl, optionally in a solvent and in the presence of from about 1 mole equivalent to about 10 moles of base, wherein the base is an alkali metal bis (trialkylsilyl) amide or an alkaline earth bis (trialkylsilyl) amide including lithium bis (trialkylsilyl) amide sodium bis (trialkylsilyl) amide, potassium bis (trialkylsilyl) amide at a temperature and time sufficient to form a compound of formula I. A 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl; m is 0 or 1; n is 0, 1, 2, 3, 4; Z is COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ , -C (O) N (R ¹⁸ ) OR ¹⁹ , NO ₂ or CN, wherein R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently hydrogen, alkyl, alkenyl, phenyl and benzyl; R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl ; including: (a) a step of reacting a compound of formula (A) (A) wherein R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above, with a compound of formula (B) 148 wherein Z, R ² , R ³ , R ⁴ and R ⁵ are as defined above, X is halogen or O-LG, wherein LG is SO ² R ²⁰ or P (= O) (OR ²⁰ ) 2, wherein R ²⁰ is alkyl or aryl, in the presence of from about 1 mole equivalent to about 10 moles of the base, wherein the base is an alkali metal bis (trialkylsilyl) amide or an alkaline earth bis (trialkylsilyl) amide, including lithium bis (trialkylsilyl) amide, sodium bis (trialkylsilyl) amide potassium bis (trialkylsilyl) amide at a temperature and for a time sufficient to give the compound of Formula I; and (b) purifying the compound of Formula I formed in step (a). A 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl; comprising (a) reacting an acid selected from trifluoroacetic acid, trichloroacetic acid, inorganic acid, alkylsulfonic acid or arylsulfonic acid with a compound of formula Ij wherein R ² -R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above , M and ^M are each independently an alkali metal or alkaline earth metal, (b) adding a carboxylic acid activating agent to the reaction mixture of step (a), and the reaction time and at a temperature sufficient to form the corresponding activated intermediates carboxylic acid, and (c ) adding, optionally in the presence of an equivalent of up to 10 moles of a tertiary organic amine, a reactant selected from: compounds of formula II HOR II. 139 wherein R ¹⁵ is as defined above, or a pharmaceutically acceptable salt thereof, or from a compound of Formula III HN (R ¹⁶ ) R ¹⁷ III, wherein R ¹⁶ and R ¹⁷ is as defined above, or a pharmaceutically acceptable salt thereof, or from a compound of formula IV HN (R ¹⁸ ) OR ¹⁹ IV, wherein R ¹⁸ and R ¹⁹ is as defined above, or a pharmaceutically acceptable salt thereof, and a reaction at a time and temperature sufficient to prepare a compound of Formula Ig or Ih or Ii. A 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl. A 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl. 124 A 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl. 114 A 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl. The process of claim 9, wherein said equivalent of an additional 0.5 to 4 moles of base is added to the reaction mixture gradually in unequal decreasing amounts. The method of claim 10, wherein in the compound of formula (B), Z is COOH and the initial amount of base is equivalent to 2 moles or Z is COOM and the initial amount of base is equivalent to 1 mol and said equivalent of an additional 0.5 to 4 moles of base is added to the reaction mixture gradually in unequal decreasing amounts as follows: equivalent of about 0.5 mol, sequentially followed by an equivalent of about 0.25 mol, about 0.13 mol, about 0.06 110 mol, and optionally followed by an equivalent of about 0.03 mol, followed by an equivalent of about 0.015 mol. 12. The process according to claim 1 characterized in that R ¹ is hydrogen. 13. The process of claim 1 wherein X is fluoro. The method of claim 1, wherein X is O-LG, wherein LG is SO ₂ CF ₃ or P (= O) (OCH ₂ CH ₃ ) 2. 15. The process of claim 1 characterized in that R ^2, R ^3, R ⁴ and R ⁵ are each independently selected from hydrogen, alkoxy, fluoro, chloro, bromo and iodo. 16 17 R 1 and R 2 together with the nitrogen atom to which they are attached form a 3- to R 3 atom 16 17 R and R together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl. 16. The process of claim 1 characterized in that R, R, R, R and R ¹⁰ are each independently selected from hydrogen, alkyl, fluoro, chloro, bromo and iodo. 17 17 R and R are independently hydrogen or alkyl; R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl ; m is 0 or 1; n is 0, 1, 2, 3, 4; Z is COOH, COOM, COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ , -C (O) N (R ¹⁸ ) OR ¹⁹ , NO ₂ or CN, wherein M is an alkali metal or alkaline earth metal cation; and R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently hydrogen, alkyl, alkenyl, phenyl benzyl or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached a 3- to 10-membered heterocyclic group containing atoms carbon and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl; involving the reaction of a compound of formula (A) NH R ¹ wherein R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above with a compound of formula (B) 121 R ² R ³ wherein Z is COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ , -C (O) N (R ¹⁸ ) OR ¹⁹ , NO 2 or CN and R ² -R ⁵ and R ¹⁵ -R ¹⁹ are as defined above and X is halogen or O-LG, wherein LG is SO ² R ²⁰ or P (= O) (OR ²⁰ ) ₂ , wherein R ²⁰ is alkyl or aryl, optionally in a solvent and in the presence of from about 1 mole to about 10 moles of a base, which base is selected from: an alkali metal bis (trialkylsilyl) amide or an alkaline earth bis (trialkylsilyl) amide, including lithium bis (trialkylsilyl) amide, sodium bis (trialkylsilyl) amide, bis ( a trialkylsilyl) potassium amide at a time and temperature sufficient to provide a compound of formula I. 17. The method of claim 1 wherein Z is COOH or COOM. The method of claim 1 wherein R ¹ is hydrogen, X is fluoro, R ² , R ³ , R ⁴ and R ⁵ are independently selected from hydrogen, alkoxy, fluoro, chloro, bromo and iodo, R ^6, R ^7, R ^8, R ⁹ and R ¹⁰ are each independently selected from hydrogen, methyl, F, ^- Cl, Br and I, and z is COOH or COOM. 19. The process of claim 1 wherein a solvent comprising acetonitrile, tetrahydrofuran, 1,2-diethoxyethane, 2,2-dimethoxypropane, 1,2-dimethoxypropane, diethyl ether, dioxane, or methyl tert-butyl ether is present. 20. The process of claim 1 wherein a solvent comprising tetrahydrofuran or acetonitrile is present. 111 The method of claim 1, wherein a solvent is present comprising a mixture of from about one volume of acetonitrile and about one volume of tetrahydrofuran to about five volumes of acetonitrile and about one volume of tetrahydrofuran. The process according to claim 1, wherein at the time of base addition, the temperature of the reaction mixture is from -78 ° C to 150 ° C. The method of claim 1, wherein the compound of formula I is a compound of formula Ia a or a pharmaceutically acceptable salt thereof in which R ⁶ is halogen or methyl, R ⁸ is bromine or iodine and Z is COOH, COOM, COOR ¹⁵ , -C (O) NR ¹⁶ ) R ¹⁷ , -C (O) NR ¹⁸ ) R ¹⁹ , NO ₂ or CN, wherein M is an alkali or alkaline earth metal, R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3 to 3 ring 24. The method of claim 1 wherein the compound of formula I is a compound of formula Ib 112 Ib, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is halogen or methyl, R ⁸ is bromine or iodine and Z is COOH, COOM, COOR ¹⁵ , -C (O) NR ¹⁶ ) R ¹⁷ , -C (O) NR ¹⁸ ) R ¹⁹ , NO ₂ or CN, wherein M is an alkali or alkaline earth metal, R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl . The method of claim 1, wherein the compound of Formula I is a compound of Formula Icl br Icl or a pharmaceutically acceptable salt thereof in which 113 R ⁶ is halogen or methyl, R ⁸ is bromo or iodo and Z is COOH, COOM, COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) NR ¹⁶ ) R ¹⁷ , -C (O) NR ¹⁸ ) R ¹⁹ , NO ₂ or CN, where M is an alkali or alkaline earth metal, R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or The method of claim 1 I is a compound of formula Ic2 characterized in that the compound of formula R ⁶ Λ Λ FROM T i IC2 F TI F or a pharmaceutically acceptable salt thereof, wherein R ⁶ is halogen or methyl, R ⁸ is bromo or iodo and Z is COOH, COOM, COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) NR ¹⁶ ) R ¹⁷ , -C (O) NR ¹⁸ ) R ¹⁹ , NO ₂ or CN, wherein M is an alkali or alkaline earth metal, R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3 to 3 ring The method of claim 11 is a compound of Formula Id characterized by compound of formula R ⁶ H FROM H Id r8 ^ F ^x X / F F or a pharmaceutically acceptable salt thereof, wherein R ⁶ is halogen or methyl, R ⁸ is bromo or iodo and Z is COOH, COOM, COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) NR ¹⁶ ) R ¹⁷ , -C (O) NR ¹⁸ ) R ¹⁹ , NO ₂ or CN, wherein M is an alkali or alkaline earth metal, R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl . 28. The method of claim 1, wherein the compound of formula I is a compound of formula 115 or a pharmaceutically acceptable salt thereof. 29. The method of claim 1 wherein the compound of formula I is a compound of formula Cl, CH _3, or a pharmaceutically acceptable salt thereof. 30. The method of claim 1 wherein the compound of formula I is a compound of formula or a pharmaceutically acceptable salt thereof. A method according to any one of claims 1 to 22, wherein the compound of formula I is a compound of formula 116 _{(CH2) 3} COOH or a pharmaceutically acceptable salt thereof. 32. The method of claim 1 wherein I is a compound of formula I, wherein the compound of formula or a pharmaceutically acceptable salt thereof. The method of claim 1, characterized in I is a compound of the formula I and I by that compound of the formula I COOH A method according to any one of claims 1 to 22, characterized by 117 or a pharmaceutically acceptable salt thereof. wherein the compound of formula I is a compound of formula or a pharmaceutically acceptable salt thereof. 35. The method of claim 1, wherein the compound of formula I is a compound of formula or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the compound of formula I is a compound of formula 118 or a pharmaceutically acceptable salt thereof. 37. The method of claim 1, wherein the compound of formula I is a compound of formula CO ₂ H or a pharmaceutically acceptable salt thereof. A method of synthesizing a compound of Formula I 119 or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hydrogen, alkyl, alkoxy or aryl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro . CN, - (OMCM-R) or - [N (H)] _m CH _{2) n} R ⁱⁿ which m, the R ¹¹ are as defined below, or any two substituents selected from R ^2, R ^3, R ^4, R ^5, R ^6, R ^7, R ⁸ , R ⁹ and R ¹⁰ , which are bonded to adjacent carbon atoms of the ring and may together form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom, to which R ¹ is attached and the carbon atom to which R ⁶ is attached and the carbon atom adjacent to said nitrogen atom to which R ¹ is attached form a 5-membered or 6-membered aromatic or dihydrogen aromatic ring containing carbon atoms, and 1 or 2 nitrogen atoms; R ¹¹ is hydrogen, hydroxy, -CO ₂ H or N (R ¹² ) R ¹³ , 120 39. The process of claim 38 wherein the base is selected from: lithium bis (trialkylsilyl) amide, sodium bis (trialkylsilyl) amide and potassium bis (trialkylsilyl) amide. 40. The process of claim 38 wherein the base is lithium bis (trialkylsilyl) amide. The method of claim 38, wherein an equivalent of 1 to 5 moles of base is used initially and optionally an equivalent of 0.5 to 4 moles of base is added to the reaction over time, either in one portion and / or sequentially in the same batch. or different doses at the same or different time intervals. 122 42. The process of claim 41, wherein said equivalent of 0.5 to 4 moles of base is added to the reaction mixture gradually in unequal decreasing amounts. 43. The method of claim 38 characterized in that R ¹ is hydrogen. 44. The process of claim 38 wherein X is fluoro. The method of claim 38, wherein X is O-LG, wherein LG is SO ₂ CF ₃ or P (= O) (OCH ₂ CH ₃ ) ₂ . 46. The method of claim 38 characterized in that R ^2, R ^3, R ⁴ and R ⁵ are each independently selected from hydrogen, alkoxy, fluoro, chloro, bromo and iodo. The method of claim 38 wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from hydrogen, alkyl, fluoro, chloro, bromo and iodo. 48. The method of claim 38 characterized in that Z is -C (O) N (R ¹⁸⁾ OR ¹⁹ wherein R ¹⁸ and R ¹⁹ are independently hydrogen, alkyl, alkenyl, phenyl and benzyl. The method of claim 38 wherein R ¹ is hydrogen, X is fluoro, R ² , R ³ , R ⁴ and R ⁵ are independently selected from hydrogen, alkoxy, fluoro, chloro, bromo and iodo; R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from hydrogen, alkyl, fluorine, chlorine, bromine and iodine and Z is -C (O) N (R ¹⁸ ) OR ¹⁹ , wherein R ¹⁸ and R ^{18 19} are independently hydrogen, alkyl, alkenyl, phenyl and benzyl. 50. The process of claim 38 wherein a solvent comprising acetonitrile, tetrahydrofuran, 1,2-diethoxyethane, 2,2-dimethoxypropane, 1,2-dimethoxypropane, diethyl ether, dioxane, or methyl tert-butyl ether is present. 123 51. The process of claim 38 wherein a solvent comprising tetrahydrofuran or acetonitrile is present. 52. The process of claim 38, wherein a solvent is present comprising a mixture of from about one volume of acetonitrile and about one volume of tetrahydrofuran to about five volumes of acetonitrile and about one volume of tetrahydrofuran. 53. The process of claim 38, wherein at the time of base addition, the temperature of the reaction mixture is from -78 ° C to 150 ° C. 54. The method of claim 38 wherein the compound of Formula I is a compound of Formula Ia or a pharmaceutically acceptable salt thereof, wherein: R ⁶ is halogen or methyl, -R ⁸ is bromo or iodo, and Z is COOH, COOM, COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) NR ¹⁶ ) R ¹⁷ , -C (O) NR ¹⁸ ) R ¹⁹ , NO ₂ or CN, R ¹⁵ is alkyl, alkenyl, alkynyl, aryl or heterocyclic and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3 to 3 ring 55. The method of claim 38 wherein the compound of formula I is a compound of Formula 1b 1b, or a pharmaceutically acceptable salt thereof, wherein: R ⁶ is halogen or methyl, R ⁸ is bromine or iodine and Z is COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) NR ¹⁶ ) R ¹⁷ , -C (O) NR ¹⁸ ) R ¹⁹ , NO ₂ or CN, wherein R ¹⁵ is alkyl, alkenyl, alkynyl, aryl or heterocyclic and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl . The method of claim 38, wherein the compound of Formula I is a compound of Formula Icl 125 Ici, or a pharmaceutically acceptable salt thereof, wherein: R ⁶ is halogen or methyl, R ⁸ is bromine or iodine and Z is COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) NR ¹⁶ ) R ¹⁷ , -C (O) NR ¹⁸ ) R ¹⁹ , NO ₂ or CN, wherein R ¹⁵ is alkyl, alkenyl, alkynyl, aryl or heterocyclic and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3 to 3 ring 57. The method of claim 38 wherein the compound of formula I is a compound of formula Ic2 Ic2 or a pharmaceutically acceptable salt thereof, wherein R ⁶ is halogen or methyl, R ⁸ is bromine or iodine and Z is COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) NR ¹⁶ ) R ¹⁷ , -C (O) NR ¹⁸ , R ¹⁹ , NO 1 or CN, where R ¹⁵ is alkyl, alkenyl, alkynyl, aryl or heterocyclic and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, 126 alkenyl, phenyl, and benzyl; R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl . 58. The method of claim 38 wherein the compound of formula I is a compound of formula Id R ⁶ H FROM r j Γ J Id R ⁸ ' Y ' F T or a pharmaceutically acceptable salt thereof, wherein R ⁶ is halogen or methyl, R ⁸ is bromine or iodine and Z is COOR ¹⁵ , -C (O) R ¹⁵ , -C (O) NR ¹⁶ ) R ¹⁷ , -C (O) NR ¹⁸ ) R ¹⁹ , NO ₂ or CN, wherein R ¹⁵ is alkyl, alkenyl, alkynyl, aryl or heterocyclic and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl . A process according to any one of claims 38 to 53, wherein the compound of formula I is a compound of formula 127 or a pharmaceutically acceptable salt thereof. 60. The method of claim 38 characterized in that it comprises, moreover, the hydrolysis of a compound of formula I, wherein Z is COOR ¹⁵ wherein R ¹⁵ is alkyl, alkenyl, alkynyl, aryl or heterocyclic group to form a compound of Formula Id2 Id2 or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hydrogen, alkyl, alkoxy or aryl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, 128 alkoxy, nitro, CN, - (O) _m - (CH ₂ ) _n -R ^1; or - [N (H)] _m CH _{2) n} -R ^n, m, the R ¹¹ are as defined below, or any two substituents selected from R ^2, R ^3, R ^4, R ^5, R ^6, R ^7, R ⁸ , R ⁹ and R ¹⁰ , which are attached to adjacent carbon atoms of the ring and may together form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom, to which R ¹ and the carbon atom to which R ⁶ is attached and the carbon atom adjacent to said nitrogen atom to which R ¹ is attached form a 5-membered or 6-membered aromatic or dihydrogen aromatic ring containing carbon atoms and 1 or 2 nitrogen atoms; R ¹¹ is hydrogen, hydroxy, -CO ₂ H or N (R ¹² ) R ¹³ , R and R are independently hydrogen or alkyl, or R and R together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl; m is 0 or 1; n is 0, 1, 2, 3, 4. 61. The method of claim 60 wherein the compound of Formula Id2 is a compound of Formula HOOC Cl 129 or a pharmaceutically acceptable salt thereof. 62. The method of claim 60 wherein the compound of formula Id2 is a compound of formula or a pharmaceutically acceptable salt thereof. 63. The method of claim 60 wherein the compound of formula Id2 is a compound of formula or a pharmaceutically acceptable salt thereof. 64. The method of claim 60 wherein the compound of formula Id2 is a compound of formula that compound of formula 130 or a pharmaceutically acceptable salt thereof. 65. The method of claim 60, wherein: Id2 is a compound of formula or a pharmaceutically acceptable salt thereof. 66. The method of claim 60 wherein the compound of formula Id2 is a compound of formula or a pharmaceutically acceptable salt thereof. 67. The method of claim 60 wherein the compound of formula Id2 is a compound of formula 131 or a pharmaceutically acceptable salt thereof. 68. The method of claim 60 wherein the compound of Formula Id2 is a compound of the formula or a pharmaceutically acceptable salt thereof. 69. The method of claim 60 wherein the compound of formula Id2 is a compound of formula 132 CO ₂ H or a pharmaceutically acceptable salt thereof. 70. The method of claim 60 wherein the compound of Formula Id2 is a compound of formula or a pharmaceutically acceptable salt thereof. 71. A method for the synthesis of a compound of formula Ie 133 or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hydrogen, alkyl, alkoxy or aryl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro . CN, - (O) _m - (CH ₂ ) _n -R ¹¹ or - [N (H)] _m CH _{2) n} -R ¹¹ wherein m is _5, the R ⁿ are as defined below, or any two substituents selected from R ^2, R ^3, R ^4, R ^5, R ^6, R ^7, R ⁸ , R ⁹ and R ¹⁰ , which are bonded to adjacent carbon atoms of the ring and may be taken together to form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom to which R ¹ is attached and the carbon atom to which R ⁶ is attached and the carbon atom adjacent to said nitrogen atom to which R ¹ is attached may form a 5-membered or 6-membered member an aromatic or dihydrogen-aromatic cycle containing carbon atoms and 1 or 2 nitrogen atoms; R ¹¹ is hydrogen, hydroxy, -CO ₂ H or N (R ¹² ) R ¹³ , R and R are independently hydrogen or alkyl or R and R are formed 134 together with the nitrogen atom to which they are attached a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl; m is 0 or 1; n is 0, 1, 2, 3, 4; Z is COOR ¹⁵ , -C (O) N (R ¹⁶ ) R ¹⁷ or -C (O) N (R ¹⁸ ) OR ¹⁹ , wherein R ¹⁵ is alkyl, alkenyl, alkynyl, aryl or a heterocyclic group and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently hydrogen, alkyl, alkenyl, phenyl and benzyl, or R and R together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl; comprising pairing a compound of formula If wherein Z is COOH or COOM, wherein M is an alkali or alkaline earth metal cation and R ¹ , R ² -R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above, or when Z is COOM, R * is optionally an alkali metal or alkaline earth metal cation with a compound of formula II HOR ¹⁵ II, wherein R ¹⁵ is as defined above, or a pharmaceutically acceptable salt thereof, or a compound of Formula III HN (R ¹⁶ ) R ¹⁷ III 135] | Wherein R and R is as defined above, or a pharmaceutically acceptable salt thereof, or a compound of formula IV HN (R ¹⁸ ) OR ¹⁹ IV, wherein R ¹⁸ and R ¹⁹ is as defined above, or a pharmaceutically acceptable salt thereof. 72. The method of claim 71, characterized in that R ¹⁸ is hydrogen and R ¹⁹ is selected from methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, 2-methyl-prop-l-yl, 1,1 -dimethyl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2-yl, 1 -methylcyclopropyl, 2-methylcyclopropyl, 1-methylcyclobutyl, 2-methylcyclobutyl, 3-methylcyclobutyl, 1-methylcyclopentyl, 2-methylcyclopentyl, 3-methylcyclopentyl, 1-methylcyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 4-methylcyclohexyl, 4-methylcyclohexyl , cyclopentylmethyl, cyclohexylmethyl, phenyl and benzyl. 73. The method of claim 72, characterized in that R ¹⁸ is hydrogen and R ¹⁹ is cyclopropylmethyl. A process according to any one of claims 71 to 73, wherein the compound of formula I is a compound of formula or a pharmaceutically acceptable salt thereof. 136 75. The method according to claim 71, characterized in that R ¹⁶ is hydrogen and R ¹⁷ is cyclopropylmethyl, 2-cyclopropylmethyl, cyclobutylmethyl, 2-cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 2cyklohexylmetyl, cyklopropyldifluórmetyl or 2-cyclopropyl-l, l-difluoroethyl. A process according to claim 71 for the synthesis of a compound of formula Ig Ig or a pharmaceutically acceptable salt or compound of formula Ih Ih or a pharmaceutically acceptable salt or compound of Formula Ii thereof 137 Or a pharmaceutically acceptable salt thereof, wherein: R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro . CN, - (O) _m - (CH ₂ ) _n -R ^H or - [N (H)] _m CH ₂₎ n R ¹ \ wherein m, n and R ¹¹ are as defined below, or any two substituents selected from R ^2, R ^3, R ^4, R ^5, R ^6, R ^7, R ⁸ R ⁹ and R ¹⁰ , which are bonded to adjacent carbon atoms of the ring and may be taken together to form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms; R ¹¹ is hydrogen, hydroxy, -CO ₂ H or N (R ¹² ) R ¹³ , 77. The method of claim 76 wherein M ^a is selected from a lithium cation, a sodium cation, or a potassium cation. 78. The method of claim 76 wherein M ^a is a lithium cation. 79. The method of claim 76 wherein the acid used in step (a) is trifluoroacetic acid, trichloroacetic acid, an inorganic acid selected from HCl, HBr or H2SO4, an alkylsulfonic acid selected from CH3SO3H and CF3SO3H, or an arylsulfonic acid selected from phenyl-SO ₃ H and para-toluenesulfonic acid. 80. The process of claim 76 wherein the acid used in step (a) is CH3SO3H. The method of claim 76, wherein the carboxylic acid activating agent used in step (b) is selected from: (COCl) ₂ , S (O) Cl ₂ , S (O) ₂ Cl ₂ , P (O) C 1 -C _3, (phenyl) ₂ P (O) Cl, 1 ' -carbonyldiimidazole, trifenylfosfíndietylazokarboxylátu, EDC, EDCI, and N, N'-dicyclohexylcarbodiimide. 140 82. The process of claim 76 wherein the carboxylic acid activating agent used in step (b) is S (O) C12- 83. The process of claim 76, wherein the carboxylic acid activating agent used in step (b) is (phenyl) 2P (= O) Cl. 84. The process of claim 76 wherein the reactant added in step (c) is O-cyclopropylmethylhydroxylamine or a pharmaceutically acceptable acid addition salt thereof. A process according to any one of claims 76 to 84, wherein the compound of formula I is a compound of formula NH-O or a pharmaceutically acceptable salt thereof. 86. A method of synthesizing a compound of Formula Ik 141 Ik or a pharmaceutically acceptable salt thereof, in which: R ¹ is hydrogen, alkyl, alkoxy or aryl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro . CN, - (O) _m - (CH _{2) n} -R, or ^the - [N (H)] _m -CH _{2 n} -R ^H , wherein m, on R ¹¹ are as defined below or any two substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , which are bonded to adjacent carbon atoms of the ring and may together form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom, to which R ¹ and the carbon atom to which R ⁶ is attached and the carbon atom adjacent to said nitrogen atom to which R ¹ is attached form a 5-membered or 6-membered aromatic or dihydrogenaromatic ring containing carbon atoms and 1 or 2 nitrogen atoms; 142 R ¹¹ is hydrogen, hydroxy, -CO 2 H or N (R ¹² ) R ¹³ , 1212 12 13 R and R are independently hydrogen or alkyl or R and R together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl; m is 0 or 1; n is 0, 1, 2, 3, 4; Z is COOR ¹⁵ wherein R ¹⁵ is alkyl, alkenyl, alkynyl, aryl or heterocyclic; comprising pairing a compound of formula If wherein Z is COOH or COOM, wherein M is an alkali or alkaline earth metal cation and R ¹ , R ² -R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above, or when Z is COOM, R ¹ is optionally an alkali metal or alkaline earth metal cation, with a compound of formula II HOR ¹⁵ II, wherein R ¹⁵ is as defined above, or a pharmaceutically acceptable salt thereof, or a compound of formula IIa LR ^15a , or a pharmaceutically acceptable salt thereof, wherein R ¹⁵ is as defined above and L is a group selected from: bromine, chlorine, iodine, alkylsulfonyloxy, arylsulfonyloxy, acyloxy, optionally in the presence of a nucleophilic base. 143 87. A process for the synthesis of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hydrogen, alkyl, alkoxy or aryl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro . CN, - (O) _m - (CH ₂ ) _n -R ¹¹ or - [N (H)] _m -CH ₂ ) _n -R ¹¹ wherein m, on R ¹¹ are as defined below or any two substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , which are attached to adjacent carbon atoms of the ring and may together form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom to which it is attached attached by R ¹ and the carbon atom to which R ⁶ is attached and the carbon atom adjacent to said nitrogen atom to which R ¹ is attached 144 to form a 5-membered or 6-membered aromatic or dihydrogenaromatic cycle containing carbon atoms and 1 or 2 nitrogen atoms; R ¹¹ is hydrogen, hydroxy, -CO 2 H or N (R ¹² ) R ¹³ , 1919 17 19 R and R are independently hydrogen or alkyl or R and R together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or alkyl; m is 0 or 1; n is 0, 1, 2, 3, 4; Z is COOH, COOM, COOR ^15, C (O) R ^15, -C (O) N ^{(R16) R17,} -C (O) N (R ¹⁸ ) OR ¹⁹ , NO ₂ or CN, wherein M is an alkali or alkaline earth metal cation and R ¹⁵ is an alkyl, alkenyl, alkynyl, aryl or heterocyclic group; and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently hydrogen, alkyl, alkenyl, phenyl and benzyl; R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group containing carbon atoms and one, two or three heteroatoms selected from O, S and NR ¹⁴ , wherein R ¹⁴ is hydrogen or alkyl ; including: (a) a step of reacting a compound of formula (A) wherein R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above, with a compound of formula (B) 145 R ² R ³ (B) wherein Z, R ² , R ³ , R ⁴ and R ⁵ are as defined above, X is halogen or O-LG, wherein LG is SO ² R ²⁰ or P (= O) (OR ²⁰ ) 2, wherein R ²⁰ is alkyl or aryl, in the presence of from about 1 mole equivalent to about 10 moles of a base selected from: alkali metal hydride or alkaline earth metal hydride including lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal dialkylamide or alkaline earth metal dialkylamide including lithium diisopropylamide, alkali metal amide or alkaline earth metal amide, including lithium amide, sodium amide and potassium amide, alkali metal alkoxide or alkaline earth metal alkoxide, including sodium ethoxide, potassium tert-butoxide, and magnesium ethoxide at a temperature and for a time sufficient to give the compound of Formula I; 88. A method of synthesizing a compound of Formula I 146 or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hydrogen, alkyl, alkoxy or aryl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro . CN, - (O) _m - (CH ₂ ) _n -R ¹¹ or - [N (H)] _m -CH ₂ ) _n -R ¹ wherein m, on R ¹¹ are defined below or any two substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R 11 ⁸ , R ⁹ and R ¹⁰ , which are attached to adjacent carbon atoms of the ring and may together form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom to which it is attached attached by R ¹ and the carbon atom to which R ⁶ is attached and the carbon atom adjacent to said nitrogen atom to which R ¹ is attached form a 5-membered or 6-membered member 147 an aromatic or dihydrogenaromatic cycle containing carbon atoms and 1 or 2 nitrogen atoms; R ¹¹ is hydrogen, hydroxy, -CO 2 H or N (R ¹² ) R ¹³ , R ¹² and R ¹³ are independently hydrogen or alkyl; R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 3- to R 3 89. A method of synthesizing a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hydrogen, alkyl, alkoxy or aryl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group: hydrogen, halogen, 149 alkyl, aryl, heterocyclic, haloalkyl, alkoxy, nitro, CN, - (O) _m - (CH ₂ ) _n -R ⁿ or - [NH 4] -CH 2 -n ¹¹ , wherein m, on R ¹¹ are defined below or any two substituents selected from R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ which are bonded to adjacent carbon atoms of the ring and may be taken together to form an aryl, heteroaryl, heterocycle or cycloalkyl of 4 to 7 ring atoms, or R ¹ and R ⁶ together with the nitrogen atom to which R ¹ and the atom are attached the carbon to which R ⁶ is attached and the carbon atom adjacent to said nitrogen to which R ¹ is attached to form a 5-membered or 6-membered aromatic or dihydrogenaromatic cycle containing carbon atoms and 1 or 2 nitrogen atoms; R ¹¹ is hydrogen, hydroxy, -CO ₂ H or N (R ¹² ) R ¹³ , R ¹² and R ¹³ are independently hydrogen or alkyl; R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 3- to R ³ atom A method according to any one of claims 1, 38, 71, 86, 87, 88 or 89, characterized in that it is carried out on an industrial scale.