MX2008009284A - Compounds for the treatment of inflammatory disorders - Google Patents

Abstract

This invention relates to compounds of the Formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, ADAMs, TACE, aggrecanase, TNF- or combinations thereof.

Description

COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY DISORDERS CROSS REFERENCE This Application is a continuation in part of patent application Serial No. 11 / 180,863 filed on July 13, 2005, which claims priority of Provisional Application serial number 60 / 588,502 filed on July 16, 2004.

TECHNICAL FIELD This invention relates in general to new hydantoin derivatives that can inhibit matrix metalloproteinases (MMPs), a dentengine and metalloproteases (ADAM) and / or the enzyme converting tumor necrosis factor-alpha (TACE) and by doing so prevent the release of tumor necrosis factor-alpha (TNF-a), pharmaceutical compositions comprising said compounds, and methods of treatment using said compounds.

BACKGROUND OF THE INVENTION Osteo arthritis and / or rheumatoid arthritis (OA and RA, respectively) are destructive diseases of articular cartilage that are characterized by localized erosion of the cartilage surface. Several discoveries have shown that the articular cartilage of the femoral heads of patients with OA, for example, had a reduced incorporation of radiorotulated sulfate with respect to the controls, which suggests that there must be an increased rate of cartilage degradation in OA (Mankin et al., J. Bone Joint Surg, 52A (1970) 424-434). There are four classes of protein degrading enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteases. The available evidence supports the view that metalloproteases are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in cartilage with OA and the activity is correlated with the severity of the lesion (Mankin et al., Arthritis Rheum, 21, 1978, 761-766, Woessner et al., Arthritis Rheum, 26, 1983). , 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase (a recently identified metalloprotease) has been identified that provides the specific dissociation product of proteoglycan, which is found in patients suffering from RA and OA (Lohmander LS et al., Arthritis Rheum., 36, 1993, 1214-22. ).

Metalloproteases (MP) have been implicated as primordial enzymes in the destruction of cartilage and bone in mammals. It can be expected that the pathogenesis of such diseases can be beneficially modified by the administration of MP inhibitors (see Wahl et al Ann.Rem. Med. Chem. 25, 175-184, AP, San Diego, 1990). MMPs are a family of more than 20 different enzymes that are involved in a variety of biological processes important in the uncontrolled decomposition of connective tissue, including proteoglycan and collagens, which leads to the resorption of the extracellular matrix. This is a characteristic of many pathological disorders, such as RA and OA, corneal, epidermal or gastric ulceration; metastasis or tumor invasion; periodontal disease and bone diseases. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as in their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of MPs), which form complexes inactive with the MMP. The tumor necrosis factor-alpha (TNF-a) is a cell-associated anthocyanin that is processed from a precursor form of 26 kDa to an active form of 17 kd. See Black R.A. "Tumor necrosis factor-alpha converting enzyme" Int J Biochem Cell Biol. 2002 January; 34 (1): 1-5 and Moss ML, White JM, Lambert MH, Andrews RC.'TACE and other ADAM proteases as targets for drug discovery "Drug Discov Today, 2001 April 1; 6 (8): 417-426, each of which is incorporated herein by reference.

It has been shown that TNF-a plays a key role in immune and inflammatory responses. An inappropriate expression or hyper expression of TNF-a is a hallmark of a number of diseases, which include RA, Crohn's disease, multiple sclerosis, psoriasis and septicemia. It has been shown that the inhibition of TNF-α production is beneficial in many preclinical models of inflammatory diseases, converting the inhibition of production or signaling of TNF-a, in an attractive target for the development of new anti-inflammatory drugs. TNF-a is a basic mediator in responses to inflammation, fever and acute phases, similar to what was observed during acute infection and shock. It has been shown that the excess of TNF-a is lethal. Blocking the effects of TNF-a with specific antibodies can be beneficial in a variety of disorders, including autoimmune diseases such as RA (Feldman et al, Lancet, (1994) 344, 1110), non-insulin-dependent diabetes mellitus. (Lohmander LS et al., Arthritis Rheum 36 (1993) 1214-22) and Crohn's disease (Macdonald T. et al., Clin. Exp. Immunol., 81 (1990) 301). The compounds that inhibit the production of TNF-a are therefore of therapeutic importance for the treatment of inflammatory disorders. It has recently been shown that metalloproteases, such as TACE, are capable of converting TNF-a from its inactive form to an active form (Gearing et al. Nature, 1994, 370, 555). Because it has observed that the excessive production of TNF-a in several diseases is also characterized by a tissue degradation mediated by MMP, the compounds that inhibit both the production of MMP and TNF-a, can also be particularly advantageous in diseases in which they are involved both mechanisms. One approach to inhibit the deleterious effects of TNF-a is inhibition of the enzyme, TACE before it can process TNF-a to its soluble form. TACE is a member of the ADAM family of type I membrane proteins and is an intermediary in the ectodomain proteolysis of several signaling and adhesion proteins anchored to membranes. TACE is increasingly important in the study of several diseases, including inflammatory disease, due to its role in the dissociation of TNF-a from its "conduit" sequence and therefore in the release of the soluble form of the TNF-α protein (Black RA Int J Biochem Cell Biol. 2002 34, 1-5). There are numerous patents and publications describing MMP inhibitors based on hydroxamate, sulfonamide, hydantoin, carboxylate and / or lactam. U.S. Patent 6,677,355 and U.S. Patent 6,534,491 (B2) disclose compounds that are hydroxamic acid derivatives and MMP inhibitors. US Patent 6,495,565 describes lactam derivatives which are potential inhibitors of MMP and / or TNF-a.

PCT publications WO2002 / 074750, WO2002 / 096426, WO20040067996, WO2004012663, WO200274750 and WO2004024721 describe hydantoin derivatives which are potential inhibitors of MMP. PCT publications WO2004024698 and WO2004024715 describe sulfonamide derivatives that are potential inhibitors of MMP. PCT publications WO2004056766, WO2003053940 and WO2003053941 also describe potential inhibitors of TACE and MMP. There is a need in the art for inhibitors of MMP, ADAM, TACE, and TNF-a, which may be useful as anti-inflammatory and therapeutic cartilage protective compounds. Inhibition of TNF-a, TACE and other MMPs can prevent cartilage degradation by these enzymes, thereby relieving the pathological disorders of OA and RA as well as many other autoimmune diseases.

BRIEF DESCRIPTION OF THE INVENTION In its many embodiments, the present invention provides a new class of compounds as inhibitors of TACE, the production of TNF-a, MMP, ADAM or any combination thereof, methods for preparing said compounds, pharmaceutical compositions comprising one or more of said compounds, methods for preparing pharmaceutical formulations comprising one or more of said compounds, and methods of treatment, prevention, inhibition or improvement of one or more diseases associated with TACE, TNF-a, MMP, ADAM or any combination thereof using said compounds or pharmaceutical compositions. In one embodiment, the present application describes a compound having the general structure shown in formula (I): (l) or a pharmaceutically acceptable salt, solvate, ester, or isomer thereof, wherein: X is selected from the group consisting of -S-, -C (R) 2- or N (R4) -T is selected from the group consisting of H (where U and V are absent), alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, and arylalkyl, wherein said aryl, heteroaryl, heterocyclyl, cycloalkyl, Alkylaryl and arylalkyl are optionally fused to one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of said alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl groups and arylalkyl of T are unsubstituted or are optionally independently substituted with one to four R10 moieties which may be the same or different, where each moiety of R10 is independently selected from the group of R10 moieties; U is absent or present, and if present U is selected from the group consisting of a covalent bond, -N (R) -, -N (R4) C (R) 2-, -N (R4) C (0 ) -, -O-, -N (R4) S (0) 2-, -N (R4) C (0) N (R4) -, and - N (R4) C (S) N (R4) -; V is absent or present, and if present V is selected from the group consisting of alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl are optionally fused to one or more selected moieties of the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of any of the aforementioned alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally independently substituted with one to four R10 moieties which they may be the same or different, where each R10 residue is independently selected from the group of R10 residues which follow; Y is absent or present, and if present Y is selected from the group consisting of a covalent bond, - (C (R4) 2) n-, - N (R4) -, -C (0) N (R4) - , -N (R4) C (0) -, -N (R4) C (0) N (R4) -, -S (0) 2N (R4) -, -N (R4) -S (0) 2, -O-, -S-, -C (O) -, -S (O) -, and -S (0) 2-; Z is absent or present, and if present Z is selected from the group consisting of a covalent bond, - (C (R4) 2) n-, -N (R4) -, -C (0) N (R4) - , -N (R4) C (0) -, -N (R4) C (0) N (R4) -, -S (0) 2N (R4) -, -N (R4) -S (0) 2- , -0-, -S-, -C (O) -, -S (O) -, and -S (0) 2-; n is 1 to 3; R is selected from the group consisting of H, -OR4, halogen, alkyl, fluoralkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl, wherein each of the alkyl, fluoralkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl groups and 1 arylalkyl of R is unsubstituted or is optionally substituted independently with one to four R20 moieties which may be the same or different, wherein each R20 moiety is independently selected from the group of R20 moieties below, provided that when Y is present and And it is N, S or O, then R1 is not halogen; R is selected from the group consisting of H, -OR4, halogen, alkyl, fluoralkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl, wherein each of the alkyl, fluoralkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl groups and 2 arylalkyl of R are unsubstituted or optionally independently substituted with one to four R20 moieties which may be the same or different, wherein each R20 moiety is independently selected from the group of R20 moieties below, provided that when Z is present and Z is N, S or O, then R2 is not halogen; each R is the same or different and is independently selected from the group consisting of H and alkyl, alkynyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl wherein each of said alkynyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are independently optionally substituted with one or two moieties selected from the group consisting of hydroxyl, alkyl, cycloalkyl, aryl, heteroaryl, -arylheteroaryl, and -heteroarylaryl; R is selected from the group consisting of -OR4, -N (R) 2, -S (0) -R4, -S (0) 2 -R4, -N (R4) S (0) 2 -R4, -S (0) 2N (R4) 2, -O (fluoralkyl), halogen, alkyl, fluoralkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcycloalkyl-alkylaryl and -arylalkyl, wherein each of the alkyl, fluoralkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkyl-alkylcycloalkyl, -alkylaryl, and -arylalkyl of R is unsubstituted or is optionally substituted independently with one to four R30 moieties which may be the same or different, wherein each R30 moiety is independently selected from the group of R30 moieties below; R is selected from the group consisting of halogen, alkyl, fluoroalkyl; and R is selected from the group consisting of halogen, alkyl, and fluoralkyl. The compounds of Formula I may be useful as inhibitors of TACE and may be useful in the treatment and prevention of diseases associated with TACE, TNF-α, MMP, ADAM or any combination thereof.

DETAILED DESCRIPTION OF THE INVENTION In its various embodiments, the present invention provides a new class of TACE inhibitors, the production of TNF-α, MMP, ADAM or any combination thereof, pharmaceutical compositions containing one or more of the compounds, methods of preparing the formulations Pharmaceuticals, comprising one or more of said compounds, and methods of treatment, prevention, or improvement of one or more of the symptoms of inflammation. In one embodiment, the present invention provides compounds that are represented by the above structural Formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, wherein the various moieties are as described above. In another embodiment, the isomer mentioned in the preceding paragraph is a stereoisomer. In one embodiment, T is alkyl or aryl; X is -C (R) 2-; And he is 2 absent; Z is absent or present; R is selected from the group consisting of H, halogen and alkyl; and if Z is present Z is -O-. In another embodiment, T is alkyl or aryl; X is -C (R) 2-; And this 2 absent; Z is absent or present, and if present Z is -O-; and R is selected from the group consisting of alkylaryl and alkylheteroaryl.

In another embodiment, T is alkyl or aryl; X is -N (R) -; And he is 2 absent; Z is absent or present; R is selected from the group consisting of H, halogen and alkyl; and if Z is present Z is -O-. 4 In another embodiment, X is -CH2- or -N (R) -. In one more mode, X is -CH2-. A In another modality, X is -N (R) -. In another embodiment, R is H. In another embodiment, T is alkyl. In a further mode, T is -CH3. In still another embodiment, T is aryl and said aryl is unsubstituted or optionally independently substituted with one to five R10 moieties which may be the same or different, wherein each R10 moiety is independently selected from the group of R10 moieties. In another embodiment, R10 is halogen. In a further embodiment, R10 is heteroaryl. In another embodiment, R10 is aryl. In a U mode it is selected from the group consisting of a covalent bond, -N (R4) -, -N (R4) C (0) -, and -N (R4) S (0) 2-. In a more mode U is a covalent bond. A In another modality, more U is -N (R) -. A In one more mode, U is -N (R) C (0) -.

In another embodiment, V is selected from the group consisting of aryl, heteroaryl, heterocyclyl, and cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl, and cycloalkyl are optionally fused to one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of said aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or is optionally independently substituted with one to four R10 moieties which may be the same or different, wherein each R10 moiety is independently selected from the group of R10 moieties. In another embodiment, Y is selected from the group consisting of a covalent bond, - (C (R4) 2) n-, -C (O) - and -O-. In one more mode, Y is -O-. In another modality more, Y is - (C (R4) 2) n-. In one more mode, Y is -C (O) -. In another modality, Y is a covalent bond. In one embodiment, R1 is selected from the group consisting of -OR4, H, alkyl, fluoralkyl, alkylaryl, halogen, and heteroaryl. In another embodiment, R1 is H. In a further embodiment, R1 is alkylaryl. In still another embodiment, R1 is alkyl. In still another embodiment, R 1 is fluoroalkyl. In a further embodiment, R1 is halogen. In another embodiment, R1 is -OR4.

In another embodiment, when R1 is -OR4, R4 is -CH2C = CCH3. In another embodiment, when R1 is -OR4, R4 is -CH2C = CCH2OH. In another embodiment, when R1 is -OR4, R4 is -CH2- < In another embodiment, the alkyl is -CH3. In still another embodiment, the alkyl is -CH 2 CH 3. In another embodiment, in formula (I), T, U, and V are taken together to form R1 is selected from the group consisting of F, Cl, OH, - OCH2C = CCH3, -OCH2CCCH2OH, -OCH3, and In another embodiment, in formula (I), T, U, and V are taken together to form and R1 is selected from the group consisting of F, Cl, OH, - OCH2C = CCH3, -OCH2C = CCH2OH, -OCH3, and -OCH2- In another embodiment, in formula (I), T, U, and V are taken together to form and R1 is selected from the group consisting of F, Cl, OH, - OCH2C = CCH3, -OCH2C = CCH2OH, -OCH3, and In another embodiment, in formula (I), T, U, and V are taken together to form and R1 is selected from the group consisting of F, Cl, OH, - OCH2C = CCH3, -OCH2C = CCH2OH, -OCH3, and -OCH2 < ] In another embodiment, in formula (I), T, U, and V are taken together to form and R1 is selected from the group consisting of F, Cl, OH, -OCH2C = CCH3, -OCH2C = CCH2OH, -OCH3, and -OCH2- < | In another embodiment, in formula (I), T, U, and V are taken together to form and R2 is selected from the group consisting of F, Cl, OH, - OCH2C = CCH3, -OCH2C = CCH2OH, -OCH3, and -OCH2].

In another embodiment, in formula (I), T, U, and V are taken together to form and R is selected from the group consisting of F, Cl, OH, -OCH2C = CCH3, -OCH2C = CCH2OH, -OCH3, and -OCH2] In another modality, in the formula (I), T, U, and V are taken together to form R2 is selected from the group consisting of F, Cl, OH, - OCH2C = CCH3, -OCH2C = CCH2OH, -OCH3, and -OCH2] In another embodiment, in formula (I), T, U, and V are taken together to form and R2 is selected from the group consisting of F, Cl, OH, -OCH2C = CCH3, -OCH2C = CCH2OH, -OCH3, and -OCH2- < ] In another modality, in formula (I), T, U, and V are taken together to form and R2 is selected from the group consisting of F, Cl, OH, -OCH2C = CCH3, -OCH2C = CCH2OH, -OCH3, and -OCH2]. In another embodiment, the fluoroalkyl is -CH2CF3. In one embodiment, the halogen is selected from the group consisting of -Br, -Cl and -F. In another embodiment, R4 is -CH3. In a further embodiment, alkyl of R is substituted with one to four residues R20 which may be identical or different, wherein each residue R20 is independently selected from the group of residues R20. In another embodiment, R20 is aryl. In another embodiment, Z is selected from the group consisting of a bond, -N (R4) -, - (C (R4) 2) n-, -C (O) - and -O-. In another modality, Z is -O-. In a further mode, Z is a covalent bond. 4 In one more mode, Z is -N (R) -. In another embodiment, Z is -C (O) -. In another embodiment, R is alkyl. In another embodiment, R2 is selected from the group consisting of -OR4, H, alkyl, fluoralkyl, alkylaryl, halogen, and heteroaryl. In another embodiment when R2 is -OR4, R4 is -CH2C = CCH3. In another embodiment when R2 is -OR4, R4 is -CH2C = CCH2OH. In another modality when R2 is -OR4, R4 is -CH2- < In one more mode, R2 is hydrogen. In still another embodiment, R2 is alkyl. In another embodiment, R2 is alkylaryl. In a further embodiment, R2 is fluoroalkyl. In another embodiment, R2 is -CH2CF3. In a further embodiment, R2 is halogen. In another embodiment, R2 is heteroaryl. In another embodiment, R4 is -CH3. Another embodiment of the invention describes the following compounds which are shown in Table A below.

TABLE A Structures fifteen twenty 15 20 ^ Another embodiment of the invention describes the referred compounds shown in the following Table B or a pharmaceutically acceptable salt, solvate, or ester thereof: TABLE B 20 Another embodiment of the invention describes the most preferable compounds shown in Table C below.

TABLE C As used above, and throughout this description, the following terms, unless otherwise indicated, will be construed as having the following meanings: "Patient" includes both humans and animals. "Mammals" means humans and other mammalian animals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 atoms of carbon in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having from about 1 to about 6 carbon atoms in the chain which may be straight or branched. The alkyl group may be substituted with one or more substituents which may be different or different, wherein each substituent is independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH (alkyl), -NH (cycloalkyl), -N (alkyl) 2, carboxy and -C (0) 0-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. "Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have from about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means approximately 2 to about 6 carbon atoms in the chain that can be straight or branched. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. "Alkynyl" means an aliphatic hydrocarbon group containing at least one triple carbon-carbon bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have from about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means that the alkynyl group may be substituted with one or more substituents which may be the same or different, wherein each substituent is independently selected from the group consisting of alkyl, aryl and cycloalkyl. "Aryl" means a monocyclic or aromatic multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be substituted optionally with one or more "ring system substituents" which may be the same or different, and which are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, where one or more of the ring atoms is a non-carbon element , for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" may be optionally substituted with one or more "ring system substituents" which may be the same or different, and which are as defined herein. The prefixes aza, oxa or tia before the name of the heteroaryl root mean that at least one nitrogen atom, oxygen or sulfur respectively, is present as a ring atom. A nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,4- thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindole, imidazo [1,2-a] pyridinyl, midazo [2,1-bjthiazole, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl , thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,4-triazinyl, benzothiazole and the like. The term "heteroaryl" also refers to partially saturated heteroaryl portions such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl-alkyl group in which aryl and alkyl are as previously described. Preferred aralkols comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The link with the main group is through the alkyl. "Alkylaryl" means an alkyl-aryl- group in which the alkyl and the aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. A non-limiting example of an appropriate alkylaryl group is tolyl. The link with the main group is through the aril. "Cycloalkyl" means a mono- or multicyclic non-aromatic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl may be optionally situted with one or more "ring system situents" which may be the same or different, and which are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbomyl, adamantyl and the like, as well as partially saturated species such as, for example, indanyl, tetrahydronaphthyl and the like. "Halogen" means fluorine, chlorine, bromine, or iodine. Fluorine, chlorine and bromine are preferred. "Substituents of the ring system" means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces a hydrogen available in the ring system. The substituents of the ring system may be the same or different, and each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C (= N-CN) -NH2, -C (= NH) -NH2, -C (= NH) -NH (alkyl), G ^ N-, G1G2N-alkyl-, G? G2NC (0) -, G? G2NS02- and -S02NG1G2, where dy and G2 may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single portion that simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) in a ring system.

Examples of such moieties are methylenedioxy, ethylenedioxy, -C (CH3) 2- and the like forming moieties such as, for example: "Heterocyclyl" means a non-aromatic monocyclic or saturated multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, wherein one or more of the ring system atoms are an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There is no adjacent oxygen and / or sulfur atom that is present in the ring system. Preferred heterocycls contain about 5 to about 6 ring atoms. The prefixes aza, oxa or thia before the heterocyclic root name mean that at least one nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclic ring may exist protected such as, for example, as a group -N (Boc), -N (CBz), -N (Tos) and the like; said protections are also considered part of this invention. The heterocyclyl may be optionally substituted with one or more "ring system substituents" which may be the same or different, and which are as defined herein. The nitrogen or sulfur atom of the heterocyclyl may be oxidized optionally to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocyclic rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. "Heterocyclyl" also includes a ring system in which a single moiety (ie, carbonyl) simultaneously replaces two available hydrogens on the same carbon atom in the ring system. Examples of said moieties are pyrrolidone: and thiomorpholinone: It should be noted that the tautomeric forms such as, for example, the residues: they are considered equivalent in certain embodiments of this invention.

"Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and the alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl group and a lower alkyl group. The link with the main group is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. "Heteroaralkyl" means a heteroaryl-alkyl- group in which heteroaryl and alkyl are as previously described. Preferred heteroatoms contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ilmethyl. The link with the main group is through the alkyl. "Hydroxyalkyl" means an HO-alkyl- group in which the alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. "Acyl" means a group H-C (O) -, alkyl-C (O) - or cycloalkyl-C (O) -, in which the various groups are as previously described. The link with the main group is through carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl. "Aroyl" means an aryl-C (O) - group in which the aryl group is as previously described. The link with the main group is through of carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond with the main group is through the oxygen of the ether. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond with the main group is through the oxygen of the ether. "Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond with the main group is through the oxygen of the ether. "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The link with the main group is through sulfur. "Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The link with the main group is through sulfur.

"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. A non-limiting example of an appropriate aralkylthio group is benzylthio. The link with the main group is through sulfur. "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The link with the main group is through carbonyl. "Aryloxycarbonyl" means an aryl-O-C (O) - group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The link with the main group is through carbonyl. "Aralkoxycarbonyl" means an aralkyl-O-C (O) - group. A non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The link with the main group is through carbonyl. "Alkylsulfonyl" means an alkyl-S (02) - group. Preferred groups are those in which the alkyl group is lower alkyl. The link with the main group is through the sulfonyl. "Arylsulfonyl" means an aryl-S (02) - group. The link with the main group is through the sulfonyl. The term "substituted" means that one or more hydrogens in the designated atom are replaced with a selection of the indicated group with the proviso that the normal valence of the designated atom under the existing circumstances is not exceeded, and that the substitution results in a stable compound. The combinations of substituents and / or Variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a degree of useful purity from a reaction mixture, and its formulation in the form of an effective therapeutic agent. The term "optionally substituted" means an optional substitution, with radical groups or specified moieties. The term "isolated" or "in isolated form" for a compound refers to the physical state of said compound after having been isolated from a synthesis process or natural source or combination thereof. The term "purified" or "in purified form" for a compound refers to the physical state of said compound after it has been obtained from a purification process or methods described herein or well known to a person skilled in the art, with purity sufficient to be characterized by conventional analytical techniques such as those described herein or well known to a person skilled in the art. It should be noted that any carbon as well as heteroatom with valences not met in the text, Schemes, Examples and Tables given here is considered to have the amount of hydrogen atoms sufficient to satisfy the valences. When a functional group in a compound is called "protected", this means that the group is in modified form to avoid any undesirable secondary reaction in the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those skilled in the art as well as by references in conventional textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York. When any variable (for example, aryl, heterocyclic, R2, etc.) occurs more than once in any constituent or in formula I, its definition each time it occurs is independent of its definition each time it occurs again. As used herein, the term "composition" encompasses a product that comprises the specified ingredients in the specified amounts, as well as any product that is the result, direct or indirect, of the combination of the specified ingredients in the specified amounts. The prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug", as used herein, denotes a compound that is a precursor of a drug which, upon administration to a subject, undergoes a chemical conversion by metabolic or chemical processes that provides a compound of Formula I or a salt and / or a solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A. C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated here as a reference. The term "prodrug" means a compound (e.g., a precursor of a drug) that is transformed in vivo to provide a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation can occur by several mechanisms, (for example, by metabolic or chemical processes), such as, for example, through hydrolysis in the blood. A discussion of the use of prodrugs has been provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of A. C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. For example, if a compound of Formula (I) or a salt, hydrate or solvate of the pharmaceutically acceptable compound contains a carboxylic acid functional group, a prodrug may comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-Cß) alkyl, (C 2 -C 2) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having from 4 to 9 atoms of carbon, 1-methyl-1 - (alkanoyloxy) -ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms , 1-methyl-1 - (alkoxycarbonyloxy) ethyl tending from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl which ranges from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N-alkylamine of (d-C2) (C2-C3) alkyl (such as β-dimethylaminoethyl), carbamoyl-alkyl (d-C2), N, N-dialkylcarbamoyl of (d-C2) -alkyl of (C C2) and piperidino-, pyrrolidino- or morpholino (C2-C3) alkyl, and the like. Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C 1 -C 6) alkanoyloxymethyl. ((Ci-C? JJethyl, 1-methyl-1- ((C) C) alkanoyloxy) ethyl, (C6C6) alkoxycarbonyloxymethyl, (Ci-C3) N-alkoxycarbonylaminomethyl, succinoyl, Ci (C) alkanoyloxy -Cß), α-aminoalkane of (d-C4), arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each a-aminoacyl group is independently selected from among L-amino acids occurring naturally, P (0) (OH) 2, -P (0) (O-alkyl (C? -C6)) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group from the hemiacetal form of a carbohydrate), and the like. If a compound of Formula (I) incorporates an amine functional group, a prodrug can be formed by replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R 'are each independently of (C -? - C10) alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural a-aminoacyl or natural a-aminoacyl, - C (OH) C (0) OY1 where Y1 is H, (C6) alkyl or benzyl, - C (OY2) Y3 where Y2 is (C4) alkyl and Y3 is (CrC6) alkyl, (CrC6) carboxyalkyl, aminoalkyl of (CrC) or mono-N- or di-N, N-alkylaminoalkyl of (C C6), - C (Y4) Y5 where Y4 is H or methyl and Y5 is mono-N- or di-N, N-alkylamino of (Ci-Cβ) ) morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like. "Solvate" means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves several degrees of ionic and covalent binding, including hydrogen bonding. In these cases the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystalline lattice of the crystalline solid. "Solvate" covers both solvates in the solution phase and solvates that can be isolated. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate in which the solvent molecule is H20. "Effective amount" "therapeutically effective amount" describes an amount of compound or composition of the present invention that is effective to inhibit TACE, the production of TNF-a, MMP, ADAMS or any combination thereof and thus produce the therapeutic effect improvement, inhibitor or preventive desired. The compounds of Formula I can form salts that are also within the scope of this invention. The reference to a compound of Formula I given herein is interpreted including reference to its salts, unless otherwise indicated. The term "salt (s)", as used herein, denotes acid salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases.

In addition, when a compound of Formula I contains both as a basic moiety, as such, but without limiting it to pyridine or imidazole, and an acidic moiety, as such, but not limited to a carboxylic acid, zwetterions ("internal salts") can be formed. ) and are included within the term "salt (s)" as used herein. Pharmaceutically acceptable salts (ie, non-toxic, physiologically acceptable) are preferred, although other salts are also useful. The salts of the compounds of Formula I can be formed, for example, by reaction of a compound of Formula I with an amount of acid or base, such as an amount of equivalent, in a medium such as that in which the salt precipitates or in an aqueous medium followed by lyophilization. Examples of acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphor sulfonates, fumarates, hydrochlorides, hydrobromides, yohydrates, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates), and the like. Additionally, acids that are generally considered appropriate for the formation of pharmaceutically useful salts from basic pharmaceutical compounds have been discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food &Drug Administration, Washington, D.C. on its website). These descriptions are incorporated herein by reference. Examples of basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as dicyclohexylamines, t-butylamines, and salts with amino acids such as arginine, lysine and the like. The basic groups containing nitrogen can be quaternized with agents such as lower alkyl halides (for example chlorides such as bromides and methyl iodides), ethyl, and butyl), dialkyl sulfates (for example dimethyl, diethyl, and dibutyl sulfate), long chain halides (for example decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. All said acid salts and basic salts are pharmaceutically acceptable salts within the scope of the invention and all the acidic and basic salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention. The compounds of Formula I, and salts, solvates and prodrugs thereof, may exist in tautomeric form (eg, in the form of an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

All stereoisomers (e.g., geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those that may exist due to asymmetric carbons in various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated as being within the scope of this invention, as positional isomers (such as , for example, 4-pyridyl and 3-pyridyl). The individual stereoisomers of the compounds of the invention may be, for example, substantially free of other isomers, or may be mixed, for example, as racemates or with all others, or other selected stereoisomers. The chemistry centers of the present invention can have the S or R configuration as defined by the recommendations of lUPAC 1974. The use of the term "salt", "solvate", "prodrug" and the like applies equally to salt, solvate and prodrug of the enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the compounds of the invention. The polymorphic forms of the compounds of Formula I, and of the salts, solvates and prodrugs of the compounds of Formula I, will be included in the present invention.

The compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can be inhibitors of TACE, TNF-a and / or MMP activity. In one aspect, the invention provides a pharmaceutical composition comprising as an active ingredient at least one compound of formula (I). In another aspect, the invention provides a pharmaceutical composition of formula (I) which additionally comprises at least one pharmaceutically acceptable carrier. In another aspect, the invention provides a method for the treatment of disorders associated with TACE, TNF-α, MMP, ADAM or any combination thereof, wherein said method comprises administering to a patient in need of such treatment a pharmaceutical composition comprising amounts therapeutically effective of at least one compound of formula (I). In another aspect, the invention provides the use of the compound of formula (I) for the manufacture of a medicament for treating disorders associated with TACE, TNF-α, MMP, ADAM or any combination thereof. The compounds of Formula I may have anti-inflammatory activity and / or immunomodulatory activity and may be useful in the treatment of diseases including but not limited to septic shock, hemodynamic shock, septicemic syndrome, post-ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, rejection of grafts, cancers, such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, diseases of inflammation of the skin, diseases of intestinal inflammation such as the disease of Crohn and colitis, OA and RA, ankylosing spondylitis, psoriatic arthritis, Still's disease, ureitis, Wegener's granulomatosis, Behcehe's disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, damage radiation, hyperoxic alveolar lesions, periodontal disease, HIV, non-insulin-dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinaal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, brain accidents vascular , cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing alveolitis, psoriasis, rejection of transplants, atopic dermatitis, vasculitis, allergic, seasonal allergic rhinitis, reversible obstruction of the respiratory tract, respiratory distress syndrome in adults, asthma, chronic obstructive pulmonary disease (COPD) and / or bronchitis. It has been contemplated that a compound of this invention may be useful in the treatment of one or more of the listed diseases. In another aspect, the invention provides a method for preparing a pharmaceutical composition for treating disorders associated with TACE, TNF-α, MMP, ADAM or any combination thereof, wherein said method comprises intimately contacting a compound of formula (I) and at least one pharmaceutically acceptable carrier. In another aspect, the invention provides a compound of formula (I) which exhibits TACE, TNF-α, MMP, ADAM or any combination of this inhibitory activity, including enantiomers, stereoisomers and tautomers of said compound, and salts, esters, or solvates pharmaceutically acceptable said compound, wherein said compound is selected from the compounds of the structures listed in Table A provided above. In another aspect, the invention provides a pharmaceutical composition for the treatment of disorders associated with TACE, TNF-α, MMP, ADAM or any combination thereof in a subject comprising, administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof. In another aspect, the invention provides a compound of formula (I) in purified form. In another aspect, the invention provides a method for the treatment of a disorder or disease mediated by TACE, MMP, TNF-α, aggrecanase, or any combination thereof in a subject comprising: administering to the subject in need of such treatment an amount Therapeutically effective of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof. In another aspect, the invention provides a method for the treatment of a disorder or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, growth of solid tumors, and tumor invasion by secondary metastases, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in a subject, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof acceptable. In another aspect, the invention provides a method for the treatment of disorder or disease selected from the group consisting of fever, cardiovascular disorders, haemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft reaction. versus host, autoimmune diseases and HIV infection in a subject, which comprises administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof . In another aspect, the invention provides a method for the treatment of a disorder or disease selected from the group consisting of septic shock, hemodynamic shock, syndrome sepsis, post-ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, rejection of grafts, cancers such as cutaneous T-cell lymphoma, diseases that involve angigogenesis, autoimmune diseases, inflammation of the skin, diseases of intestinal inflammation such as Crohn's disease and colitis, osteo and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Still's disease in adults, ureitis, Wegener's granulomatosis, Behcehe's disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar lesions, periodontal disease, HIV, non-insulin-dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchoplasia dysplasia ulmonar, retinal disease, scleroderma, osteoporosis, renal ischemia ischemia, myocardial infarction, cerebrovascular accident, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fribrosing alveolitis, psoriasis, rejection of transplants, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible obstruction of the respiratory tract, insufficiency syndrome adult respiratory syndrome, asthma, chronic obstructive pulmonary disease (COPD) and bronchitis in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt, solvate, ester or isomer of this pharmaceutically acceptable.

In another aspect, the invention provides a method for the treatment of a disorder or disease associated with COPD, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt, solvate, ester or isomer thereof pharmaceutically acceptable. In another aspect, the invention provides a method for the treatment of a disorder or disease associated with rheumatoid arthritis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt , solvate, ester or isomer thereof pharmaceutically acceptable. In another aspect, the invention provides a method for the treatment of a disorder or disease associated with Crohn's disease, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof. In another aspect, the invention provides a method for the treatment of a disorder or disease associated with psoriasis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt, solvate, ester or isomer thereof pharmaceutically acceptable. In another aspect, the invention provides a method for the treatment of a disorder or disease associated with spondylitis. ankylosing agent, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, or ester isomer. In another aspect, the invention provides a method for the treatment of a disorder or disease associated with sciatica, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt, solvate, ester or isomer thereof pharmaceutically acceptable. In another aspect, the invention provides a method for the treatment of a disorder or disease associated with a complex regional pain syndrome, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) ) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof. In another aspect, the invention provides a method for the treatment of a disorder or disease associated with psoriatic arthritis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt , solvate, ester or isomer thereof pharmaceutically acceptable. In another aspect, the invention provides a method for the treatment of a disorder or disease associated with multiple sclerosis, comprising: administering to the subject in need of said treatment a Therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, in combination with a compound selected from the group consisting of Avonex®, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis. Additionally, a compound of the present invention can be co-administered or used in combination with disease-modifying antirheumatic drugs (DMARDS) such as methotrexate, azathioprine, leflunomide, pencilinamine, gold salts, mycophenolate mofetil, cyclophosphamide and other similar drugs. They can also be co-administered or used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) such as piroxicam, naproxen, indomethacin, ibuprofen and the like; selective inhibitors of cycloxygenase-2 (COX-2) such as Vioxx® and Celebrex®; immunosuppressants such as steroids, cyclosporin, tacrolimus, rapamycin and the like; biological response modifiers (BRM) such as Enbrel®, Remicade®, IL-1 antagonists, anti-CD40, anti-CD28, IL-10, anti-adhesion molecules and the like; and other antiinflammatory agents such as p38 kinase inhibitors, PDE4 inhibitors, other chemically different TACE inhibitors, chemokine receptor antagonists, Thalidomide and other small molecule inhibitors of pro-inflammatory cytokine production.

Also, a compound of the present invention can be co-administered or used in combination with an H1 antagonist for the treatment of seasonal allergic rhinitis and / or asthma. Suitable H1 antagonists can be, for example, Claritin®, Clarinex®, Allegra®, or Zyrtec®. In another aspect, the invention provides a method for the treatment of a disorder or disease mediated by TACE, MMP, TNF-α, aggrecanase, or any combination thereof in a subject comprising: administering to the subject in need of such treatment an amount therapeutically effective of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof in combination with a therapeutically effective amount of at least one medicament selected from the group consisting of disease-modifying antirheumatic drugs (DMARDS), NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressants, biological response modifiers (BRM), anti-inflammatory agents and H1 antagonists. In another aspect, the invention provides a method for the treatment of a disorder or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, growth of solid tumors and tumor invasion by secondary metastases, neovascular glaucoma, disease of intestinal inflammation, multiple sclerosis and psoriasis in a subject, comprising: administering to the subject in need of such treatment a therapeutically effective amount of less a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof in combination with a therapeutically effective amount of at least one medicament selected from the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, inhibitors of COX-1, immunosuppressants, BRM, anti-inflammatory agents and H1 antagonists. In another aspect, the invention provides a method for the treatment of a disorder or disease selected from the group consisting of septic shock, hemodynamic shock, septicemic syndrome, post ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure. , fibrotic diseases, cachexia, rejection of the grafts, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, inflammatory skin diseases, inflammatory skin diseases, inflammatory bowel diseases such as Crohn's disease and colitis, osteo and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Still's disease in adults, ureitis, Wegener's granulomatosis, Behcehe's disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, gives or radiation, hyperoxic alveolar injury, periodontal disease, HIV, diabetes mellitus non-insulin dependent, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral vascular accidents, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing alveolitis, psoriasis, rejection of transplants, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible obstruction of respiratory tract, acute distress syndrome of the adult, asthma, chronic obstructive pulmonary disease (COPD) and bronchitis in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt , solvate, ester or isomer thereof pharmaceutically acceptable in combination with a therapeutically effective amount of at least one medicament selected from the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressants, BRM, agents anti-inflammatories and H1 antagonists. In another aspect, the invention provides a method for treating RA comprising administering a compound of formula I in combination with a compound selected from the class consisting of a COX-2 inhibitor for example Celebrex® or Vioxx®; a COX-1 inhibitor for example Feldene®; an immunosuppressant for example methotrexate or cyclosporin; a steroid for example β-metasone; and an anti-TNF-α compound, for example Enbrel® or Remicade®; an inhibitor of PDE IV, or other classes of compounds indicated for the treatment of RA. In another aspect, the invention provides a method for treating multiple sclerosis comprising administering a compound of the formula I in combination with a compound selected from the group consisting of Avonex®, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis. The activity of TACE is determined by a kinetic assay that measures the rate of fluorescent intensity increase generated by TACE catalyzed cleavage of an internally quenched peptide substrate (SPDL-3). The purified catalytic domain of recombinant human TACE (rhTACEc, Residue 215 to 477 with two mutations (S266A and N452Q) and a 6xHis tail) was used in the assay. It is purified from the baculovirus / Hi5 cell expression system using affinity chromatography. The SPDL-3 substrate is an internally quenched peptide (MCA-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Dpa-Arg-NH2), with its sequence derived from the dissociation site. TNFa. MCA is (7-Methoxycoumarin-4-yl) acetyl. Dpa is N-3- (2,4-Dinitrophenyl) -L-2,3-diaminopropionyl. A 50 μl assay mixture contains 20 mM HEPES, pH 7. 3.5 mM CaCl2, 100 μM ZnCl2, 2% DMSO, 0.04% Methylcellulose, 30 μM SPDL-3, 70 pM rhTACEc and one test compound. The RhTACEc is pre-incubated with the test compound for 90 min. at 25 ° C. The reaction is initiated by the addition of the substrate. Fluorescent intensity (excitation at 320 nm, emission at 405 nm) was measured every 45 seconds for 30 minutes, using a fluorescetrometer (GEMINI XS, Molecular Devices). The enzymatic reaction rate is shown as Units per second.

The effect of a test compound is shown as% of TACE activity in the absence of the compound. Compounds useful for TACE inhibitory activity may exhibit K, values of less than about 1000 nm, preferably about 0.01 nm to about 1000 nm, more preferably about 0J nm to about 100 nm, and more preferably less than about 15 nm. The TACE inhibitory activity (Ki values) of some representative compounds of the present invention is listed in the section of "EXAMPLES" given below. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. The compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and said compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents for provide pharmaceutically pleasing and tasty preparations. The tablets contain the active ingredient in mixtures with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents, such such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action for a longer period of time. For example, a delayed release material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in U.S. Patent Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release. The term "pharmaceutical composition" also encompasses both the bulk composition and the individual dosage units comprising more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the list of additional agents described herein, together with any pharmaceutically inactive excipient. The bulk composition and each individual dosage unit may contain fixed amounts of "more than one pharmaceutically active agent" mentioned above. Mass composition is a material that has not yet been formed in individual dosage units. A unit of Illustrative dosage is an oral dosage unit such as tablets, pills and the like. Similarly, the method described herein for the treatment of a patient by administration of the pharmaceutical composition of the present invention also encompasses the administration of the aforementioned bulk composition and individual dosage units. Formulations for oral use can also be presented in the form of capsules and hard gelatin where the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or with soft gelatine capsules which Active ingredient is mixed with water or in an aqueous medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active material mixed with excipients suitable for the manufacture of aqueous suspensions. Said excipients are suspending agents, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and acacia gum; the dispersing or wetting agents may be a natural phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethylene-oxicetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylenesorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame. . Oily suspensions may be formulated by suspending the active ingredient in the vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin, or cetyl alcohol. Sweetening agents such as those indicated above, and flavoring agents can be added to provide a tasty oral preparation. These compositions can be prepared by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent such as a suspending agent and one or more preservatives. The dispersing agents or wetting agents and suspending agents are exemplified by those that have already been mentioned above. As well additional excipients may be present, for example, sweetening, flavoring and coloring agents. The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be natural phosphatides, for example, soy beans, lecithin, and partial esters or esters derived from fatty acids and hexitol anhydride such as, for example, sorbitan monooleate, and condensation products of said partial esters with oxide. of ethylene, for example polyoxyethylene monooleate sorbitan. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Said formulations may also contain a demulgent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated in accordance with known techniques employing suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable solvent or diluent, for example, in the form of a solution in 1,3-butane. Among the vehicles and acceptable solvents that can be used is water, Ringer's solution and isotonic sodium chloride solution. In addition, fixative oils are conventionally used as a solvent or suspension medium. For this purpose, any soft fixative oil including synthetic mono- or diglycerides can be employed. In addition, fatty acids such as oleic acids are useful in the preparation of injectables. The compounds of the invention can also be administered in the form of suppositories for rectal administration of the drug. The compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at normal temperatures but this liquid at the rectal temperature and therefore melts in the rectum to release the drug. These materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc. are used, which contain the compounds of the invention. (For the purposes of this application, the topical application will include mouthwash and gargle). The compounds of the present invention can be administered by intranasal form through the topical use of appropriate intranasal vehicles or through transdermal routes using those forms of transdermal skin patches that are well known to those skilled in the art. To be administered in the form of a transdermal delivery system, the administration of the dose will naturally be continuous instead of of flashing through the entire dosing speed. The compounds of the present invention can also be released in the form of suppositories using bases such as cocoa butter, glycerin gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. The dosage regimen using the compounds of the present invention is selected according to a variety of factors including the type, species, weight, sex and health status of the patient; the severity of the disease that must be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound that is used. A doctor or veterinarian with common experience can easily determine and pre-write the effective amount of drug required to prevent, counteract, stop or reverse the progress of the disease. The optimal precision to achieve drug concentration within the scale that provides efficacy without toxicity requires a speed based on the kinetics of the drug's affordability at the target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug. Preferably, the doses of the compound of Formula I that are useful in the method of the present invention are on a scale of from 0.01 to 1000 mg per day. More preferably, the doses are on a scale from 0J to 1000 mg / day. More preferably, the doses are on a scale of from 0J to 500 mg / day. For oral administration, the compositions are preferably provided in the form of tablets that They contain 0.01 to 1000 milligrams of active ingredient, particularly 0.01, 0.05, OJ, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for symptomatic adjustment of the dose for the patient who It should be treated. An effective amount of the drug is commonly provided at a dose level of from about 0.0002 mg / kg to about 50 mg / kg of body weight per day. The scale is more particularly from about 0.001 mg / kg to 1 mg / kg of weight per day. Advantageously, the active agent of the present invention can be administered in a single daily dose, or the total daily dose can be administered in divided doses of two, three or four times per day. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. It will be understood, however, that the specific dosage level for any particular patient will depend on a variety of factors including age, body weight, general health, sex, diet, time of administration, route of administration, the rate of excretion, the combination of the drug and the severity of the particular disease undergoing therapy. The compounds of the invention can be produced by methods known to those skilled in the art and are shown in reaction schemes below and in the preparations and examples described below.

EXAMPLES The following abbreviations can be used in the procedures and schemes: ACN Acetonitrile AcOH Acetic acid Aq Aqueous BOC Ter-butoxycarbonyl BOC-ON [2- (tert-butoxycarbonyllamine) -2-phenylacetonitrile] BOC20 BOC anhydride C Degrees Celsius CBZCI Benzyl chloroformate DBU 1, 8-Diazabicyclo [5.4.0] undec-7-ene DCM Dichloromethane DEAD Diethyl Azodicarboxylate (DHQ) 2PHAL 1,4-Hydroquinoline hydrolyzate DIAD Diisopropylazodicarboxylate DIPEA Dipropylethylamine DMA N, N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DME Dimethoxyethane DMF Dimethylformamide DMFDMA N, N-Dimethylformamide dimethylacetal DMPU 1, 3-Dimethyl-3,4,5,6-tetrahydro-2 (1 h) -pyrimidinone DMSO Dimethyl sulfoxide EDCI 1 - (3-dimethylaminopropyl) - hydrochloride 3-ethylcarbodiimide Ionization electp Eq Equivalents EtOAc Ethyl acetate EtOH Ethanol 9 grams h. hours 1H proton HATU Hexafluorophosphate N, N, N ', N'-tetramethyl-0- (7- Azabenzotriazol-1-yl) Uronium Hex hexanes HOBT 1-Hydroxybenzotriazole HPLC High pressure liquid chromatography LAH Lithium aluminum hydride LDA Diisopropylamide lithium M Molar MMM mCPBA mefa-Chloroperoxybenzoic acid Me Methyl MeCN Acetonitrile MeOH Methanol min Minutes mg Milligrams MHZ Megahertz mL Milliliter MPLC Average Pressure Liquid Chromatography NMR Nuclear Magnetic Resonance MS NBS Mass Spectroscopy N-Bromosuccinimide NMM N-Methylmorpholine NMP 1-methyl-2-pyrrolidone ON Overnight PCC Pyridinium Chlorochromate PTLC Thin Film Preparative Chromatography PyBrOP bromo-tris-pyrrolidino-phosphonium hexafluorophosphate Pyr Pyridine RT Ambient temperature sgc Silica gel chromatography 60 tBOC Ter-butoxycarbonyl TACE Enzyme converter TNF-alpha TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography The NMR spectra were acquired by the following instruments: 400 MHz NMR (Bruker), 500 MHz NMR (Bruker), 400 MHz NMR (Varied), 300 MHz NMR (Varied) using CD3OD, CDCI3 or DMSO-d6 as solvents. The LC-MS data were obtained using a PESciex API 150EX quadrupole mass spectrometer using electroscopic ionization. Purification by reverse phase chromatography (Gilson) was carried out using a C18 reverse phase column with a gradient of (0.1% formic acid) 5:95 to 90:10 acetonitrile: water, a flow rate of 14 mL / min. Samples were collected using UV detection. Alternatively, by ISCO Companion (0.1% formic acid) 5:95 to 95: 5 acetonitrile: water, at a flow rate of = 10-55 mL / min. Normal phase silica gel chromatography was carried out on a Biotage instrument using 12 / M, 25 / M, or 40 / M to 60 A evaporation cartridges, or with a Jones Flash Master Personal instrument using Isolute evaporation with Cartridges of Sl 5g, 10g, 20g, 50g, or 70g. The compounds of formula (I) can be produced by methods known to those skilled in the art as shown in the following reaction schemes, and in the preparations and examples described below. These preparations and examples should not considered limiting of the scope of the description. Alternative mechanical tracks and analogous structures will be apparent to those skilled in the art. Some of the compounds prepared by these procedures are listed in the following tables. All kinds of isomeric forms of the compounds are considered to be within the scope of this invention.

Ways of synthesis and examples EXAMPLE 1 General Procedures for Example 1: In step 1, Compound 1A (either commercially obtainable, or one prepared by a procedure similar to that described by Abdalla, GM and Sowell, JW Journal of Heterocyclic Chemistry, 1987, 24 (2), 297-301) was treated with an equivalent of Di-tert-butyl dicarbonate in a polar solvent, such as DMF, for 30 minutes at 12 hours. The solvent was removed and compound 1B could be used without further purification or purified by silica gel chromatography. In Step 2, compound 1 B was reacted with potassium cyanide and ammonium carbonate in an appropriate alcohol and in a solution of water, at 50 ° C up to 90 ° C, for 5 hours up to 48 hours. After cooling, water was added and compound 1C was collected by filtration. In step 3, compound 1C was stirred with 2 to 20 equivalents of hydrogen chloride in methanol for 5 to 48 hours. After adding ethyl ether, the 1D compound could be collected by filtration.

EXAMPLE 2 Step 1 Compound 2A (Abdalla, GM and Sowell, JW Journal of Heterocyclic Chemistry, 1987, 24 (2), 297-301) (Hydrochloride salt, 8.60 g, 45.4 mmol), triethylamine (19.0 mL, 136 mmol ), and di-tert-butyl bicarbonate (11.9 g, 54.4 mmol) were stirred in methylene chloride (100 mL) at 25 ° C for 16 hours. Saturated aqueous NaHC 3 (150 mL) was added. The aqueous layer was extracted with CH2Cl2 (100 mL) twice. The organic phase was washed with brine (100 mL) and dried over Na 2 SO 4. The solvent was removed by rotary evaporator to provide compound 2B which was used without further purification.

Step 2 Compound 2B (9.06 g, 35.8 mmol), KCN (3.49 g, 53.7 mmol), and (NH4) 2 C03 (12.0 g, 125.2 mmol) were suspended in a mixture of EtOH (35 mL) and water (35 mL). ). The solution was stirred at 70 ° C for three days. After cooling, water (35 mL) was added. The solid was filtered and washed with water three times. The solid was dried under vacuum at 40 ° C for 16 hours to provide compound 2C (7.9 g, 68%).

Step 3: Compound 2C (4.0 g) methanol (50 mL) was suspended and HCl (4M in dioxane, 20 mL) was added. The solution was stirred at 25 ° C for 3 hours. Ethyl ether (50 ml) was added. The solid was filtered, washed with ethyl ether twice, and dried under vacuum for 12 hours to give compound 2D (2.7 g, 84%). The following intermediates were prepared as described in Examples 1 and 2.

EXAMPLE 3 3F General procedures for Example 3 In step 1, 5-Hydroxy-2-nitro-benzoic acid (compound 3A) was dissolved in an appropriate solvent, such as DMF, and reacted with an alkyl chloride or an alkyl bromide in the presence of cesium carbonate at room temperature for 2 to 16 hours. Water and EtOAc were added. The organic phase was washed with water 1 to 5 times to remove the DMF. The organic phase was washed with brine, dried, concentrated to give the crude product (compound 3B) which was used without further purification. In step 2, compound 3B was dissolved in dioxane / water (3: 1) and treated with lithium hydroxide at room temperature for 3 to 6 hours. The solution was acidified by addition of a 1N HCl solution and extracted with EtOAc. The products (compound 3C) were used without further purification or they were purified by chromatography depending on the boiling point of the by-products of the alcohol. In step 3, compound 3C was dissolved in an appropriate solvent, such as DMF, and coupled with compound 3D using EDCI and HOBT at room temperature overnight. After an aqueous work-up / EtOAc, the product (compound 3E) was isolated by chromatography. In step 4, compound 3E was suspended in MeOH / water (1: 1) under N2 atmosphere. NaOH and Zinc powder were added and the reaction mixture was stirred at 70 ° C to 80 ° C for 8 to 24 hours. After cooling to room temperature, the solution was adjusted to pH = 6 ~ 7 with a 1N HCl solution. The product (compound 3F) was extracted with EtOAc and purified by reverse phase HPLC.

EXAMPLE 4 4D Step 3 A 25 mL flask was charged with Compound 4C (331 mg, 1.68 mmol), Compound 4D (Stratford, ES and Curley, RW Jr, J. Med. Chem. 1983, 26, 1463-1469) (200 mg , 1.4 mmol), EDCI (403 mg, 2.1 mmol), HOBT (227 mg, 1.68 mmol), NMM (0.46 mL, 4.2 mmol), and DMF (7 mL). The solution was stirred at room temperature overnight. Saturated aqueous NaHCO3 (30 mL) and EtOAc (50 mL) were added. The organic phase was separated and washed with water (20 mL) and brine (20 mL), and then dried over Na2SO4. The solvent was evaporated and the crude product was isolated by silica gel chromatography (CH2Cl2 / MeOH / NH4OH 20: 1: 0.1 to 10: 1: 0.1) to provide compound 4E (201 mg, 45%).

Stage 4 To a 10 mL bottle was added Compound 4E (50 mg, 0J55 mmol), NaOH (25 mg, 0.62 mmol), Zinc powder (62 mg, 0.47 mmol), MeOH (0.5 mL), and water ( 0.5 mL). The solution was stirred at 75 ° C for 16 hours. After cooling to room temperature, the solid was removed by filtration. The filtrate was adjusted to pH = 5, by the addition of 2N HCl. The aqueous phase was extracted with EtOAc (10 mL). The organic solution was dried over Na2SO4 and concentrated. The product was isolated by silica gel chromatography (CH2Cl2 / MeOH / NH4OH, 40: 1: 0.1 to 20: 1: 0.1 to 10: 1: 0.1) to provide 6.5 mg of compound 4F (14%).

EXAMPLE 5 Step 1 Compound 5A (1.33 g, 7.26 mmol), benzyl bromide (2.73 g, 16.0 mmol), and Cs2CO3 (7.1 g, 22.0 mmol) were mixed in DMF (30 mL) and stirred at room temperature overnight . Saturated aqueous NaHCO3 (100 mL) was added and the aqueous phase was extracted with EtOAc (100 mL) twice. The combined organic phases were washed with brine (50 mL), dried over Na 2 SO 4, filtered, and concentrated on a rotary evaporator. The product was isolated by silica gel chromatography (Hexane / EtOAc: 10: 1 to 5: 1) to provide compound 5B (2.25 g, 89%).

Step 2 Compound 5B (2.25 g, 6.44 mmol) was dissolved in dioxane / water (3: 1, 35 mL) and LiOH (810 mg, 19.3 mmol) was added. The solution was stirred at room temperature for 3 hours. Water was added (30 mL) followed by addition of 2N HCl (30 mL). The aqueous phase was extracted with EtOAc (50 mL) three times. The organic phase was washed with brine, dried Na2SO, filtered and concentrated by rotary evaporator. The crude product was purified by silica gel chromatography (CH2Cl2 / MeOH / HC02H: 40: 1: 0.1 to 20: 1: 0.1) to give compound 5C (1.6 g, 91%). The following compounds were prepared as described in Examples 3-5. In each of the following tables, those compounds having a Ki value of less than 10 nM (< 10 nM) are designated with the letter "A"; those with a Ki value from 10 to less than 100 nM (10 - <100 nM) are designated with the letter "B"; those with a K value of from 100 to 1000 nM are designated with the letter "C"; and those with a Ki value of more than 1000 nM (> 000 nM) are designated with the letter "D".

TABLE 1 EXAMPLE 6 6A 6B 6C 6D > -NH HN? »-, Stage 4 6E 6G 6F General procedures for Example 6 In step 1, 4-bromo-2-nitro-benzoic acid (compound 6A) was dissolved in an appropriate solvent, such as DMF, and reacted with methyl iodide in the presence of cesium carbonate. at room temperature for 2-16 hours. Water and EtOAc were added and the organic phase was washed with water 1-5 times to remove the DMF. The organic phase was washed with brine, dried, concentrated, and dried to provide the crude product (compound 6B) which was used without further purification. In step 2, the methyl ester (compound 6B) was mixed with Pd (OAc) 2, Cs2C03, and with an appropriate ligand, such as racemic-2- (Di-r-butylphosphino) -1, 1 x-phosphoryl. The mixture was placed under vacuum for 1 to 10 minutes to remove the oxygen, and it was a filled with N2. Alcohol and toluene were added and the solution was stirred at 50 ° C at reflux temperature for 12 to 72 hours. After cooling to room temperature, the solid was removed by filtration and the solvent was removed. The product could be purified by chromatography. During this reaction, the methyl ester can be partially converted to the ester of the alcohol that is used. This secondary product was also collected and hydrolyzed in the next step. In step 3, compound 6C was dissolved in Dioxane / water (3: 1) and treated with lithium hydroxide at room temperature for 3-6 hours. The solution was acidified by addition of a 1N HCl solution and subjected to aqueous work-up / EtOAc. The products (compound 6D) were used without further purification or were purified by chromatography depending on the boiling point of the alcohol by-products. In step 4, compound 6D was dissolved in an appropriate solvent, such as DMF, and coupled with compound 6E under conditions of EDCI and HOBT at room temperature overnight. After an aqueous work-up / EtOAc, the product (compound 6F) could be isolated by chromatography.

In step 5, compound 6F was placed in suspension in MeOH / water (1: 1) under N2 atmosphere. NaOH and zinc powder were added and the reaction mixture was stirred at 70 ° C to 80 ° C for 8 to 24 hours. After cooling to room temperature, the solution was adjusted to pH = 6 ~ 7 with a 1N HCl solution. Compound 6G was extracted with EtOAc and isolated by reverse phase HPLC.

EXAMPLE 7 7A 7B 7C TD Step 1 Compound 7A (10.0 g, 40.7 mmol) was dissolved in DMF (100 mL). They were added in Cs2CO3 (27. Og, 81.3 mmol) and methyl iodide (7.60 mL, 122.0 mmol). The solution was stirred at room temperature overnight. EtOAc (250 mL) and water (100 mL) were added. The organic phase was separated and washed with water (100 mL) three times and with brine (50 mL), and then dried over Na 2 SO 4, filtered, and concentrated using a rotary evaporator. The product was dried under vacuum to provide compound 7B (10.3 g, 97%).

Stage 2 Pd (OAc) 2 (43 mg, 0.19 mmol), racemic-2- (di-f-butyl phosphino) -1,1-phenylphthalate (92 mg, 0.23 mmol), and Cs2C03 (1.88 g, 5.76 g. mmoles) in a 50 mL flask. The flask was placed under vacuum for 2 minutes and then filled again with N2. Compound 7B (1.00 g, 3.84 mmol) and MeOH (0.311 mL, 7.69 mmol) were dissolved in toluene (10 mL). The resulting solution was added to the previous bottle by pipette. The reaction mixture was stirred at 70 ° C in an oil bath for 48 hours. After cooling to room temperature, the solid was filtered and the solvent was removed using a rotary evaporator. The product was isolated by silica gel chromatography (Hexane / EtOAc 20: 1 to 10: 1) to provide compound 7C (380 mg, 47%).

Step 3 Compound 7C (380 mg, 1.80 mmol) was dissolved in dioxane / water (3: 1.8 mL) and LiOH (378 mg, 9.0 mmol) was added. The solution was stirred at room temperature for 3 hours. Water (5 mL) was added followed by addition of 2N HCl to adjust the pH = 2-4. The aqueous phase was extracted with EtOAc (10 mL) three times. The organic phase was washed with brine, dried over Na 2 SO, filtered, and concentrated. The crude product was dried under vacuum to provide compound 7D which was used without further purification.

The following compounds were prepared as described in Examples 6-7. TABLE 2 EXAMPLE 8 Stage 3 * | CO I ME COCHCH, 8A SB SC 8D 0 Stage 4 H, HJNX J * ar0, 8E ~ Stage 5 SG sr General procedure for Example 8 In step 1, Compound 8A was dissolved in an appropriate solvent, such as DMF, and reacted with methyl iodide in the presence of cesium carbonate at room temperature for 2-16 hours. Water and EtOAc were added and the organic phase was washed with water 1-5 times to remove the DMF. The organic phase was washed with brine, dried, concentrated, and dried to provide the crude product (compound 8B) which was used without further purification. In step 2, which alcohol was used, the reaction was carried out in a manner similar to step 2 in example 6. When a heterocyclic aromatic stannane was used, the reaction was operated in the following manner. The aromatic or heterocyclic stannane was added to a dry flask, followed by addition of 4-Bromo-2-methyl-benzoic acid methyl ester (compound 8B), a base, such as Cs2C03, K3P04, and a palladium catalyst, such as Pd (PPh3) 2Cl2. The bottle was placed under vacuum for 1 to 10 minutes to Remove the oxygen and fill again N2. An appropriate solvent, such as dry CH3CN, was added and the solution was stirred at 60 ° C at reflux temperature overnight for up to 3 days. The solid was removed by filtration and the solvent was removed. Compound 8C was isolated by chromatography. In step 3, compound 8C was dissolved in a suitable inert solvent, such as benzene, CCI4 or a, a, a-Trifluortoluene. NBS and benzoyl peroxide were added and the solution was stirred at 50 ° C to 90 ° C for 1 to 24 hours. The solid was filtered and the solvent was removed. The residue was dissolved in ether and washed with water. The ether was removed to provide compound 8D which was used without further purification. In stage 4, benzyl bromide (compound 8D) was mixed with hydantoinmethylamine 8E, K2C03, and DMF. The solution was stirred at room temperature for 12 to 24 hours. Then the solid was removed by filtration. The product could be purified by reverse phase HPLC. Compounds 8F and 8G could be obtained with a variable ratio. Step 5 was used when compound 8F was isolated in step 4. Compound 8F was dissolved in an appropriate solvent, such as MeOH, and stirred at 50 ° C to reflux temperature for 1 to 12 hours. The product could be obtained by removal of the solvent by rotary evaporator or by purification through reverse phase chromatography.

EXAMPLE 9 Me0 9E Step 3 Compound 9C (prepared according to the procedure described by Wyrick, SD et al, Journal of Medicinal Chemistry, 1987, 30 (10), 1798-806) (3.33 g, 18.05 mmol) was dissolved in dry benzene ( 40 mL). NBS (3.45 g, 19.4 mmol) and benzoyl peroxide (134 mg, 0.55 mmol) were added. The solution was stirred in an oil bath of 75 ° C for about 2 hours. After cooling, the solid was filtered and washed with Et20 (150 mL). The organic solution was then washed with water (50 mL) twice, dried over Na 2 SO or MgSO 4, filtered, and concentrated by rotary evaporator. The crude product was dried under vacuum to provide compound 9D which was used without further purification. The 1 H-NMR seemed to indicate that approximately 75% of this material consisted of the compound 9D.

Step 4 Compound 9D (4.62 mmol), compound 9E (824 mg, 4.62 mmol), and K2C03 (1.28 g, 9.24 mmol) were mixed in DMF (30 mL). The The solution was stirred at room temperature for 20 hours. DMF (15 mL) was added and the solid was filtered and washed with DMF. The entire DMF solution was combined and concentrated to 25 mL. The resulting solution was applied to reverse phase MPLC (CH3CN / water, 5% to 90%, containing 0.1% HC02H) to provide compound 9F (198 mg, 15%).

EXAMPLE 10 Step 4 Compound 10D (prepared in Example 9) (902 mg, 2.07 mmol, factor = 0.75), compound 10E (prepared as described in Example 1, 500 mg, 2.07 mmol), and K2C03 (629 mg , 4.56 mmoles) were mixed in DMF (15 mL). The solution was stirred at room temperature for 20 hours. DMF (15 mL) was added and the solid was filtered and washed with DMF. The whole DMF solution was combined and concentrated to 20 mL. It was applied to reverse phase MPLC (CH3CN / water: 5% to 90%, containing 0.1% HC02H) to provide compound 10F.

Step 5 Compound 10F (prepared in step 4) was dissolved in MeOH (5 mL), stirred at 65 ° C for 5 hours, and then concentrated to dryness. The compound was suspended in water and dried with lyophilizer to give compound 10G (68.3 mg, 9.4%).

EXAMPLE 11 11B 11C Step 2 Compound 11B (500 mg, 2.18 mmol), 2-tributyltin-thiazole (0.97 mL, 2.84 mmol), Pd (PPh3) 2 Cl2, and dry CH3CN were stirred under nitrogen at reflux temperature overnight. After cooling to room temperature, the solid was filtered. The product was isolated by silica gel chromatography (Hexane / EtOAc: 20: 1 to 10: 1 to 5: 1) to provide compound 11C (480 mg, 94%). The following compounds were prepared as described in Examples 8-11.

TABLE 3 The following additional compounds were prepared as described in Examples 8 to 11.

TABLE 4 EXAMPLE 12 12A 12B 12C 12D Stage 3 12E 12F General procedures for Example 12 In step 1, racemic compound 12A was treated with one equivalent of di-tert-butyl dicarbonate and 4-N, N-dimethylaminopyridine in polar solvent, such as DMF, for 30 minutes at 12 hours. The solvent was removed and the product (compound 12B) was isolated by silica gel chromatography (pretreated with 1% triethylamine in Hexane). In step 2, compound 12B was dissolved in the appropriate solvents allowed by the HPLC column, and resolved by HPLC using a preparative Chiralpak AD or Chiralcel OD column to provide compounds 12C and 12D. In step 3, compounds 12C and 12D were treated with an excess of HCl in methanol at 25 ° C to 60 ° C for one hour up to 12 hours. The solvent was concentrated to provide compounds 12E and 12F.

EXAMPLE 13 13D 13A 1JB C. Stage 3 15E 13F Step 1 Compound 13A (810 mg, 2.07 mmol), di-tert-butyl dicarbonate (429 mg, 1.97 mmol), and 4-dimethylaminopyridine (20 mg) were dissolved in a mixture of DMF (10 mL) and THF ( 20 mL). The solution was stirred at 25 ° C overnight. The solvents were removed by rotary evaporator. The product was isolated by C18 chromatography (CH3CN / water: 5% to 90%) to provide product 13B (650 mg, 70%).

Step 2 Compound 13B (600 mg) was dissolved in a mixture of isopropanol (6 mL) and CHCl 3 (4 mL). 2.5 mL was separated via HPLC with a preparative chiralcel OD column (Mobile phase: iso-propanol / Hexane: 1: 4). The fractions were collected for each peak and concentrated by rotary evaporator to provide compound 13C (First peak, 197 mg) and compound 13D (Second peak, 178 mg).

Step 3 Compound 13C (197 mg) was dissolved in methanol (3 mL). HCl (4M in Dioxane, 0.5 mL) was added. The solution was stirred in an oil bath at 60 ° C for three hours. The methanol was removed on the rotary evaporator to provide compound 13E. Compound 13F was prepared in the same manner as compound 13D (178 mg). The following compounds were prepared as described in Examples 12-13.

TABLE 5 Proton NMR Spectrographic Data for Compounds Selected in Table 5 Compound 25. 1 H NMR (500 Hz, DMSO-d6) d 4.06 (d, J = 14 Hz, 1 H), 4.20 (d, J = 14 Hz, 1 H), 4.32 (d, J = 18 Hz, 1 H), 4.38 (d, J = 18 Hz, 1 H), 7.19-7.39 (m, 2H), 7.55-7.80 (m, 5H), 8.93 (s) , 1 H), 10.96 (s, 1H).

EXAMPLE 14 General procedure for Example 14 In step 1, compound 14A (prepared as described in Example 1) was treated with a benzyl bromide (Compound 14B) and DIPEA base in DMF at 25 ° C to 60 ° C for 12 to 24 hours. The reaction solution was purified through C18 reverse phase chromatography to provide compound 14C. In step 2, compound 14C was treated with one equivalent of di-tert-butyl dicarbonate in a polar solvent, such as DMF, for 30 minutes up to 12 hours. The solvent was removed and the product (compound 14D) was isolated by silica gel chromatography (pretreated with 1% triethylamine in Hexane). In step 3, the compound 14D was subjected to a Pd-catalyzed reaction with a heterocyclic boronic acid or a heterocyclic stannano, or with a reaction catalyzed by copper with a heterocyclic amine. The reactions were heated in appropriate solvents, such as DMF and acetonitrile, at 60 ° C to 150 ° C, for 5 minutes to 12 hours. In some cases, a microwell reactor was used. The product was purified by silica gel chromatography to provide compound 14E or compound 14F. In step 4, compound 14E was dissolved in methanol and stirred with HCl for 1 hour up to 12 hours at 25 ° C to 60 ° C. The solvent was removed to provide compound 14F. The following compounds were prepared as described in step 1 of Example 14 above.

TABLE 6 EXAMPLE 15 Step 1: Compound 15A (prepared as described in Example 1, 1.0 g, 3.12 mmol), compound 15B (prepared in Example 9, 1.06 g, 3.12 mmol, factor = 0.76), and DIPEA base (1.14 mL, 6.55 mmol) were mixed in DMF (22 mL) . The solution was stirred at 55 ° C for 20 hours. The reaction solution was purified through C18 reverse phase MPLC (130 g column, CH 3 CN / water / 0.1% HC02H, 5% to 90%, two separations) to provide compound 15C (900 mg, 67%) .

Step 2 Compound 15C (2.7 g, 6.28 mmol) was suspended in a mixture of DMF (20 mL) and THF (40 mL). Di-tert-butyl bicarbonate (1.51 g, 6.91 mmol) and 4-dimethylamino pyridine (38 mg, 0.31 mmol) were added. The solution was stirred at 25 ° C for 16 hours. The solvents were extracted by rotary evaporator. The residue was subjected to silica gel chromatography (Hexane / EtOAc: 2: 1 to 1: 1) to give compound 15D (2.36 g, 71%).

Step 3 Compound 15D (100 mg, 0.19 mmol), acid was added 3,4,5-trifluorophenyl boronic acid (40 mg, 0.23 mmol), 1,1 '-bis (triphenylphosphino) ferrocene palladium (II) chloride (15 mg, 0.02 mmol), potassium carbonate (1 M in water, 1 mL) and acetonitrile (1 mL) were added to a microwave reactor tube. The tube was sealed and allowed to react in the microwave reactor at 150 ° C for 10 minutes. After cooling, the aqueous layer was removed and the organic layer was concentrated. The crude product was purified by silica gel chromatography (CH2Cl2 / MeOH / NH3: 40: 1: 0.1) to provide compound 15E.

Step 4 The compound 15E obtained in step 3 was suspended in MeOH. HCl (2M in ethyl ether, 0.5 mL) was added. The reaction mixture was stirred at 50 ° C for five hours. The solvent was removed. The product was purified through C18 reverse phase chromatography (CH3CN / water / 0J% HC02H, 5% to 90%) to provide compound 15F (8 mg, 8.8% from compound 15D).

EXAMPLE 16 Step 3 Compound 16D (50 mg, 0.094 mmol, prepared in example 13), 2-tributylstannyl thiazole (53 mg, 0.14 mmol), dichlorobis (triphenylphosphine) palladium (II) (7 mg, 0.01 mmol), and acetonitrile (1 mL) were added to a microwave reactor tube. The tube was sealed and allowed to react in a microwave reactor at 150 ° C for 10 minutes. The solvent was evaporated and the product was purified by silica gel chromatography (CH2Cl2 / MeOH / NH3: 40: 1: 0.1 to 20: 1: 0.1) to provide compound 16F (15 mg, 37%).

EXAMPLE 17 17D 17F Step 3 Compound 17D (100 mg, 0J9 mmol, prepared in example 13), pyrazole (15.4 mg, 0.23 mmol), cesium carbonate (124 mg, 0.38 mmol), copper iodide (7.2 mg, 0.038 mmol), 1, 10-phenanthroline (14 mg, 0.076 mmol), and N, N-dimethylacetamide (0.5 mL) were added to a dry reaction tube and filled with nitrogen. The reaction tube was sealed and heated to 120 ° C in an oil bath for two days. After cooling, the reaction solution was purified by C18 chromatography (CH3CN / water / 0J% HC02H, 5% to 90%) to provide compound 17F (5 mg, 6.4%). The following compounds were prepared as described in Examples 14-17 TABLE 7 EXAMPLE 18 Step 1 Compound 18A (1.0 g, 6.4 mmol) and compound 18B (1324 g, 7.68 mmol) were dissolved in toluene (4 mL) and stirred at 80 ° C for 24 hours. After cooling to room temperature, the solvent was removed by rotary evaporator. Half of the crude product was dissolved in THF / 1 N HCl (1: 1, 14 mL) and stirred at room temperature for 2 hours. EtOAc (15 mL) and water (5 mL) were added. The organic phase was separated and the aqueous phase was extracted with EtOAc (15 mL) twice. The combined organic phase was dried over Na2SO4 and concentrated by rotary evaporator to provide compound 18C which was used without further purification.

Step 2 Compound 18C (prepared in step 1) was dissolved in DMF (15 mL) and cooled to 0 ° C in an ice water bath. Compound 18D (571 mg, 3.2 mmol) was added in one portion. The solution was allowed to warm to room temperature for 2 hours, and was stirred at room temperature for 3 days. A solution of 2N HCl (20 mL) was added and the aqueous phase was extracted with EtOAc (50 mL) three times. The organic phases were combined, dried over Na 2 SO, and concentrated to dryness. The product was isolated by reverse phase LC (CH3CN / water / 0J% HC02H: 5% to 90%) to provide compound 18E (65 mg, 7.4% of step 1) and compound 18F (16 mg, 1.8 % of stage 1).

The following compounds were prepared as described Example 18 TABLE 8 EXAMPLE 19 General procedures for Example 19 In step 1, compound 19A was treated with two equivalents of Boc20 in an appropriate solvent, such as dichloromethane, for 30 minutes at 12 hours. The solvent was removed and compound 19B could be used without further purification or purified by silica gel chromatography. In step 2, compound 19B was treated with PCC and celite in an appropriate solvent such as dichloromethane, for 2 hours up to 12 hours. Compound 19C was purified by silica gel chromatography. In step 3, compound 19C was reacted with potassium cyanide and ammonium carbonate in an appropriate alcohol and a water solution, at 50 ° C to 90 ° C, for 5 hours up to 48 hours. After cooling water was added, and the compound can be collected by filtration 19D. In step 4, compound 19D was stirred with 2 to 20 equivalents of hydrogen chloride in methanol for 5 to 48 hours. The solvent was removed and compound 19E could be used without further purification. In step 5, benzyl bromide (compound 19G) was mixed with hydantoin methylamine 19E, DIPEA, and DMF. The solution was stirred at room temperature for 12 to 24 hours. The product (19F) was removed by filtration or purified by silica gel chromatography.

EXAMPLE 20 General procedures for Example 20 In step 1, Compound 20A was treated with BOC-ON in an appropriate solvent such as dichloromethane, for 2 hours to 12 hours. Compound 20B was purified by silica gel chromatography. In step 2, compound 20B was treated with CbzCI and a base such as DIPEA, in an appropriate solvent, such as dichloromethane, for 2 hours to 12 hours. Compound 20C was purified by silica gel chromatography. In step 3, compound 20C was treated with PCC and celite in an appropriate solvent such as dichloromethane, for 2 to 12 hours. Compound 20D was purified by silica gel chromatography.

In step 4, compound 20D was reacted with potassium cyanide and ammonium carbonate in the appropriate alcohol and water solution, at 50 ° C to 90 ° C, for 1 hour up to 48 hours. After cooling water was added and the 20E compound could be collected by filtration. In step 5, compound 20E was treated with Pd / C in an appropriate solvent such as methanol, on a Parr stirrer under H 2 atmosphere. After filtration of the catalyst and concentration of the solvent the product was used without further purification. In step 6, the benzyl bromide (compound 20M) was mixed with hydantoin methyl amine 20F, DIPEA, and DMF. The solution was stirred at room temperature at 80 ° C for 12 to 24 hours. The product was removed by filtration or purified by silica gel chromatography. In step 7, the 20G compound was stirred with 2 to 20 equivalents of hydrogen chloride in dioxane for 1 to 12 hours. The solvent was removed and the 20H compound was used without further purification. In step 8, compound 20H was coupled with carboxylic acid to provide compound 20J which was purified by silica gel chromatography. In step 9, compound 20H was coupled with a sulfonyl chloride compound to provide compound 20L which was purified by silica gel chromatography. In step 10, the compound 20H was reacted with the carbonyl compound under conditions of reductive amination to provide compound 20I. Alternatively, compound 20H was treated with an appropriate electrophile and base to provide product 20I, which was purified by silica gel chromatography. In step 11, compound 20I was reacted with the carbonyl compound under reductive amine conditions to provide the 20K product. Alternatively, compound 20I was treated with an appropriate electrophile and base to provide the 20K product, which was purified by silica gel chromatography.

EXAMPLE 21 Compound 21 B: Compound 21 A (7 g, 77.7 mmol), and di-tert-butyl bicarbonate (35.6 g, 163 mmol) were stirred in methylene chloride (100 mL) at 25 ° C for 2 hours. Saturated aqueous NaCl was added (150 mL). The aqueous layer was extracted with CH2Cl2 (100 mL) twice. The organic phase was washed with brine (100 mL), dried over Na2SO4. The solvent was removed by rotary evaporator to provide compound 21 B (17g, 76%) which was used without further purification. Compound 21C: Compound 21 B (17 g, 58.6 mmol) was dissolved in methylene chloride (100 mL). PCC (25.2 g, 117 mmol) and celite (15 g) were added and the reaction mixture was stirred at 25 ° C overnight. The solid was separated by filtration and the resulting solution was concentrated and purified through sgc (40% EtOAc / Hexanes) to provide 3.62 g (22%) of compound 21 C. Compound 21 D: compound 21 C (3.62, 12.6 mmoles), KCN (1.23g, 18.9 mmoles), and (NH) 2C03 (3.62 g, 37.7 mmoles) were suspended in a mixture EtOH (30 mL) and water (30 mL). The solution was stirred at 80 ° C overnight. After cooling, water (35 mL) was added. The solid was filtered and washed three times with water. The solid was dried under vacuum to provide compound 21 D (3 g, 67%). Compound 21 E: Compound 21 D (3.0 g) was suspended in methanol (50 mL) and HCl (4M in dioxane) was added., 20 mL). The solution was stirred at 25 ° C for 3 hours. Ethyl ether (50 ml) was added. The solid was filtered, washed with ethyl ether twice, and dried under vacuum to obtain compound 21 E (1.34 g, 70%). Compound 21 F: Compound 21 E (130 mg, 0.82 mmol), compound 21 H (0.27 g, 1 mmol) and DIPEA (0.55 mL, 2 mmol) were mixed in DMF (5 mL). The solution was stirred at room temperature overnight. The solvent was extracted and the crude material was purified through of sgc (5% NH3'MeOH / CH2Cl2) to provide 129 mg (35%) of compound 21 E.

EXAMPLE 22 Compound 22B: Compound 22A (7.3 g, 81 mmol) was treated with BOC-ON (21.9 g, 89 mmol) in dichloromethane for 3 hours. The solvent was removed and the crude material was purified through sgc (10% NH 3"MeOH / CH 2 Cl 2) to provide 6.5 (42%) of compound 22B. Compound 22C: Compound 22B (1.5g, 7.9 mmol) was dissolved in dichloromethane (50 mL) at 0 ° C. CbzCI (1.24 ml, 8.7 mmol) and DIPEA (1.52 ml, 8.7 mmol) were added, the reaction was stirred at 0 ° C for 30 minutes. The reaction mixture was washed with HCl (1 N, 50 mL) and brine (50 mL). mL). The organic layer was dried and concentrated to give a crude product 22C (2.6 g, 99%) which was used without further purification. Compound 22D: Compound 22C (2.78g, 8.57 mmol) was dissolved in methylene chloride (100 mL). PCC (4.62 g, 21.4 mmol) and celite (4.6 g) were added and the reaction mixture was stirred at 25 ° C overnight. Another 0.5 eq. of PCC (923 mg, 4.3 mmol) and stirred for 3 hours at room temperature. The solid was separated by filtration and the resulting solution was concentrated and purified through sgc (50% EtOAc / Hexanes) to provide 1.86 g (73%) of compound 22D. Compound 22E: compound 22D (1.86, 5.8 mmole), KCN (0.56 g, 8.65 mmol), and (NH4) 2 C03 (1.66 g, 17.3 mmol) were suspended in a mixture of EtOH (20 mL) and water (20 mL). The solution was stirred at 80 ° C overnight. After cooling, EtOH was removed. The solid was filtered and washed with water three times. The solid was dried under vacuum to provide compound 22E (1.45 g, 64%). Compound 22F: Compound 22E (1.45 g, 3.68 mmol) was treated with Pd / C in methanol on a Parr shaker under an H 2 atmosphere of 344.5 kPa (50 psi) for 60 hours. After filtering off the catalyst and concentrating the solvent, the compound 22E (0.95 g, 99%) was used without further purification. Compound 22G: Compound 22F (150 mg, 0.58 mmol), compound 22M (170 mg, 0.64 mmol) and DIPEA (0.22 mL, 1.28 mmol) were mixed in DMF (5 mL). The solution was stirred at 70 ° C overnight. HE The solvent was extracted and the crude material was purified through sgc (5% NH3 * MeOH / CH2Cl2) to give 166 mg (71%) of compound 22G. Compound 22H: Compound 22G (166 mg) was suspended in methanol (10 mL) and HCl (4M in dioxane, 4 mL) was added. The solution was stirred at 25 ° C for 2 hours. Ethyl ether (50 ml) was added. The solvent was removed and gave the compound 22H (0J4 g, 99%). Compound 22I: Compound 22H (42 mg, 0J2 mmole) and compound 22J (26 mg, 0J6 mmole) were dissolved in DMF (20 mL). EDCI (30 mg, 0J6 mmol), HOBT (21 mg, 0J6 mmol) and DIPEA (0.05 mL, 0.28 mmol) were added and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed and the crude material was purified through sgc (10% NH 3 * MeOH / CH 2 Cl 2) to provide 7 mg (13%) of compound 22I. Compound 22L: Compound 22H (25 mg, 0.073 mmol) and cyclopentanone (7.5 mg, 0.088 mmol) were stirred in methylene chloride (5 mL). Titanium tetraisopropoxide (0.043 mL, 0J5 mmol) was added followed by addition of DIPEA (0.015 mL, 0.088 mmol). The reaction mixture was stirred at room temperature for 2 hours. Then, Na (OAc) 3BH (31 mg, 0J 5 mmol) was added and the mixture was stirred at room temperature overnight. Aqueous K2CO3 (20 mL) was added, and the mixture was stirred briefly at room temperature. The solid was removed by filtration through a pad of celite. The filtrate was diluted with methylene chloride (30 mL), and extracted with brine. The organic layer was dried and concentrated to dryness.

The crude material was purified through PTLC (10% NH 3"MeOH / CH 2 Cl 2) to provide 7 mg (26%) of compound 22L. Compound 22K: Compound 22H (20 mg, 0.06 mmol) and isopropyl sulfonyl (27 mg, 0J 8 mmol) were dissolved in methylene chloride (10 mL). DIPEA (0.04 mL, 0.26 mmol) was added and the reaction mixture was stirred at room temperature for 48 hours. The solvent was removed and the crude material was purified through sgc (10% NH3 * MeOH / CH2Cl2) to give 2 mg (8%) of compound 22K. The following compounds were prepared as described in Examples 19-22.

TABLE 9 EXAMPLE 1001 1001E 100 ID Step 1 To a solution of compound 1001 A (1.65 g, 3.95 mmol) in Anhydrous DMF (35 mL) was added 2- (trimethylsilyl) ethoxymethyl chloride (SEMCI, 0. 93 mL, 4.73 mmol) and DIPEA (0.9 mL, 5.14 mmol). The solution was stirred at 25 ° C overnight. The DMF was removed in vacuo. The product 1001 B was purified by SGC (Hexane / EtOAc, 2: 1, yield: 1.6 g, 74%).

Step 2 Compound 1001B was resolved by Chiralcel OD column (Mobile phase: Hexane / 2-propanol 3: 1). The first peak was collected and concentrated to provide compound 1001 C.

Step 3 To a dry flask was added compound 1001C (1.5 g, 2.73 mmole) and 4-pyridyl boronic acid (670 mg, 5.50 mmole). The bottle was emptied and again filled with nitrogen three times. Pd (dppf) Cl2 (220 mg, 0.30 mmol) was added followed by addition of CH3CN (20 mL) and aqueous K2C03 (1 M, 15 mL). The solution was stirred at 80 ° C (oil bath) for 16 hours. After cooling, CH3CN (100 mL) was added and the solid was removed by filtration. The aqueous layer was separated and extracted with EtOAc (20 mL) once. The organic solution was combined and concentrated. The product was purified by SGC (CH2Cl2 / MeOH / NH4OH: 20: 1: 0.1) to provide compound 1001 D.

Step 4 Compound 1001 D was dissolved in a mixture of methanol and HCl (4M in dioxane) (2: 1, 30 mL) and stirred overnight in a sealed flask under pressure at 90 ° C (oil bath). After cooling the solution, the solution was transferred to a 250 mL round bottom flask. It was concentrated and dried under vacuum. The crude mixture was dissolved in methanol (50 mL) and Et3N (0.5 mL) was added and stirred overnight at 25 ° C. The solvent was then removed and the product was purified by C18 reverse phase chromatography (CH3CN / 5% to 90% water, with addition of 0.1% HC02H) to provide compound 1001E (815 g, 71% of compound 1001C).

EXAMPLE 1002 1003 A 1003B The compound 1003A (100 mg, 0.182 mmol), [1,4-bis (diphenylphosphino) butane] palladium dichloride (ll) was added to a flask dried under flame.

[Pd (dppb) CI2, 12 mg, 0.02 mmol], and copper (II) oxide (15 mg, 0.18 mmol). The bottle was emptied and again filled with nitrogen. 2-tri-n-butylstannylpyridine (0.076 mL, 0.237 mmol) and DMF (1 mL) were added.

The solution was stirred at 100 ° C in an oil bath for 5 hours. After cooling the DMF was removed by rotary evaporator. The product was purified by SGC (Hexane / EtOAc 2: 1) to give 1003B (84 mg, 84%).

EXAMPLE 1003 1003A 1003B To a dry tube under pressure was added compound 1003 A (50 mg, 0.091 mmol), bis (dibenzylidene ketone) palladium [Pd (dba) 2, 1.6 mg, 0.0018 mmol], 9,9-dimethyl-4,5 bis (diphenylphosphino) xanthene (Xantphos, 3.0 mg, 0.0055 mmol), and Cs2C03 (60 mg, 0.182 mmol). The tube under pressure was emptied and again filled with nitrogen. Pyrrolidinone (14 mg, 0.16 mmol) and dioxane (0.5 mL) were added. The tube was sealed and stirred overnight at 100 ° C (oil bath). After cooling, dioxane (2 mL) was added and the solid was removed by filtration. The solution was concentrated and purified by SGC (CH2Cl2 / MeOH: 40: 1) to provide compound 1003B (27 mg).

EXAMPLE 1004 1001 C HOMA 10O B 100 C Step 1 Compound 1001C was prepared as described in Example 1001, A mixture of compound 1001C (0.3 g, 0.55 mmole), bis (pinacolato) diboron (1004A, 170 mg, 0.65 mmole), potassium acetate (170 mg , 1.70 mmole), and [PdCI2 (dppf)] CH2Cl2 (50 mg, 0.05 mmole) in 1,4-dioxane (10 mL) was drained and re-filled with argon three times. The reaction mixture was stirred at 100 ° C (oil bath) for 1.5 hours. After cooling, the mixture was diluted in EtOAc (50 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo and the residual material was purified by silica gel column chromatography (2% MeOH in CH 2 Cl 2) to provide compound 1004B (300 mg, 91% yield).

Step 2 To a solution of compound 1004B (60 mg, EYO mmole), 3-bromoimidazo [1,2-a] pyridine (30 mg, 0.15 mmole), and [PdCI2 (dppf)] CH2Cl2 (8.2 mg, 0.01 mmol) in CH3CN (3 mL) was treated with potassium carbonate (0.6 mL, 0.6 mmol, 1 M in H20). The mixture was removed under vacuum and refilled with argon three times. The reaction mixture was stirred at 90 ° C (oil bath) for 17 hours. After cooling, the mixture was diluted in EtOAc (20 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo and the residual material was purified by preparative TLC (10% MeOH in CH 2 Cl 2) to give compound 1004C (42 mg, 71% yield). The following compounds were prepared as described in Examples 1001, 1002, 1003 or 1004.

TABLE 1000 Spectrographic Data of Proton NMR for Compounds Selected in Table 1000 Compound 111, 1 H-NMR (500 MHz, DMSO-d 6) d 9.0 (s, 1 H), 8.79 (d, J = 6.0 Hz, 2 H), 7.92 ( d, J = 8.7 Hz, 2H), 7.79 (d, J = 8.7 Hz, 2H), 7.76 (d, J = 6.0 Hz, 2H), 7.65 (m, 1H), 7.48 (m, 2H), 4.40 ( d, J = 17.3 H, 1H), 4.31 (d, J = 17.3 Hz, 1H), 4.27 (d, J = 14.2 Hz, 1H), 4.14 (d, J = 14.2 Hz, 1H). Compound 120, 1 H-NMR (500 MHz, DMSO-d 6) d 8.99 (s, 1 H), 8.03 (d, J = 8.8 Hz, 2 H), 7.96 (d, J = 3.3 Hz, 1 H), 7.84 (d, J = 3.3 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.65 (s, 1H), 7.47 (m, 2H), 4.38 (d, J = 17.6 Hz, 1H), 4.28 (d, J = 17.6 Hz, 1H), 4.27 (d, J = 14.3 Hz, 1H), 4.13 (d, J = 14.3 Hz, 1H). Compound 123, 1 H-NMR (500 MHz, DMSO-d 6) d 8.99 (s, 1H), 7. 84 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.66 (dd, J = 8.5, 4.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.49 (m, 2H), 6.65 (s, 1H), 4.40 (d, J = 17.5 Hz, 1H), 4.31 (d, J = 17. 5 Hz, 1H), 4.29 (d, J = 14.2 Hz, 1H), 4J09d, J = 14.2 Hz, 1H). Compound 139.1H NMR (500 MHz, CD3OD) d 3.17-3.21 (m, 4H), 3.83-3.88 (m, 4H), 4.14-4.52 (m, 4H), 7.01 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8 Hz, 1H), 7.46-7.48 (m , 3H), 7.75 (s, 1H). Compound 143, 1 H NMR (400 MHz, CDCl 3) d.4.21-4.50 (m, 4H), 7.498 (d, J = 0.8 Hz, 1H), 7.52 (d, J = 0.4 Hz, 1H), 7.73-7.76 (m, 3H), 7.76-7.87 (m, 4H), 8.60 (d, J = 6 Hz, 2H). Compound 155, 1 H NMR (500 MHz, CD 3 OD) d 8.84 (dd, J = 1.89, 4.1 Hz, 1H); 8.43 (dd, J = 1.58, 8.2 Hz, 1H); 7.99 (dd, J = 1.58, 8.2 Hz, 1H); 7.85 (m, 3H); 7.8 (dd, J = 1.26 Hz, 6.94 Hz, 1H); 7.75 (m, 3H), 7.70 (dd, J = 7.25 Hz, 0.95 Hz, 1 H); 7.59 (dd, J = 4.73 Hz, 7.57 Hz, 1 H); 7.58 (dd, J = 4.4Hz, 8.2Hz, 1 H); 7.51 (dd, J = 2.5 Hz, 7.8 Hz, 1 H); 7.40 (m, 1 H); 4.54 (d, J = 17.0 Hz, 1 H); 4.48 (d, J = 17.0 Hz, 1 H); 4.48 (d, J = 14.5 Hz, 1 H); 4.32 (1 H, d, J = 14.5 Hz, 1 H).

EXAMPLE 1005 1005 A 1005B General procedure for example 1005 Compound 1005A was treated with one equivalent of hexamethylene tetraamine in chloroform or in another appropriate solvent for about 5 hours. The product was collected by filtration and then treated with HCl in ethanol for one day for up to three days. The solid was then collected by filtration to provide compound 1005B.

EXAMPLE 1006 1006A 1006B 1-Benzofuran-2-yl-2-bromo-ethanone (1006A, 3.0 g, 12.55 mmol), hexamethylene tetraamine (1.94 g, 13.80 mmol), and Nal (350 mg) were stirred in CHCl3 (40 mL) for five hours . The solid was collected by filtration and dried in vacuo. The solid was then suspended in ethanol (30 mL) and HCl (concentrated, 36% in water, 10 mL) was added. The solution was stirred at 25 ° C for 4 d. The solid was collected by filtration and washed with ethanol, dried under vacuum to provide compound 1006B (3.05 g, NH 4 Cl content).

EXAMPLE 1007 1007A 1007B 1007C Step 1 To a flask dried under flame was added 2-bromo-1 H-benzimidazole (1007A, 2.94 g, 14.92 mmol), anhydrous THF (75 mL), and NaH (95%, 490 mg, 19.4 mmol). The solution was stirred at 25 ° C for 45 minutes; SEMCI (3J 7 mL, 17.9 mmol) was added. The solution was stirred at 25 ° C for 2.5 hours. Water (50 mL) and EtOAc (100 mL) were added. The aqueous layer was separated and extracted with EtOAc (100 mL) once. The organic layers were combined and concentrated in vacuo. The product was purified by SGC (Hexane / EtOAc: 3: 1) to provide compound 1007B (3.6 g, 74%).

Step 2 To the flask dried under flame was added compound 1007B (1427 g, 4.35 mmol) and anhydrous ethyl ether / THF (2: 1, 15 mL). The solution was cooled to -78 ° C. N-Butyllithium (1.6 M, 0.46 mL, 0.73 mmol) was added and stirred at -78 ° C for 30 minutes. In another flame-dried pear shaped flask, N- (tert-butoxycarbonyl) glycine-N'-methoxy-N'-methylamide (949 mg, 4.35 mmol) and anhydrous THF (2 mL) were added. Isopropyl magnesium chloride (2 M, 2.5 mL, 5.0 mmol) was added at 0 ° C. The solution was stirred at 0 ° C for 5 minutes and then added to the solution of Compound 1003C through a cannula at -78 ° C. Then the solution was gradually heated to -20 ° C and stirred between -20 ° C. and 10 ° C for 4 hours. A saturated solution of NH4Cl was added and the aqueous solution was extracted with EtOAc (50 mL) three times. The organic phases were combined and concentrated. The product was purified by SGC (Hexane / EtOAc: 3: 1) to provide compound 1007C (1.0 g, 57%). The following compounds were prepared as described in Example 1, 14, 1005, 1006 and / or 1007.

TABLE 1001 Spectrographic Data of Proton NMR for Compounds Selected in Table 1003 Compound 181, 1 H-NMR (500 MHz, DMSO-d 6) d 11.3 (s, 1H), 9.34 (s, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.67 (m, 1H), 7.61 (m, 1H), 7.50 (m, 3H), 4.65 (d, J = 14.3 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.38 (d, J = 17.3 Hz, 1H), 4.34 (d, J = 14.3 Hz, 1H).

EXAMPLE 1008 The compounds 1008A (20 g, 81.61 mmol), 1008 B (13.36 mL, 97. 93 mmole), Pd (dppf) CI2 (1.0g, 1.36 mmole), dioxane (350 mL), water (50 mL), and Cs2C03 (22.5g, 163 mmol) were stirred at 110 ° C (oil bath) under nitrogen for 16 hours. After cooling, the solid was removed by filtration. The solution was concentrated and purified by SGC (Hexane / EtOAc, 10: 1) to provide 1008C (12J g, 80%). The following compounds were prepared as described in Examples 14 and 1008 and 1009.

PICTURE 1002 EXAMPLE 1009 1009A 1009B 1009C Stage 3 1009E 1009D Step 1 Compound 1009A (1.18 g, 3.36 mmole) and pyridine hydrochloride (2.33 g, 20.17 mmole) were added to a 20 mL microwave reactor tube and allowed to react at 200 ° C for 1 hour. After cooling, the solvent was dissolved in DMF and purified by C18 chromatography (CH3CN / 5% to 90% water, with 0.1% HC02H) to provide compound 1009B (0.87 g, 77%).

Step 2 Compound 1009B (0.75 g, 2.22 mmol) was dissolved in DMF (12 mL). SEMCI (0.48 mL, 2.44 mmol) and DIPEA (0.775 mL, 4. 44 mmol) and the solution was stirred at 25 ° C for 4 hours. DMF was removed under vacuum and the product was purified by SGC (Hexane / EtOAc: 3: 1 to 1: 1) to provide compound 1009C (0.81 g, 78%).

Step 3 Compound 1009C was resolved on a Chiralcel OD column using Hexane and 2-propanol as the mobile phase. The first peak was collected and concentrated to provide compound 1009D.

Step 4 Compound 1009D (100 mg, 0.214 mmol), 1-bromo-2-butine (34 mg, 0.257 mmol), and Cs2CO3 (140 mg, 0.428 mmol) in DMF (2 mL) were stirred at 0 ° C for 2 hours, and then at 25 ° C during the night. Water (5 mL) was added and the aqueous solution was extracted with EtOAc (10 mL) three times. The organic phases were combined and concentrated. The product was purified by SGC (Hexane / EtOAc: 3: 1) to provide compound 1009E (81 mg).

EXAMPLE 1010 Step 1 Compound 1010A (1.03 g, 1.88 mmol), (BOC) 20 (493 mg, 2.26 mmol), and Cs2CO3 (741 mg, 2.26 mmol) were stirred overnight in CHCl3 (20 mL). Water was added. The aqueous layer was extracted with EtOAc (3 ^ 50 mL). The combined organic layers were concentrated and purified by SGC (5% to 90% Hexane / EtOAc) to provide compound 1010B (1.01 g, 83%).

Step 2 To a dry flask was added compound 1010B (500 mg, 0.77 mmole) and 4-pyridyl boronic acid (190 mg, 1.55 mmole). The bottle was emptied and again filled with nitrogen three times. Pd (dppf) CI2 (28 mg, 0. 04 mmole) followed by addition of CH 3 CN (5 mL) and K 2 CO 3 (1 M, 4 mL). The solution was stirred at 80 ° C (oil bath) for 16 hours. After cooling, CH3CN (100 mL) was added and the solid was removed by filtration. The aqueous layer was separated and extracted once with EtOAc (20 mL). The organic solution was combined and concentrated. The product was purified by SGC (CH2Cl2 / MeOH / NH4OH: 20: 1: 0.1) to provide 1010C.

Step 3 Compound 1010C obtained in step 2 was dissolved in MeOH (10 mL) and HCl (4M in dioxane, 3 mL) was added and stirred overnight at 25 ° C. The MeOH was then removed and the product was dried under vacuum to provide compound 1010D (315 mg, 75% of compound 1010B). The following compounds were prepared as described in Examples 14 and 1009 or 1010.

PICTURE 1003 Spectrographic Data of Proton NMR for the Compounds Selected in Table 1003 Compound 198.1H-NMR (400 MHz, DMSO-d6) d 9.22 (s, 1H), 7.64 (m, 2H), 7.43 (m, 4H), 7.22 ( t, J = 2.2 Hz, 1H), 7.16 (dd, J = 9.6, 1.2 Hz, 1H), 4.82 (d, J = 2.0 Hz, 2H), 4.16 (m, 4H), 3.33 (s, 3H). Compound 203, 1 H-NMR (400 MHz, DMSO-d 6) d 7.63 (dd, J = 8.8, 5.6 Hz, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.13 (m, 4H), 4.80 ( d, J = 0.8 Hz, 1H), 4.39 (d, J = 17.6 Hz, 1H), 4.17 (d, J = 17.6 Hz, 1H), 4.13 (d, J = 13.6 Hz, 1H), 3.71 (d, J = 13.6 Hz, 1H) 3.34 (s, 3H). Compound 213, 1 H NMR (500 Hz, CD3OD) d 4.11 (d, J = 15 Hz, 1H), 4.27 (d, J = 15Hz, 1H), 4.29 (d, J = 17Hz, 1H), 4.38 (d, J = 17Hz, 1H), 6.84-6.89 (m, 2H), 7.16-7.21 (m , 2H), 7.56-7.60 (m, 1H), 7.71-7.76 (m, 2H). Compound 219.1H NMR (500 Hz, CD3OD) d 0.36-0.40 (m, 2H), 0.61-0.68 (m, 2H), 1.25-1.35 (m, 1H), 3.91 (d, J = 7Hz, 2H), 4.14 (d, J = 15HZJH), 4.30 (d, J = 15Hz.1H), 4.34 (d, J = 17Hz, 1H), 4.43 (d, J = 17HzJH), 7.01-7.05 (m, 2H), 7.17- 7.23 (m, 2H), 7.65-7.69 (m, 1H), 7.72-7.77 (m, 2H). Compound 232, 1H NMR (500 Hz, CD3OD) d 1.13 (t, J = 8Hz, 3H), 2.21-2.27 (m, 2H), 4.15 (d, J = 14HzJH), 4.31 (d, J = 14Hz, 1H ), 4.36 (d, J = 17Hz, 1H), 4.45 (d, J = 17Hz, 1H), 4.79 (t, J = 2Hz, 2H), 7.04-7.14 (m, 2H), 7.16-7.25 (m, 2H), 7.64-7.79 (m, 3H). Compound 233, 1 H NMR (500 Hz, CD3OD) d 7.678 (d, J = 8.5 Hz, 1H); 7.455 (d, J = 4.1Hz, 1H), 7.817 (d, J = 4JHz, 1H); 7.099 (s, 1H); 7,052 (dd, J = 2,207, 6,305Hz, 1H); 4.515 (d, J = 17.3 Hz, 1H), 4.450 (d, J = 17. 3 Hz, 1H); 4.065 (d, J = 14.5 Hz, 1H); 3.89 (s, 3H); 3.87 (d, J = 14.5 Hz, 1H); 3.85 (m, 1H); 2.46 (m, 2H); 2.09 (m, 1H) 1.89 (m, 1H); 1.76 (m, 1H); 1.67 (m, 1H); 1.54 (m, 1H); 1.32 (m, 1H). Compound 239.1H NMR (500 Hz, DMSO-d6) 54.11 (d, J = 15 Hz, 1H), 4.27 (d, J = 15 HzJH), 4.29 (d, J = 17 Hz, 1H), 4.38 (d, J = 17 Hz, 1H), 6.84-6.89 (m, 2H), 7J6-7.21 (m, 2H), 7.56-7.60 (m, 1H), 7.71-7.76 (m, 2H). Compound 243, 1 H-NMR (500 MHz, CD3OD) d 8.53 (s, 1H), 7.67 (dd, J = 8.5, 5 Hz, 2H), 7.46 (d, J = 8 Hz, 1H), 7.27 (t, J = 8.5 Hz, 2H), 7J5 (m, 2H), 4.319d, J = 17.0 Hz, 1H), 4.22 (d, J = 17 Hz, 1H), 4J3 (d, J = 14.2 Hz, 1H), 4.06 (d, J = 14.2 Hz, 1H), 3.889d, J = 6.5 Hz, 2H), 3.359m, 2H), 1.22 (m, 1H), 0.57 (d, J = 8 Hz, 1H), 0.33 ( d, J = 5 Hz, 1H).

EXAMPLE 1011 1011 A 101 IB To a solution of compound 1011A (100 mg) in DMF (5 mL) was added m-chlorobenzoyl peroxide (MCPBA, 100 mg). The solution was stirred overnight at 25 ° C. The product was purified by chromatography of reverse phase C18 (CH3CN / water 5% to 90%, with 0.1% HC02H) to provide compound 1011 B (73 mg). The following compounds were prepared as described in Examples 1010 and 1011.

PICTURE 1004 EXAMPLE 12 In step 1, compound 1012A was treated with nitromethane and KO'Bu in a mixture of THF and f-BuOH for 2 to 12 hours. Alternatively, compound 1012A was treated with nitromethane and TBAF in an appropriate solvent such as THF for 2 to 12 hours. Compound 1012B was purified by silica gel chromatography. In stage 2, Compound 1012B was treated with Pd / C in an appropriate solvent such as methanol, in a Parr stirrer under H2? After filtering off the catalyst and concentrating the solvent, the product was used without any further purification. In step 3, benzyl bromide (compound 1012D) was mixed with compound 1012C, DIPEA and DMF. The solution was stirred at 0 ° C to room temperature for 12 to 24 hours. The product was removed by filtration or purified by silica gel chromatography. In step 4, compound 1012E was treated with PCC and Celite in an appropriate solvent such as dichloromethane for 2 to 12 hours. Compound 1012F was purified by silica gel chromatography.

In step 5, compound 1012F was allowed to react with potassium cyanide and ammonium carbonate in an appropriate solution of alcohol and water, at 50 ° C to 90 ° C, for 5 to 48 hours. After cooling, water was added and the compound 1012G was collected by filtration.

EXAMPLE 1013 Boc CH2Clj QIPEA Compound 1013B: To a solution of THF (15 mL) and t-BuOH (15 mL) was added compound 1013A (1.2 g, 5.6 mmol) and nitromethane (0.61 mL, 11.2 mmol) followed by addition of KO'Bu (0.63). g, 5.6 mmoles). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 6 using HOAc. The reaction mixture was diluted with EtOAc (30 mL), and extracted with brine. The aqueous layer was extracted with EtOAc (30 mL * 2). The combined organic layers were washed with brine, dried and concentrated to dryness. The crude material was purified by PTLC (25% EtOAc / Hexanes) to provide 1.24 g (81%) of compound 1013B.

Compound 1013C: Compound 1013B (1.24 g, 4.5 mmol) was treated with Pd / C in methanol on a Parr shaker under an atmosphere of H2 of 344.5 kPa (50 psi) overnight. After filtering off the catalyst and concentrating the solvent, compound 1013C (1 J g, 99%) was used without further purification. Compound 1013E: Compound 1013C (1.02 g, 4.2 mmol) was dissolved in dichloromethane (30 mL) at 0 ° C. Compound 1013D (1 J 3 g, 4.2 mmol) and DIPEA (0.73 mL, 4.2 mmol) were added and the reaction was stirred at 0 ° C and slowly warmed to room temperature overnight. The reaction mixture was washed with HCl (1 N, 50 mL) and brine (50 mL). The organic layer was dried and concentrated to dryness. The crude material was purified through PTLC (50% EtOAc / Hexanes) to provide 0.88 g (54%) of compound 1013E. Compound 1013F: Compound 1013E (0.88 g, 2.25 mmol) was dissolved in methylene chloride (30 mL). PCC (1.22 g, 5.63 mmol) and Celite (1.22 g) and the reaction mixture was stirred at 25 ° C overnight. The solid was separated by filtration and the resulting solution was concentrated and purified through sgc (90% EtOAc / Hexanes) to provide 0.62 g (71%) of compound 1013F. Compound 1013G: Compound 1013F (1.01 g, 2.6 mmol), KCN (0.25 g, 3.9 mmol), and (NH 4) 2 CO 3 (0.75 g, 7.8 mmol) were suspended in a mixture of NH 3 in methanol (7 N, 10 mL ) and water (10 mL). The solution was stirred at 90 ° C overnight. After cooling, water was added (20 mL). The solid was filtered and washed with water three times. The solid was dried under vacuum to provide compound 1013G (0.86 g, 72%).

EXAMPLE 1014 Step 1 Compound 1014A was stirred with 2 to 20 equivalents of hydrogen chloride in methanol for 5 to 48 hours. The solvent was removed and compound 1014B could be used without further purification.

Step 2 Compound 1014B was treated with carboxylic anhydride and DIPEA to provide compound 1014C which was purified by silica gel chromatography.

Step 3 Compound 1014B was coupled with sulfonyl chloride compound to provide compound 1014D, which was purified by silica gel chromatography.

Step 4 Compound 1014B was allowed to react with the carbonyl compound under reductive amination conditions to provide compound 1014E. Alternatively, compound 1014B was treated with an appropriate electrophile and base to provide compound 1014E, which was purified by silica gel chromatography.

Step 5 Compound 1014B was allowed to react with the isocyanate compound and DIPEA to provide compound 1014F, which was purified by silica gel chromatography.

EXAMPLE 1015 1 016 F Compound 1015B: Compound 1015A (0.86 g) was suspended in methanol (10 mL) and HCl (4M in dioxane, 10 mL) was added. The solution was stirred at 25 ° C for 3 hours. The solvent was removed and the material was dried under vacuum to provide compound 1015B (0.74 g, 99%). Compound 1015C: Compound 1015B (40 mg, 0.11 mmol) and benzoic anhydride (25 mg, 0.11 mmol) were dissolved in DMF (1 mL). DIPEA (0.06 mL, 0.33 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the crude material was purified through sgc (5% NH 3 »MeOH / CH 2 Cl 2) to provide 3.7 mg (7%) of compound 1015C.

Compound 1015D: Compound 1015B (40 mg, 0J 1 mmol) and compound 1015H (30 mg, 0.11 mmol) were dissolved in DMF (1 mL). DIPEA (0.25 mL, 1.4 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the crude material was purified through sgc (5% NH 3 * MeOH / CH 2 Cl 2) to provide 2.2 mg (3%) of compound 1015D. Compound 1015E: compound 1015B (40 mg, 0J 1 mmol) and compound 10151 (0.024 mL, 0.22 mmol) were dissolved in DMF (1 mL). K2C03 (46 mg, 0.33 mmol) was added and the reaction mixture was stirred at 90 ° C overnight. The solvent was removed and the crude material was purified through sgc (5% NH 3"MeOH / CH 2 Cl 2) to provide 2.6 mg (5%) of compound 1015E. Compound 1015F: Compound 1015B (46 mg, 0J 3 mmol) and cyclobutanone (0.2 mL) were stirred in methylene chloride (1 mL). Titanium tetraisopropoxide (0.045 mL, 0J 5 mmol) was added followed by addition of DIPEA (0.027 mL, 0J6 mmol). The reaction mixture was stirred at room temperature for 2 h. Then NaCNBH3 (41 mg, 0.65 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was removed. The crude material was purified through PTLC (10% NH 3"MeOH / CH 2 Cl 2) to provide 3.1 mg (6%) of compound 1015F. Compound 1015G: compound 1015B (80 mg, 0.24 mmol) and ethyl isocyanate (0.018 mL, 0.24 mmol) was dissolved in DMF (1 mL). DIPEA (0.17 mL, 0.97 mmol) was added and the reaction mixture was stirred at Room temperature during the night. The solvent was removed and the crude material was purified through sgc (9% NH 3"MeOH / CH 2 Cl 2) to provide 11 mg (11%) of compound 1015G. The following compounds were prepared as described in Examples 1012 to 1015.

PICTURE 1005 Spectrographic Data of Proton NMR for Selected Compounds in Table 1005 Compound 262, H NMR (500 Hz, CD3OD) d.8.921 (m, 1H); 8.433 (d, J = 8.6 Hz, 1H); 8.357 (s, 1H); 8,072 (m, 4H); 7.622 (m, 1H); 7.545 (m, 1H); 7.476 (m, 1H); 7369 (m, 1H); 4.522 (d, J = 17 Hz, 1H); 4.510 (d, J = 14.5 Hz, 1H); 4,425 (d, J = 17 Hz, 1H), 4,350 (d, J = 14.5 Hz, 1H).

EXAMPLE 1016 Compound 1016B: Compound 1016A (500 mg, 1.77 mmol) was suspended in CH 3 CN (5 mL) followed by addition of NaN (CHO) 2 (202 mg, 2.12 mmol). The reaction mixture was stirred at room temperature for 30 minutes before heating to 70 ° C and stirring for 2 hours. A solid was collected by suction filtration and washed with acetonitrile to give 1016B (380 mg, 78%) as a tan solid. Compound 1016C: Compound 1016B (380 mg, 1.38 mmol) was stirred with HCl (36% aqueous, 1 mL) and EtOH (10 mL) at room temperature for 2 days. Then it was heated at 60 ° C for 2 hours. The solvent was removed and then dried under vacuum to provide 1016C (345 mg, 98%). The material was used without further purification. The following compounds were prepared as described in Examples 1016, Example 2 and Example 8.

PICTURE 1006 Spectrographic Data of Proton NMR for Selected Compounds in Table 1006 Compound 278. 1 H NMR (500 Hz, CD3OD) d 8,503 (d, J = 4.73 Hz, 1 H); 7.84 (m, 2H); 7.67 (d, J = 3.8 Hz, 1 H); 7.56 (dd, J = 4.4 Hz, 8.5 Hz, 1 H); 7.50 (dd, J = 2.5 Hz, 7.8 Hz, 1 H); 7.38 (m, 1 H); 7.33 (d, J = 4.1 Hz, 2H); 7.3 (m, 1 H); 4.52 (d, J = 17 Hz, 1 H); 4.45 (d, J = 17 Hz, 1 H); 4.43 (d, J = 14.2 Hz, 1 H); 4.28 (d, J = 14.2 Hz, 1 H).

EXAMPLE 1017 Compound 1017C: Compound 1017A (1.5 g, 8.26 mmol) was dissolved in dichloromethane (20 mL) and methanol (10 mL) at 0 ° C. Compound 1017B (2.64 g, 10 mmol) and DIPEA (2.9 mL, 16.5 mmol) were added and the The reaction was stirred at 0 ° C and slowly warmed to room temperature overnight. The reaction mixture was then heated to 50 ° C and stirred for 2 hours. The reaction mixture was washed with brine (50 mL). The organic layer was dried and concentrated to dryness. The crude material was purified through PTLC (50% EtOAc / Hexanes) to provide 0.7 g (29%) of compound 1017C. Compound 1017D: Compound 1017C (200 mg, 0.68 mmole) was stirred in CH2Cl2 (15 mL) at 0 ° C followed by addition of compound 10171 (0.5 mL, 2.04 mmol) and TMS-OTf (13 μL, 0.07 mmol). The reaction mixture was stirred at 0 ° C to 5 ° C for 6 hours before heating to room temperature and stirring overnight. The solvent was removed and the crude material was purified through PTLC (EtOAc) to provide 0.21 g (91%) of compound 1017D. Compound 1017E: Compound 1017D (210 mg, 0.62 mmol) was heated in a sealed tube with NH2NH2 (0.2 mL, 6.2 mmol) and EtOH (2 mL) at 60 ° C overnight. The solvent was extracted and the crude material 1017E (210 mg, 99%) was obtained which was used without further purification. Compound 1017F: Compound 1017E (210 mg, 0.62 mmol) and ethyl isocyanate (59 μL, 0.74 mmol) were dissolved in CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature overnight. To this mixture was added Et3N (0.43 mL, 3.1 mmol), DMAP (15 mg, cat.) And p-TsCI (141 mg, 0.74 mmol). The reaction was stirred at room temperature overnight. The solvent was removed and the crude material was purified through sgc (10% NH 3"MeOH / CH 2 Cl 2) to provide 60 mg (25%) of compound 1017F. Compound 1017G: Compound 1017F (60 mg, 0.15 mmol) was heated in a sealed tube with HCl (3 mL, 4N in dioxane) at 65 ° C for 48 hours. The solvent was removed and the crude material was purified through sgc (5% NH 3"MeOH / CH 2 Cl 2) to provide 35 mg (66%) of the compound 1017G. Compound 1017H: Compound 1017G (34 mg, OJ mmole), KCN (10 mg, 0.15 mmol), and (NH4) 2C03 (30 mg, 0.3 mmol) were suspended in a mixture of NH3 * H20 (1 mL) and ethanol (1 mL). The solution was stirred at 90 ° C overnight. The solvent was removed and the crude material was purified through sgc (10% NH 3 »MeOH / CH 2 Cl 2) to give 6 mg (15%) of compound 1017H. The following compounds were prepared as described in Example 1017 PICTURE 1007 EXAMPLE 1018 1018A 1018B Compound 1018A: Compound 1018A was synthesized following the procedures of Example 1012 Compound 1018B: Compound 1018A (180 mg, 047 mmol) was stirred in MeOH (1 mL) at room temperature. HCl (3 L, 4N in dioxane) was added and the reaction mixture was heated at 70 ° C overnight. The solvent was evaporated. The crude material was taken up in water and the solid was collected by suction filtration to provide 1018B (115 mg, 71%).

EXAMPLE 1019 Compound 1019A: Compound 1019A was synthesized following procedures as described in Example 1012 Compound 1019B: Compound 1019A (74 mg, 0.18 mmol) was dissolved in EtOH (2 mL) and HCl (0.4 mL, 36% aqueous) was added. and the reaction mixture was heated at 70 ° C overnight. The solvent was removed and gave 1019B as a light yellow solid (74 mg, 99%). Compound 1019C: Compound 1019B (20 mg, 0.05 mmol) was stirred in DMF (1 mL) and HCl (cat., 4 N in dioxane) at 120 ° C overnight. The solvent was removed and the crude material was purified through PTLC (9% NH 3"MeOH / CH 2 Cl 2) to provide e mg (37%) of compound 1019C. The following compounds were prepared as described in Example 1012, 1018 and 1019.

BOX 1008 EXAMPLE 1020 B 1020A Compound 1020A: Compound 1020A was synthesized following the procedures described in Example 22. Compound 1020B: Compound 1020A (855 mg, 1.86 mmol) was stirred in MeOH (10 mL) and HCl (10 mL, 4N in dioxane) at room temperature for 2 hours. The solvent was removed and the material was dried to give 1020B (735 mg, 99%). The following compounds were prepared as described in Example 22 and Example 1020.

TABLE 1009 EXAMPLE 1021 1021E ^ n) Step 1 DMF (100 mL), cesium carbonate (41.13 g, 126 mmol), and 2-chloro-5-methylphenol (1021A) (15.0 g, 105 mmol) were added to a flask. Methyl iodide (17.92 g, 126 mmol) was added dropwise through an addition funnel. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc, washed with water and brine, and dried with Na2SO4. The resulting material was filtered, and concentrated to dryness. The crude product was purified through evaporative sgc using 1: 4 EtOAc: hexanes as mobile phase to provide 15.93 g of 1021 B.

Step 2 A vial containing AICI3 (2.55 g, 19.1 mmol), and LiCI (0.41 g, 9.6 mmol) was placed in a cold bath at -30 ° C. A solution of 1021 B (1.0 g, 6.38 mmol) and acetyl chloride (0.75 g, 9.5 mmol) in 20 mL of CH2Cl2 was added dropwise. The reaction mixture was stirred for 1 hour at -30 ° C, then the mixture was stirred for 1 hour at -30 ° C. allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was poured into a mixture of ice and EtOAc. The organic layer was washed with water, with saturated aqueous NaHCO 3 and water, and then dried with Na 2 SO, and concentrated to dryness to provide 1 J 8 g of compound 1021C.

Step 3 Sodium hydroxide (58 g, 1.45 mol) was dissolved in water (260 mL) and the flask was cooled in an ice bath. Bromine (19 mL) was added dropwise to the flask, with stirring. The reaction mixture was stirred for 0.5 hour after which the addition was completed. The resulting solution was added dropwise to a flask cooled with ice water containing 1021C (18.5 g, 93.1 mmol). Afthe addition was complete, the reaction mixture was allowed to warm to room temperature and was left under stirring overnight. The reaction mixture was heated at 40 ° C for 2 hours. NaHS03 (55 g) was added. The reaction mixture was stirred for 1 hour. The resulting maal was diluted with 10% aqueous NaOH and extracted with EtOAc to remove the starting maal. The aqueous layer was adjusted to pH 1 and extracted with additional EtOAc. The organic layer was dried with Na 2 SO 4, fild and concentrated to dryness to provide 12.31 g of 1021D.

Step 4 DMF (10 mL), compound 1021D (0.50 g, 2.49 mmol), and K2C03 (0.41 g, 2.96 mmol) was added to a flask. Methyl iodide (0.42 g, 2.96 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness to give 0.52 g of 1021 E. The following compounds were prepared as described in step 1 in Example 14 and Example 1021.

TABLE 1010 Spectrographic Data of Proton NMR for the Compounds Selected in Table 1010 Compound 296. 1 H NMR (500 Hz, DMSO-d6) d 3.93 (s, 3 H), 4.00 (d, J = 14 Hz, 1 H), 4.19 (d, J = 14 Hz, 1H), 4.23 (d, J = 18 HzJH), 4.34 (d, J = 18 Hz, 1H), 7.24-7.34 (m, 2H), 7.42 (s, 1H), 7.62-7.73 ( m, 3H), 8.92 (s, 1H), 10.95 (s, 1H).

The specific inhibitory activity of TACE (Ki value) of some representative compounds of the present invention is indicated below. TABLE 1011 The following additional compounds were also prepared by the methods described above as well as in the description discussed below.

BOX 3000 8016 428.15 429.2 [M + H] + 8017 444.14 445.2 [M + H] + 8018 417.14 418.2 [M + H] + 8019 428.15 429.2 [M + H] + 8020 414.13 415.2 [M + H] + 8021 485.13 486.3 [M + H] + 8022 442.16 443.2 [M + H] + 8023 443.16 444.2 [M + H] + 2030A 375.08 376J [M + H] + 2030C 400.13 401.2 [M + H] + 2030B 426.15 I 427J [M + H] + B 2031C 387.10 388.1 [M + Hr 2031 D 441.11 442.0 [M + H] + 2030D 477.16 478J [M + H] + B 2031A 463.13 464.0 [M + H] + B 2031 B 373.09 374.0 [M + H] + B 2032B 382.11 383.1 [M + H] + B 2031 E 431.13 432J [M + H] + B 2031 F 417.11 418J [M + H] + B Procedures EXAMPLE 4000 4000A 4000B 4000C Compound 4000C was prepared from 4000A commercially obtainable according to a two-step procedure published: Ebenbeck, W .; Rampf, F .; Marhold, A. Sol. Int. PCT of E.U.A 2004/0142820 A1 (July 22, 2004). Compound 4000D was prepared by the procedures given in Examples 14,1008, 9 and 1001, Compound 4032 was prepared from Compound 4000D as described in Example 1004, but substituting 3-bromoimidazo [1, 2-ajpyridine of Compound 4000C in step 2.

EXAMPLE 4100 Compound 4100C was prepared from Compound 4100A and Compound 4100B commercially obtainable by the procedures given in Example 14 and 1009. Subsequently, Compound 4100C (123 mg, 0.2 mmol) was dissolved in methanol (1 mL) in a pressure tube and treated with HCl (0.4 mL, 4 M in dioxane). The tube was sealed and heated with stirring at 90 ° C for 18 hours. The reaction mixture was allowed to cool to room temperature and the solvent was then stirred under reduced pressure. The residue was re-dissolved in methanol (1 mL) and DIPEA (0.27 mL, 0.20 mg, 1.6 mmol) was added. The reaction mixture was stirred overnight at room temperature. The volatile components were removed by evaporation and the residue was purified by PTLC (8% MeOH-CH 2 Cl 2) to provide Compound 4017 (59 mg, 61% yield) as a beige solid.

EXAMPLE 1022 Step 1 To a solution of 1022A (500 mg, 3.33 mmol) in acetone (40 mL) was added potassium carbonate (920 mg, 6.7 mmol) and 1-bromo-2-butine (0.32 mL, 3.7 mmol, in the case in which R = CH2CCCH3). The reaction mixture was heated to reflux for 2 hours. After cooling to room temperature, the mixture was added to ice water / CH2Cl2? The organic layers were extracted with CH2CI2 and the combined organic solution was washed with a saturated NaCl solution, dried (Na2SO4), and concentrated in vacuo to provide 1022B (674 mg, quantitative yield).

Steps 2 and 3 A suspension of 1022B (100 mg, 0.5 mmol) in a 1 N NaOH solution (0.5 mL) was heated at 100 ° C. The reaction mixture was stirred for 1 hour at said temperature and concentrated in vacuo. The residue was dried by azeotropic distillation with toluene and the resulting solid was dissolved in DMF (0.6 mL) followed by addition of xs. Mel (0.1 mL, 1.5 mmol). The mixture was stirred at room temperature for 2 hours and diluted with EtOAc. The organic solution was washed with water, with a saturated aqueous solution of NaCl, dried (Na2SO4), and concentrated in vacuo to give crude 1022C (117 mg). The crude 1022C (67 mg, 0.28 mmol) was dissolved in CH2Cl2 (2 mL) and the solution was treated with PPh3 (150 mg, 0.57 mmol) and CBr4 (189 mg, 0.57 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2) to give 1022D (50 mg, 60% yield).

EXAMPLE 1023 Step 1 A mixture of 1023A (370 mg, 0.72 mmol), 1-methyl-4- (4, 4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl) -1 H-pyrazole (225 mg, 1.08 mmol), potassium carbonate (1 M aqueous solution, 2.9 mL, 2.9 mmol), and [PdCI2 (dppf)] CH2Cl2 (59 mg, 0.072 mmol) in acetonitrile (12 mL) was evacuated and filled again with argon three times. The reaction mixture was stirred at 80 ° C in an oil bath for 17 hours. After cooling, the mixture was diluted in EtOAc (50 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo and the residual material was purified by silica gel column chromatography (1% to 1.5% MeOH in CH 2 Cl 2) to provide compound 1023B (369 mg, 99% yield).

Step 2 A solution of 1023B (109 mg, 0.21 mmol) in EtOAc / MeOH (4 / 1.5 mL) was treated with 4N HCl in dioxane (2 mL). The reaction mixture was stirred at room temperature for 15 hours and concentrated in vacuo. The residue was dissolved in DMF (1 mL) and treated with 1022D (75 mg, 0.25 mmol, R = CH2CCCH3) and diisopropylethylamine (0.22 mL, 1.26 mmol). The mixture was stirred at 60 ° C for 9.5 hours and concentrated in vacuo. The residue was dissolved in MeOH (5 mL) and treated with 4N HCl in dioxane (1 mL) at 70 ° C for 17 hours in a vessel under pressure. After cooling to room temperature, the mixture was concentrated and the residue was treated with ammonia in MeOH for 0.5 hour. The precipitate was separated by filtration and the filtrate was concentrated. The residue was dissolved in DMF (3-4 mL) and purified by reverse phase column chromatography (0.01% HC02H in water-0.01% HC02H in acetonitrile) to provide 6018 (48 mg, 49% yield).

EXAMPLE 1024 1024A 1024B 1024C Step 1 A mixture of 1024A (81 1 mg, 2.8 mmol) and sodium diformyl amide (291 mg, 3.0 mmol) in acetonitrile (15 mL) was stirred at room temperature for 19 hours. The resulting suspension was removed by filtration through celite and the filtrate was concentrated in vacuo. The residue was purified by Si02 column chromatography (CH2Cl2) to give 1024B (611 mg, 77% yield).

Step 2 A solution of 1024B (611 mg, 2J 6 mmol) in EtOH (40 mL) was treated with 4N HCl in dioxane (8 mL) at room temperature. The resulting solution was stirred at room temperature for 16 hours and concentrated in vacuo. The residue was dissolved in dioxane / water (5 / 1.24 mL) and the solution was stirred at room temperature for 2 hours. The mixture was added to water and the organic layers were extracted with CH 2 Cl 2 and the combined organic solution was washed with a saturated aqueous NaCl solution, dried (Na 2 SO 4), and concentrated in vacuo. The residue was purified by Si02 in column chromatography (CH2CI2 / hexane = 1/1 to CH2CI2 only) to provide 1024C (679 mg, 96% yield).

EXAMPLE 1025 1025 to 6027 Step 1 A mixture of 1025A (52 mg, 0.11 mmol), benzyl bromide (13 μL, 0.11 mmol), and cesium carbonate (108 mg, 0.33 mmol) in DMF (0.5 mL) was stirred at room temperature for 2 hours . The mixture was diluted in EtOAc and the organic solution was washed with water, with saturated aqueous NaCl solution, dried (Na 2 SO), and concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH in CH 2 Cl 2) to give 6027 (34 mg, 54% yield).

EXAMPLE 1026 1026A 1026B Step 1 To a solution of 1026A (41 mg, 0.084 mmol), 5-hydroxymethyl-4-methyl-1,3-oxazole (19 mg, 0.17 mmol), and PPh3 (66 mg, 0.25 mmol) in THF (1 mL ) was added diisopropyl azodicarboxylate (50 μL, 0.25 mmol) per drop at 0 ° C. The mixture was stirred at 0 ° C for 10 minutes and then allowed to warm to room temperature. After stirring for 2 hours at room temperature, the mixture was concentrated in vacuo and the residue was purified by preparative TLC (CH2Cl2) to provide 1026B (38 mg, 77% yield).

EXAMPLE 5021 0 5021 A 5021 5021D Compound 5021 A was prepared using the chemistry described in Examples 14, 1001 and 1008.

Step 1 Compound 5021A was resolved by Chiralcel OD column (mobile phase: Hexane: 2-propanol 4: 1). The first peak was collected and concentrated to provide compound 5021 B.

Step 2 Compound 5021 B (1.82 g, 3.25 mmol), bis (pinacolato) diboron (2.89 g, 11.4 mmol), potassium acetate (1.5 g, 15 mmol), and [PdCI2 (dppf)] CH2Cl2 (0.27 g, 0.3 mmoles) were added to a round bottom flask and placed under N2. The flask was subjected three times to cycles between vacuum and nitrogen. Dioxane was added through a syringe (30 mL, anhydrous Aldrich). The reaction mixture was stirred at 80 ° C (in an oil bath) for 4 hours. The reaction mixture was allowed to cool to room temperature. Water (30 mL) was added, followed by sodium perborate- (5.0 g, 32 mmol). The reaction mixture was left under stirring overnight at room temperature. The resulting mixture was diluted with EtOAc, washed with water and brine, dried with MgSO 4, and concentrated to dryness. The crude product was purified through silica gel evaporative chromatography using a gradient of 30% to 100% EtOAc-Hexanes as the mobile phase. A white solid (1.28 g) was collected in the form of a 5021 C product.

Step 3 Compound 5021C (40 mg, 0.12 mmol), cesium carbonate (59 mg, 1.5 eq), and DMF (1 mL) were added to a round bottom flask. The bottle was subjected to ultrasound for 30 minutes. 2-Bromopropane (18 mg, 1.2 eq) was added and the reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc, washed with water, dried with MgSO 4, and concentrated to dryness. The crude product was purified by evaporative chromatography using a gradient of 10% to 100% EtOAc-Hexanes as the mobile phase. Compound 5021 D (28 mg) was obtained as product.

Step 4 Compound 5021 D was converted to compound 5021 using procedures similar to those described in Example 1001.

EXAMPLE 7000 7025 was synthesized from 7031 using appropriate heterocyclic bromide using a procedure similar to synthesis 169. 7031 was prepared from 7030 using the procedure described below: 7030 (0.273 g, 0.5 mmol) in 5 mL DMF was treated anhydrous, with potassium carbonate (0.2 g, 0.15 mmol). The flask was equipped with an acetone trap and dry ice and difluor chlorine methane gas was bubbled in for 2 hours. The bubbling was interrupted and the excess reagent was removed by bubbling nitrogen. The reaction was diluted with 50 mL of ethyl acetate and washed with water (2 x 50 mL) and brine (1 x 25 mL). Organics were dried and concentrated to provide a crude which was purified by preparative silica gel chromatography using 1: 1 ethyl acetate: hexane to provide 0.037 g of the pure product.

The same 7030 was prepared from 214, using a conventional procedure that was previously mentioned in this case.

EXAMPLE 8001 Stage 1 HO - < 3 c i -A 8001A 800 IB Compound 8001 B was prepared according to a literature procedure (Munyemana, F .; Frisque-Hesbain, A.; Devos, A.; and Ghosez, L. Tetrahedron Letters 30 (23), 3077-3080, 1989). .

EXAMPLE 8002 Compound 8002A (746 mg, 1.32 mmol) was dissolved in anhydrous acetonitrile (10 mL) and the solution was cooled to 0 ° C in an ice water bath. BF3-Et20 (0.84 mL, 6.62 mmol) was added dropwise through a syringe. The solution was stirred at 0 ° C for two hours. DIPEA (1 mL) was added followed by NaOH (1 N, 1 mL). The solution was stirred at 25 ° C for two hours. The solvent was removed and the product was purified by C18 reverse phase chromatography (CH3CN / water, 5% to 90%, with 0.5% HC02H) to provide 8009. 8009 was dissolved in methanol and NaOH (1 N, 1.0 mL) was added. , 1.0 mmol, 0.95 equivalent). The solution was stirred at 25 ° C for 30 minutes. The solvent was removed to provide the sodium salt form of 8009 (495 mg).

EXAMPLE 2021 Step 1 To a solution of compound 2021A (4 g, 26.8 mmol) in water (25 mL) and concentrated sulfuric acid (1 mL) was added sodium nitrite (2.2 g, 31.8 mmol) in water (10 mL) with cooling in a cold bath The reaction mixture was diluted with concentrated sulfuric acid (20 mL). The reaction mixture was added to 50% sulfuric acid (50 mL) under reflux and boiled for 2 minutes. The reaction mixture was cooled to room temperature and diluted with water (250 mL). The mixture was extracted with ether diethyl ether (5 x 100 mL). The combined organic layers were washed with a solution of sodium bicarbonate and brine, dried over sodium sulfate and concentrated to provide 2021 B (1.6 g) as a yellow solid.

Step 2 A mixture of compound 2021 B (790 mg, 5.3 mmol), cesium carbonate (1.90 g, 5.8 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.47 g, 6.3 mmol) in NMP (15 mL) was stirred overnight at room temperature. The reaction mixture was filtered and the solids were washed with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. Recrystallization from 30% ethyl acetate / hexane gave 2021 C (728 mg) as a yellow solid. HPLC-MS t R = 1.54 min (UV254 nm); mass calculated for the formula C10H7F3O3 232.03, LCEM observed m / z 233.1 (M + H).

Step 3 A suspension of 2021C (168 mg, 0.72 mmol) and 1.0 N sodium hydroxide (0.72 mL, 0.72 mmol) in water (0.8 mL) was heated at 100 ° C for 1 hour. The reaction mixture was concentrated and the residue was azeotroped with toluene. The sodium salt was dissolved in DMF (1 mL) and methyl iodide (0J35 mL, 2.16 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by chromatography (S02, 30% ethyl acetate / hexane) provided 2021 D (149 mg) as a solid. HPLC-MS t R = 1.56 min (UV254 nm); mass calculated for formula C11 H11 F304 264.06, LCEM observed m / z 287J (M + Na).

Step 4 A mixture of 2021 D (149 mg, 0.56 mmol), carbon tetrabromide (371 mg, 1.12 mg), and triphenylphosphine (294 mg, 1 J 2 mmol) in dichloromethane (5 mL) was stirred for 40 minutes at room temperature. ambient. The mixture was concentrated and purified by chromatography (S02, 5% to 10% ethyl acetate / hexane) to provide 2021 E (153) mg as an oil. HPLC-MS t R = 2.04 min (UV254 nm); mass calculated for formula C11 H10BrF3O3 325.98, LCEM observed m / z 349 (M + Na).

Step 5 Compound 2021 F (136 mg) was prepared from 2021E (151 mg, 0.46 mmol) and 2D (118 mg, 0.45 mmol) using the procedures previously described. HPLC-MS t R = 1.60 min (UV25 nm); mass calculated for the formula C20H15F4N3O4 437.1, LCEM observed m / z 438J (M + Na).

EXAMPLE 2022 Step 1 Compound 2022C was prepared according to a modification of a method of Felding, J. et al. (J. Org. Chem. 1999, 64, 4196-4198) using 4-iodo-1-methyl-1 H-pyrazole 2022A and Weinreb 2022B amide as starting materials. The crude reaction mixture was chromatographed (SiO2, 60% -80% ethyl acetate / hexane) to give compound 2022C (62%). HPLC-MS t R = 1.18 min (UV254 nm); mass calculated for formula C11 H17N303 239.1, LCEM observed m / z 184.1 (M-tBu + H).

Step 2 BOCamino hydantoin 2022D was prepared using the procedures described in Example 1, Step 2, (81%) HPLC-MS t R = 0.94 min (UV254 nm); mass calculated for the formula C13H19N504 309J, LCEM observed m / z 310.1 (M + H).

Step 3 The amino hydantoin 2022E was prepared using the procedures described in Example 1, Step 3, HPLC-MS t = 0J 8 min (UV254 nm); mass calculated for the formula C8H11 N502 209J, LCEM observed m / z 210.1 (M + H).

Step 4 Hydantoin 2022G was prepared using the procedures described in Example 8. HPLC-MS tR = 2.23 min (UV254 nm, 10 min); mass calculated for the formula C17H17N504 355.1, LCEM observed m / z 356J (M + H).

EXAMPLE 2023 2023B Step 1 To a suspension of sodium hydride (95%, 0.58 g, 23 mmol) in DMF (20 mL) was added a solution of 4-iodo-1 H-pyrazole (2023A) (4.07 g, 21 mmol) in DMF. (20 mL) and the resulting mixture was stirred at room temperature for 10 minutes. Then 2-iodopropane (2.52 mL, 25.2 mmol) was added dropwise and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water (4 times), brine, dried and concentrated to give an oily residue which was chromatographed (Si02, 10% -20% acetate). ethyl / hexane) to provide 4-iodo-1-isopropyl-1 H-pyrazole 2023B (3.27 g, 66%). HPLC-MS t R = 1.66 min (UV254 nm); mass calculated for the formula C6H9IN2 235.98, LCEM observed m / z 237.0 (M + H).

EXAMPLE 2024 2024C Step 1 Compound 2024B was prepared according to a modification of a method of Roppe, J. et al. (J. Med. Chem. 2004, 47, 4645-4648) using 4-fluorophenylhydrazine hydrochloride 2024A and malondialdehyde-bis- (dimethylacetal) as starting materials (yield 95%). HPLC-MS t R = 1.62 min (UV25 nm); mass calculated for the formula C9H7FN2 162.1, LCEM observed m / z 163.1 (M + H).

Step 2 Compound 2024C was prepared according to a modification of the procedure of Rodriguez-Franco, M. I. et al. (Tetrahedron.

Lett. 2001, 42, 863-865) (yield 85%). HPLC-MS t R = 1.98 min (UV254 nm); mass calculated for the formula C9H6FIN2 287.96, LCEM observed m / z 288. 9 (M + H).

EXAMPLE 2025 HBoc Step 1 Compound 2025B was prepared according to a modification of a procedure of Evans, D.A. et al. (J. Am. Chem. Soc. 2005, 127, 8942-8943) using 1-methyl-1 H-ylidazole 2025A and Weinreb 2022B amide as starting materials (42%). HPLC-MS t R = 1.24 min (UV254 nm); mass calculated for formula C11 H17N303 239.1, LCEM observed m / z 240.1 (M + H). The following compounds were prepared using the procedures described in Examples 2021 to 2025, EXAMPLE 2026 Part A To a solution of methyl 4-acetylbenzoate (2026A) (1.9 g, 10.6 mmol) in acetic acid (10 mL) was added dropwise bromine (1.7 g, 21.3 mmol). The mixture was heated at 60 ° C for 30 minutes, and then stirred at room temperature for 1 hour, and poured into cold water (30 mL). The light yellow precipitate was collected, washed with water and dried (2.6 g, 96%).

Part B Compound 2026C was prepared from compound 2026B following the procedure described in Example 1005.

Part C Compound 2026D was prepared following the procedures described in Example 1: HPLC-MS tR = 1.36 min (UV254 nm); mass calculated for formula C17H21 N306 363.1, LCEM observed m / z 386.0 (M + Na).

Part D To a mixture of 2026D (7.87 g, 21.7 mmol) and diisopropylethylamine (7.5 mL, 43.4 mmol) in DMF (80 mL) was added 2-thymrylsilylethoxy methyl chloride (4.7 mL, 23.8 mmol). The mixture was stirred at room temperature overnight, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (SiO2, 15% EtOAc / hexane to 30% EtOAc / hexane) to give 2026E as a white solid (10.2 g, 95%): HPLC-MS tR = 2J 7 min ( UV254 nm); mass calculated for the formula C23H35N307SÍ 493.2, LCEM observed m / z 516.1 (M + Na).

Part E Compound 2026F was prepared from ester 2026E following the procedure described in Guo, Z. et. al (WO 2005 / 121130A2).

Part F Compound 2026G was prepared following a procedure previously described. HPLC-MS t R = 1.67 min (UV25 nm); mass calculated for the formula C28H33N505SSI 579.2, LCEM observed m / z 580.3 (M + H).

Part G Compound 2026G (65 mg, 0.11 mmol) was heated in a sealed tube in MeOH (2 mL) and 4 N HCl in 1,4-dioxane (2 mL) overnight at 90 ° C. The solvent was evaporated and the residue was stirred in MeOH (2 mL) and triethylamine (2 mL) at room temperature for 4 hours. The solvent was removed and the residue was purified by reverse phase chromatography to provide 2026H (11 mg, 20%): HPLC-MS t R = 1.00 min (UV254 nm); dough calculated for the formula C22H19N504S 449.1, LCEM observed m / z 450J (M + H).

EXAMPLE 2030 Part A Compound 2030A was prepared using the methods previously described from 2D. HPLC-MS t R = 3.80 min (UV25 nm), Mass calculated for the formula Ci8H12F3N3? 3 375.1, LCEM observed m / z 376.1 (M + H).

Part B Compound 2030A (100 mg, 0.27 mmol) and cyclopropylmethylamine (0.140 mL) in NMP (0.5 mL) were heated at 100 ° C for 12 hours.

After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na 2 SO 4, and concentrated. Recrystallization from EtOAc / hexane provided 2030B as a white solid (75 mg, 66%). HPLC-MS t R = 4.06 min (UV254 nm), Mass calculated for the formula C22H20F2N O3 426.2, LCEM observed m / z 427.1 (M + H).

EXAMPLE 2031 Part A Compound 2030B (250 mg, 0.67 mmol) in 1 mL of benzyl alcohol was added powdered KOH (75 mg, 1.33 mmol). The reaction mixture was stirred at 100 ° C for 2 hours and cooled to room temperature. It was diluted with EtOAc, washed with 1 N HCl, H20, and brine, dried over Na2SO, and concentrated. Evaporative column chromatography with EtOAc gave 2031 A as a white solid (280 mg, 91%). HPLC-MS tR = 4.29 min (UV254 nm) > mass calculated for the formula C25H19F2N3? 463.1, LCEM observed m / z 464.0 (M + H).

Part B Compound 2031A (250 mg, 0.54 mmole) in EtOH (30 mL) was added with 10% palladium on carbon (100 mg). The reaction mixture was stirred at room temperature for 2 hours under 1 atmosphere of hydrogen. It was then filtered through celite, washed with EtOH, and concentrated, which gave 2031 B as a white solid (120 mg, 60%). HPLC-MS t R = 2.66 min (UV254 nm), mass calculated for formula C? 8H13F2N304 373.1, LCEM observed m / z 374.0 (M + H).

EXAMPLE 2032 Part A Compound 2032A was prepared using the method previously described in 2D. HPLC-MS t R = 2.94 min (UV254 nrtl), mass calculated for the formula C19H13FN403 364.1, LCEM observed m / z 365.0 (M + H).

Part B Compound 2032A (100 mg, 0.27 mmol) was dissolved in 2 mL of 90% H2SO4. After stirring at 60 ° C for 10 hours, the mixture of The reaction was poured into 50 g of ice, and a white solid precipitated. Filtration and drying under vacuum gave 2032B as a white solid (80 mg, 78%). HPLC-MS t R = 2.01 min (UV254 nm), Mass calculated for the formula C19H15FN406 382.1, LCEM observed m / z 383.1 (M + H). The following compounds were prepared as described in Examples 2030 to 2032.

The specific inhibitory activity of TACE (Ki values) of some representative compounds of the present invention described above is established below: Those skilled in the art will appreciate that changes can be made to the specific embodiments described above without departing from the broad concept of the invention. It is therefore understood that this invention is not limited to the particular embodiments described but covers the modifications that are within the spirit and scope of the invention as defined in the claims below.

Claims (23)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound selected from the group consisting of: Compound ID Structure 3010 3029 3032 3035 3044 3047 4010 4013 4022 4025 4028 4031 4034 or a pharmaceutically acceptable salt, solvate, ester or isomer thereof.

2. The compound according to claim 1 further characterized in that it is selected from the group consisting of: 3 - .

3 - The compound according to claim 2, further characterized in that it is selected from the group consisting of or a pharmaceutically acceptable salt, solvate, ester or isomer thereof.

4. A pharmaceutical composition comprising at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester or isomer thereof and at least one pharmaceutically acceptable carrier.

5. The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, for the manufacture of a medicament useful for the treatment of disorders associated with TACE, TNF-a, MMP, ADAM or any combination of these.

6. A pharmaceutical composition for the treatment of disorders associated with TACE, TNF-α, MMP, ADAM or any combination thereof in a subject comprising administering to a subject in need of such treatment a therapeutically effective amount of the pharmaceutical composition of the claim 3.

The compound according to claim 1 in purified form.

8. The use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, for the preparation of a medicament useful for the treatment of a disorder or disease mediated by TACE, MMP, TNF-a, aggrecanase, or any combination of these.

9. The use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, for the manufacture of a medicament useful for the treatment of a disorder or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, growth of solid tumors and tumor invasion by secondary metastasis, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis.

10. The use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, for the manufacture of a medicament useful for the treatment of a disorder or disease selected from the group consisting of fever, cardiovascular disorders, haemorrhages, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune diseases and HIV infection.

11. The use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, for the manufacture of a medicament useful for the treatment of a disorder or disease selected from the group consisting of septic shock, hemodynamic shock, septic syndrome, post reperfusion injury ischemic, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases that involve angiogenesis, autoimmune diseases, skin inflammation diseases, intestinal inflammation such as Crohn's disease and colitis, osteo and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Still's disease in adults, ureitis, Wegener's granulomatosis, Behcehe's disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar lesions, periodontal disease, HIV, non-insulin-dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis sis, renal ischemia, myocardial infarction, cerebrovascular accidents, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, rejection of transplants, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible obstruction of the respiratory tract, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) and bronchitis.

12. The use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, for the manufacture of a medicament useful for the treatment of a disorder or disease associated with COPD.

13. The use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, for the manufacture of a medicament useful for the treatment of a disorder or disease associated with rheumatoid arthritis.

14. The use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, for the manufacture of a medicament useful for the treatment of a disorder or disease associated with Crohn's disease. .

15. The use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, for the manufacture of a medicament useful for the treatment of a disorder or disease associated with psoriasis.

16. The use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, for the manufacture of a medicament useful for the treatment of a disorder or disease associated with ankylosing spondylitis.

17. The use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, for the manufacture of a medicament useful for the treatment of a disorder or disease associated with sciatica.

18. The use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, for the development of a drug useful for the treatment of a disorder or disease associated with complex regional pain syndrome.

19. The use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, for the manufacture of a medicament useful for the treatment of a disorder or disease associated with psoriatic arthritis.

20. The use of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or isomer thereof in combination with a compound selected from the group consisting of Avonex, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis, for the elaboration of a medicine useful for the treatment of a disorder or disease associated with multiple sclerosis.

21. The use as claimed in claim 8, wherein the medicament is adapted to be administrable with at least one drug selected from the group consisting of disease modifying antirheumatic drugs (DMARDS), nonsteroidal anti-inflammatory drugs (NSAIDs), selective inhibitors of cycloxygenase-2 (COX-2) ), COX-1 inhibitors, immunosuppressants, biological response modifiers (BRM), anti-inflammatory agents and H1 antagonists.

22. The use as claimed in claim 9, wherein the medicament is adapted to be administrable with at least one medicament selected from the group consisting of DMARDS, NSAID, COX-2 inhibitors, COX-1 inhibitors, immunosuppressants, BRM, anti-inflammatory agents and H1 antagonists.

23. The use as claimed in claim 10, wherein the medicament is adapted to be administrable with at least one medicament selected from the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, COX-inhibitors. 1, immunosuppressants, BRM, anti-inflammatory agents and H1 antagonists.