MX2008009297A - Hydantoin 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 or isomer thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, ADAMs, TACE, aggrecanase, TNF-αor combinations thereof.

Description

HIDANTOIN COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY DISORDERS BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates in general to new hydantoin derivatives that can inhibit matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAM) and / or the tumor necrosis factor-alpha converting enzyme (TACE) and by acting in this way prevent the release of tumor necrosis factor alpha (TNF-α), to pharmaceutical compositions comprising said compounds and to treatment methods using said compounds.

PREVIOUS TECHNIQUE Osteoid and rheumatoid arthritis (OA and RA, respectively) are diseases that destroy cartilage of the joints characterized by localized wear of the cartilage surface. It was demonstrated in discoveries that the articular cartilage of the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabelled sulfate with respect to the controls, of which he deduces that with OA there must be a high rate of cartilage degradation (Mankin et al., J. Bone Joint Surg, 52A (1970) 424-434). There are four classes of enzymes that degrade proteins in mammalian cells: serine-, cysteine-, aspartic- and metalloproteases. The available evidence supports the belief that metalloproteases are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin in cartilage were found in OA and the activity correlates 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) was identified that provides the specific breakdown product of proteoglycan, which was found in RA and OA patients (Lohmander L. S. et al., Arthritis Rheum, 36, 1993, 1214-22). It was determined that metalloproteases (MP) are the key enzymes in the destruction of cartilage and bone of mammals. It can be expected that the pathogenesis of such diseases can be beneficially modified by 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 number of biological processes that are important in the uncontrolled destruction of connective tissue, including proteoglycan and collagen, producing a resorption of the extracellular matrix.

This is a characteristic of numerous pathological conditions, such as RA and OA, ulceration of the cornea, epidermis or gastric; metastasis or tumor invasion; periodontal disease and bone disease. Usually these catabolic enzymes are finely regulated at the level of their synthesis, as well as at the level of their extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (inhibitor of MP tissue), which form inactive complexes with MMPs. Tumor necrosis factor-alpha (TNF-a) is a cytokine associated with the cell 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 Jan; 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, April 1, 2001; 6 (8): 417-426, each of which is incorporated herein by reference. that TNF-a plays an important role in immune and inflammatory responses The inappropriate expression or overexpression of TNF-a is a hallmark of a number of diseases, including RA, Crohn's disease, multiple sclerosis, psoriasis and sepsis. The inhibition of TNF-a production proved to be beneficial in many preclinical models of inflammatory diseases, making the inhibition of production or signaling of TNF-a an attractive target for the development of new anti-inflammatory drugs. the TNF-a is a primary mediator of inflammation, fever and acute phase responses, similar to those seen during acute infection and shock. It was shown that the excess of TNF-a has a lethal effect. Blocking the effects of TNF-a with specific antibodies can be beneficial in a variety of conditions, including autoimmune diseases such as RA (Feldman et al, Lancet, (1994) 344, 1105), 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. Recently it was shown that metalloproteases, such as TACE, have the ability to convert FNT-a from its inactive form to its active form (Gearing et al. Nature, 1994, 370, 555). Given that excessive production of TNF-a was noted in several pathological conditions that are also characterized by tissue degradation mediated by MMPs, compounds that inhibit the production of both MMP and TNF-a can also be especially advantageous in diseases where both mechanisms are involved. One approach to inhibit the harmful effects of TNF-a is to inhibit the TACE enzyme before it can process TNF-a to its soluble form. TACE is part of the ADAM family of type I membrane proteins and mediates the release to the ectodomain of various adhesion and signaling proteins anchored to the membrane. TACE acquired growing importance in the study of several diseases, including inflammatory diseases, due to its role in the cleavage of TNF-a from its "stem" sequence, thus releasing the soluble form of the TNF-a protein (Black RA Int J Biochem Cell Biol. 2002 34,1-5). There are numerous patents and publications disclosing inhibitors of MMPs based on hydroxamates, sulfonamides, hydantoins, carboxylates and / or lactams. In US 6,677,355 and US 6,534,491 (B2), compounds are described which are hydroxamic acid derivatives and inhibitors of MMPs. US Pat. No. 4,495,565 discloses lactam derivatives which are potential inhibitors of MMP and / or TNF-a. PCT publications Nos. WO2002 / 074750, WO2002 / 096426, WO20040067996, WO2004012663, WO200274750 and WO2004024721 disclose hydantoin derivatives which are potential inhibitors of MMPs. PCT publications Nos. WO2004024698 and WO2004024715 disclose sulfonamide derivatives which are potential inhibitors of MMPs. In PCT publications Nos. WO2004056766, WO2003053940 and WO2003053941 also describe potential inhibitors of TACE and MMPs. PCT publication No. WO2006 / 019768 refers to hydantoin derivatives that are inhibitors of TACE. In the art there is a need to have inhibitors of MMP, ADAM, TACE and TNF-α, which may be useful as anti-inflammatory compounds and drugs for the protection of cartilage. The inhibition of TNF-a, TACE and / or different MMPs can prevent the degradation of cartilage due to these enzymes, thus relieving the pathological conditions of OA and RA as well as many other autoimmune diseases.

BRIEF DESCRIPTION OF THE INVENTION In its different embodiments, the present invention provides a new class of compounds such as TACE inhibitors, the production of TNF-α, MMPs, ADAMs, aggrecanases 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 alleviation of one or more diseases associated with TACE, aggrecanase, TNF-a, MMPs, ADAM or any combination thereof which use said compounds or pharmaceutical compositions. In one embodiment, the present application describes a compound, or pharmaceutically acceptable salts or solvates of said compound, said compound having the general structure shown in formula (I): (or a pharmaceutically acceptable salt, solvate or ester thereof, wherein: ring A is selected from the group consisting of aryl and heteroaryl, each of which is substituted with -Y-R1 and -Z-R2 as shown; X is selected from the group consisting of -S-, -O-, -S (O) 2, -S (O) -, - (C (R3) 2) m- and -N (R3) -, T is absent or present and, if present, T is selected from the group consisting of alkyl, aryl and heteroaryl, wherein when each of said aryl and heteroaryl T contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form an aryl or heteroaryl ring of five to eight members, wherein each of the aforementioned T aryl and heteroaryl, optionally with said aryl or heteroaryl of five to eight members is independently not substituted or substituted with one to four R10 portions that may be the same or different, U is absent present or absent and, if present, U is selected from the group consisting of -O-, -OC (O) NH-, -OC (0) N (alkyl) -, -C (O) -, -C (O) O-, -C (O) NH -, -C (0) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= N-0-alkyl) -alkyl-; V is absent or present and, if present, V is selected from the group consisting of alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and N-oxides of said heterocyclyl and heteroaryl, wherein when each of said V cycloalkyl, heterocyclyl, aryl, heteroaryl and N-oxides of said heterocyclyl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, aryl, heterocyclyl or heteroaryl of five to eight members; wherein each of said V alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and heterocyclyl, optionally with said five to eight members is independently unsubstituted or substituted with one to four portions R10 which may be the same or different; Y is selected from the group consisting of a covalent bond, - (C (R4) 2) n-, -N (R4) -, -C (O) N (R4) -, -N (R4) C (O) -, -N (R4) C (O) N (R4) -, -S (O) 2N (R4) -, -N (R4) -S (O) 2, -0 -, - S-, -C (O) -, -S (O) - and -S (O) 2-; Z is selected from the group consisting of a covalent bond, - (C (R4) 2) n-, -N (R4) -, -C (O) N (R4) -, -N (R) C (O) -, -N (R4) C (0) N (R4) -, -S (O) 2N (R4) -, -N (R4) -S (O) 2-, -0 -, - S-, - C (O) -, -S (O) - and -S (O) 2-; m is 1 to 3; n is 1 to 3; R1 is selected from the group consisting of H, cyano, -C (0) OH, -C (0) 0-alkyl, -C (O) NH2, -C (O) NH (alkyl), -C (0) N (alkyl) 2, alkynyl, halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, and heterocyclyl, wherein when each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members; wherein each of the R1 alkyl, alkynyl, aryl, heteroaryl and heterocyclyl, optionally with the cycloalkyl, aryl, heterocyclic or heteroaryl ring of five or six members is unsubstituted or in optionally is independently substituted with one to four portions R20 which They can be the same or different; with the proviso that when Y is -N (R4) -, -S- and -O-, then R1 is not halogen or cyano; R2 is selected from the group consisting of H, cyano, -C (0) OH, -C (0) O-alkyl, -C (O) NH2, -C (O) NH (alkyl), -C (O) N (alkyl) 2, alkynyl, halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, and heterocyclyl, wherein when each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members; wherein each of the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, optionally with the five or six membered cycloalkyl, aryl, heterocyclic or heteroaryl ring is not substituted or optionally is independently substituted with one to four portions R20 which may be the same or different; with the proviso that when Y is -N (R4) -, -S- or -O-, then R2 is not halogen or cyano; each R3 is the same or different and selected independently from the group consisting of H, alkyl and aryl; each R4 is the same or different and selected independently from the group consisting of H, alkyl, cycloalkyl, haloalkyl, hydroxy, -alkylcycloalkyl, -alkyl-N (alkyl) 2, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members; R10 is selected from the group consisting of hydrogen, cyano, nitro, -C (R4) = N-OR4, -OR4, -SR4, -N (R4) 2, -S (O) R4, -S (O) 2R4 , -N (R4) S (0) 2R4, -N (R4) -C (O) -R4, -N (R4) -C (O) -N (R4) 2, -N (R4) -C ( O) -OR4, -OC (O) N (R4) 2, -C (O) N (R4) -S (O) 2R4, -S (O) 2N (R4) -C (O) -R4, - C (O) N (R4) C (0) R4, -C (O) N (R4) C (O) NR4, -S (O) 2N (R4) 2, -N (R) -C (= NR4) -N (R4) 2, -N (R4) - C (= N-CN) -N (R 4) 2, -haloalkoxy, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, wherein each of the R10 alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or in optionally is independently substituted with one to four R30 portions which may be the same or different; or where two R10 moieties, when attached to the same carbon atom or adjacent carbon atoms, can optionally be taken together with the carbon atom (s) to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl ring , aryl, or heteroaryl; R20 is selected from the group consisting of cyano, nitro, -C (R4) = N-OR4, -OR4, -SR4, -N (R4) 2, -S (O) R4, -S (0) 2R4, -N (R4) S (O) 2R4, -N (R4) -C (0) -R4, -N (R4) -C (O) -N (R4) 2, -N (R4) -C (O) -OR4, -OC (O) N (R4) 2, -C (O) N (R4) -S (O) 2R4, -S (O) 2N (R4) -C (O) -R4, -C (0) N (R4) C (O) R4, -C (0) N (R4) C (O) NR4, -S (O) 2N (R) 2, -N (R4) -C (= NR4) -N (R) 2, -N (R4) - C (= N-CN) -N (R 4) 2, -haloalkoxy, -C (O) OR 4, -C (0) R 4, -C (O) N (R 4) 2, halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl; wherein when each of said aryl, heteroaryl, heterocyclyl and cycloalkyl R20 contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, aryl, heterocyclyl ring or heteroaryl of five to eight members; wherein each of said alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl R 20, optionally with said five or eight membered cycloalkyl, aryl, heterocyclic or heteroaryl ring is unsubstituted or substituted with one to four portions independently selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cyano, nitro, -NH2, -NH (alkyl) and -N (alkyl) 2; or when two R20 portions being attached to the same carbon atom or adjacent carbon atoms may optionally be taken together with the carbon atom (s) to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl ring; R30 is selected from the group consisting of cyano, nitro, -C (R4) = N-OR4, -OR4, -SR4, -N (R4) 2, -S (O) R4, -S (O) 2R4, - N (R4) S (O) 2R4, -N (R4) -C (O) -R4, -N (R4) -C (O) -N (R4) 2, -N (R4) -C (O) -OR4, -OC (O) N (R4) 2, -C (0) N (R4) -S (O) 2R4, -S (O) 2N (R4) -C (O) -R4, -C ( 0) N (R4) C (O) R4, -C (O) N (R) C (0) NR4, -S (O) 2N (R4) 2, -N (R4) -C (= NR4) - N (R4) 2, -N (R4) -C (= N-CN) -N (R4) 2, -haloalkoxy, -C (O) OR4, -C (O) R4, -C (O) N ( R) 2, halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl; wherein when each of said R30 aryl, heteroaryl, heterocyclyl and cycloalkyl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, aryl, heterocyclyl ring or heteroaryl of five to eight members; wherein each of said R 30 alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, optionally with said five or eight membered cycloalkyl, aryl, heterocyclic or heteroaryl ring is unsubstituted or substituted with one to four portions independently selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro, -NH2, -NH (alkyl) and -N (alkyl) 2; or when two R30 moieties when attached to it or to adjacent carbon atoms can optionally be taken together with the carbon atom (s) to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl, aryl ring, or heteroaryl; with the proviso that at least one of T, U and V must be present; and further that at least one of the conditions (1) - (5) which are detailed below have been met: (1) at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C ( O) N (R4) C (O) R4, -C (O) N (R4) C (O) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R4) 2, -N (R4) C (O) N (R4) 2, -N (R) -C (O) -R4, -S (O) 2N (R4) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from (2) U is present and is selected from the group consisting of -OC (0) NH-, -OC (O) N (alkyl) -, -C (O) -, -C (O) O-, -C (O) NH-, -C (0) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= NO-alkyl) -alkyl-; (3) each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2) nC (0) OH, - (C (R4) 2) nC ( O) O-alkyl, - (C (R4) 2) nC (O) NH2, - (C (R4) 2) nC (0) NH (alkyl) and - (C (R) 2) nC (O) N (alkyl) 2, wherein each R 4 independently is H or alkyl; and n is 1-3; (4) T is aryl or heteroaryl, each of which is optionally substituted with one to four independently selected R10 portions and V is alkynyl which is optionally substituted with one to two independently selected R10 portions; and (5) ring A is heteroaryl and V is different from alkynyl. In another embodiment, the present invention describes a compound, or pharmaceutically acceptable salts or solvates of said compound, said compound having the general structure shown in formula (II): or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, wherein: the ring labeled A is selected from the group consisting of aryl and heteroaryl, each of which is substituted with -Y-R1 and -Z-R2 as shown; X is selected from the group consisting of -S -, - 0-, -C (R3) 2- or -N (R3) -; T is absent or present and, if present, T is selected from the group consisting of H (absent U and V), alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl- and arylalkyl-, wherein said aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl- and arylalkyl- optionally fused with one or more portions selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of any of the aforementioned groups alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl of T is unsubstituted or optionally is independently substituted with one to four portions R10 which may be the same or different, each portion R10 being selected independently from the group of R10 portions indicated below; U is absent or present and, if present, U is selected from the group consisting of alkynyl, -C (O) -, -C (O) O- and -C (O) NR4-; V is absent or present and, if present, V is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl-, cycloalkyl, alkylaryl- and arylalkyl-, said aryl, heteroaryl, heterocyclyl, heterocyclylalkyl- , cycloalkyl, alkylaryl- and arylalkyl- optionally fused with one or more portions selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of any of the aforementioned alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl are unsubstituted or optionally independently substituted with one to four portions R10 which may be the same or different, each portion R10 being selected independently from the group of R10 portions indicated below; Y is selected from the group consisting of a covalent bond, - (C (R4) 2) n-, -N (R4) -, -C (O) N (R4) -, -N (R) C (O) -, -N (R4) C (O) N (R4) -, -S (O) 2N (R4) -, -N (R4) -S (O) 2, -0 -, - S-, -C (O) -, -S (O) - and -S (O) 2-; Z is selected from the group consisting of a covalent bond, - (C (R4) 2) n-, -N (R4) -, -C (O) N (R4) -, -N (R4) C (O) -, -N (R4) C (O) N (R4) -, -S (0) 2N (R4) -, -N (R4) -S (O) 2-, -0 -, - S-, - C (O) -, -S (O) - and -S (0) 2-; n is 1 to 3; R1 is selected from the group consisting of H, -OR4, cyano, -C (O) OR4, -C (O) N (R4) 2, halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl , wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl groups of R1 is unsubstituted or optionally is substituted independently with one to four portions R20 which may be the same or different, each portion R20 selected independently of the group of portions R20 indicated below, with the condition that when Y is present and Y is N, S or O, then R1 is not halogen or cyano; R2 is selected from the group consisting of H, -OR4, cyano, -C (O) OR 4, -C (O) N (R 4) 2, halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl groups , heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl of R2 is unsubstituted or optionally is independently substituted with one to four portions R20 which may be the same or different, each portion R20 being selected independently from the group of R20 portions indicated then, with the proviso that when Z is present and Z is N, S or O, then R2 is not halogen; each R3 is the same or different and selected independently from the group consisting of H, alkyl and aryl; each R 4 is the same or different and selected independently from the group consisting of H, alkyl, heterocyclyl, aryl and heteroaryl; R10 is selected from the group consisting of cyano, -OR4, -SR4, -N (R4) 2, -S (O) R4-, -S (O) 2R4-, -N (R4) S (0) 2R4, -S (O) 2N (R) 2, -O (fluoroalkyl) , -C (O) OR 4, -C (O) N (R) 2, halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl of R10 is unsubstituted or is optionally substituted independently with one to four portions R30 which may be the same or different, each portion R30 being selected independently of the group of portions R30 indicated below; R 20 is selected from the group consisting of halogen, alkyl, fluoroalkyl, -N (R 4) 2 and -C (O) N (R 4) 2; and R30 is selected from the group consisting of halogen, alkyl, fluoroalkyl, -N (R4) 2 and -C (O) N (R4) 2. The compounds of formula I may be useful as inhibitors of TACE and may be useful for the treatment and prevention of diseases associated with TACE, TNF-α, MMPs, ADAMs or any combination thereof.

DETAILED DESCRIPTION OF THE INVENTION In its different embodiments, the present invention provides a new class of inhibitors of TACE, aggrecanase, the production of TNF-α, MMPs, ADAMs or any combination thereof, pharmaceutical compositions containing one or more of the compounds, methods for preparing pharmaceutical formulations comprising one or more of said compounds and methods of treatment, prevention or alleviation of one or more of the symptoms of inflammation. In one embodiment, the present invention provides compounds that are represented by the above structural formulas (I) or (II) or a salt, pharmaceutically acceptable solvate, ester or isomer thereof, wherein the different portions are as described above. In another embodiment, the isomer referenced in the preceding paragraph is a stereoisomer. In another embodiment, in formula (I), X is selected from the group consisting of - (C (R3) 2) m- and -N (R3) -. In another embodiment, in formula (I), X is - (C (R3) 2) m, where m is 1 or 2. In another embodiment, in formula (I), X is - (C (R3) 2) m , where m is 1. In another embodiment, in formula (I), R3 is H. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C ( O) N (R4) C (O) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R4) 2, -N (R) C (O) N (R4) 2, -N (R4) -C (O) -R4, -S (O) 2N (R) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the condition that when R10 is -S (0) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from In another embodiment in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C ( O) N (R4) C (O) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R4) 2, -N (R4) C (O) N (R4) 2, -N (R4) -C (0) -R4, -S (O) 2N (R4) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (0) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2 and -C ( R4) = N-OR4. In another embodiment in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C ( O) N (R4) C (O) R4, -C (0) N (R4) C (O) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R4) 2, -N (R4) C (O) N (R4) 2, -N (R4) -C (0) -R4, -S (O) 2N (R4) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from wherein said T or V is substituted with at least one portion R10 which is cyano. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C ( O) N (R4) C (O) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R4) 2, -N (R4) C (O) N (R4) 2, -N (R4) -C (O) -R4, -S (O) 2N (R4) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from wherein said T or V is substituted with at least one portion R10 which is -SR4. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C ( O) N (R4) C (O) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (O) 2R4, -N (R) -C (O) OR4, -OC (O) N (R4) 2, - N (R4) C (O) N (R4) 2, -N (R4) -C (O) -R4, -S (O) 2N (R4) 2, -S (O) 2N (R4) -C ( O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N (R4) 2 and -C (R4) = N -OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl, and heteroaryl contains two adjacent carbon atom radicals , said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (0) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from wherein said T or V is substituted with at least one portion R10 which is -S (O) 2R4. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R) 2, -C ( O) N (R4) C (O) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R4) 2, -N (R4) C (O) N (R4) 2, -N (R4) -C (O) -R4, -S (O) 2N (R4) 2, - S (O) 2N (R4) -C (O) -R4, -N (R) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from wherein said T or V is substituted with at least one portion R10 which is -S (O) 2N (R4) 2. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C ( O) N (R4) C (O) R4, -C (O) N (R) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R) 2, -N (R 4) C (O) N (R 4) 2, -N (R 4) -C (0) -R 4, -S (O) 2N (R 4) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from wherein ring A is selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidyl and each of them being substituted with -Y-R1 and -Z-R2 as shown. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C ( O) N (R) C (O) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R4) 2, -N (R4) C (O) N (R4) 2, -N (R4) -C (0) -R4, -S (0) 2N (R) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R) 2 and -C (R 4) = N-OR 4, wherein each R 4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R 4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a ring of aryl, heterocyclyl, heteroaryl or cycloalkyl of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from wherein ring A is phenyl. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 that was selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, - C (O) N (R4) C (O) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, -OC (O) N (R) 2, -N (R) C (O) N (R) 2, -N (R 4) -C (O) -R 4, -S (O) 2 N (R 4) 2 , -S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R) 2, -N (R4) -C (= N-CN) - N (R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the condition that when R > 10 is -S (O) 2R, V is different from piperidinyl and when R) 10 is cyano, the compound of formula (I) is different from wherein T is selected from the group consisting of alkyl, aryl, heteroaryl, wherein when each of said aryl and heteroaryl T contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are joined to form an aryl or heteroaryl ring of five to eight members; wherein each of the aforementioned T aryl and heteroaryl, optionally with said five or six membered aryl or heteroaryl is independently unsubstituted or substituted with one to four R 10 portions which may be the same or different. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 was selected from the group consisting of cyano, -C (O) OR4, -C (O) R4, -C (O) N (R) 2, -C (O) N (R4) C (O) R4, -C (O) N (R) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, -OC (O) N (R4) 2, -N (R4) C (O) N (R4) 2, -N (R4) -C (0) -R4, -S (O) 2N (R4) 2, -S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R) 2, -N (R4) - C (= N-CN) -N (R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R 4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two adjacent carbon atom radicals, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring from five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from wherein T is selected from the group consisting of -CH2-, phenyl, each with the exception of -CH2- is optionally substituted with one to four portions R10 such that the amount of R10 for each T does not exceed the amount of four. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (0) OR4, -C (O) R4, -C (O) N (R4) 2, -C ( O) N (R4) C (0) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R4) 2, -N (R4) C (0) N (R4) 2, -N (R4) -C (O) -R4, -S (O) 2N (R) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from where U is absent or present and, if present, is selected from group consisting of -C (O) - and -C (O) O-. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C ( O) N (R4) C (O) R4, -C (O) N (R) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R4) 2, -N (R4) C (O) N (R) 2, -N (R4) -C (O) -R4, -S (O) 2N (R4) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR) -N (R) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from where V is absent or present and, if present, is selected from A group consisting of aryl and heteroaryl, wherein when each of said V aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl ring or heteropole of five to eight members; wherein each of the aforementioned V aryl and heteroaryl, optionally with said five or six membered aryl or heteroaryl is independently unsubstituted or substituted by one to four R 10 portions which may be the same or different. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C ( O) N (R4) C (O) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R4) 2, -N (R4) C (O) N (R4) 2, -N (R4) -C (O) -R4, -S (O) 2N (R4) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R 0 is cyano, the compound of formula (I) is different from wherein V is selected from the group consisting of phenyl, pyridyl, pyrazinyl, indazolyl, each of them is optionally substituted with one to four portions R10 which may be the same or different. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C ( O) N (R) C (O) R 4, -C (O) N (R 4) C (0) NR 4, -SR 4, -S (O) 2 R 4, -N (R) -C (O) OR 4, - OC (O) N (R4) 2, -N (R4) C (O) N (R4) 2, -N (R4) -C (0) -R4, -S (O) 2N (R4) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals in atoms adjacent carbon, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from where each of Y and Z selected independently of the group consisting of a covalent bond and -O-. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (0) OR4, -C (O) R4, -C (O) N (R) 2, -C ( O) N (R4) C (O) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R4) 2, -N (R4) C (O) N (R4) 2, -N (R4) -C (0) -R4, -S (O) 2N (R4) 2, - S (O) 2N (R 4) -C (O) -R 4, -N (R) -C (= NR) -N (R 4) 2, -N (R 4) -C (= N-CN) -N ( R) 2 and -C (R 4) = N-OR 4, wherein each R 4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R 4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals in atoms adjacent carbon, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from where Y is -O- and Z is a covalent bond. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C ( O) N (R4) C (O) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (O) 2R4, -N (R) -C (O) OR4, - OC (O) N (R4) 2, -N (R4) C (0) N (R4) 2, -N (R4) -C (O) -R4, -S (O) 2N (R) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R > 10 is cyano, the compound of formula (I) is different from wherein each of R, 1 and R selected independently of the group consisting of H and alkyl. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C ( O) N (R4) C (O) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R4) 2, -N (R) C (O) N (R) 2, -N (R4) -C (0) -R4, -S (O) 2N (R4) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R) 2 and -C (R 4) = N-OR 4, wherein each R 4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R 4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a ring of aryl, heterocyclyl, heteroaryl or cycloalkyl of five to eight members; with the proviso that when R10 is -S (0) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from wherein R1 is alkyl and R2 is H. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (0) OR4, -C (O) R4, -C (0) N (R4) 2, -C ( O) N (R) C (O) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R) 2, -N (R 4) C (O) N (R 4) 2, -N (R 4) -C (0) -R 4, -S (O) 2N (R 4) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the condition that when R10 is -S (O) 2R4, V is different from piperidinyl and when R > 10 is cyano, the compound of formula (I) is different from wherein R1 is methyl. In another embodiment, in formula (I), at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C ( O) N (R4) C (O) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R4) 2, -N (R4) C (O) N (R) 2, -N (R4) -C (O) -R4, -S (O) 2N (R4) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R) 10 is cyano, the compound of formula (I) is different from wherein the compound of formula (I) is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or ester thereof. In another embodiment, in formula (I), U and V are present; and U is selected from the group consisting of -OC (O) NH-, -OC (O) N (alkyl) -, -C (O) -, -C (O) O-, -C (O) NH- , -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= NO-alkyl) -alkyl-. In another embodiment, in formula (I), U and V are present; and U is selected from the group consisting of -OC (O) NH-, -OC (0) N (alkyl) -, -C (O) -, -C (0) 0-, -C (O) NH- , -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= N-0-alkyl) -alkyl-; wherein ring A is selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidyl and each of them being substituted with -Y-R1 and -Z-R2 as shown. In another embodiment, in formula (I), U and V are present; and U is selected from the group consisting of -OC (O) NH-, -OC (O) N (alkyl) -, -C (O) -, -C (O) O-, -C (O) NH- , -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= NO-alkyl) -alkyl-; where ring A is phenyl. In another embodiment, in formula (I), U and V are present; and U is selected from the group consisting of -OC (O) NH-, -OC (O) N (alkyl) -, -C (O) -, -C (O) O-, -C (O) NH- , -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= NO-alkyl) -alkyl-; and where T is absent or present and when present, is selected from the group consisting of alkyl and aryl, wherein each of these is not substituted or is substituted with one to four portions R10 which may be the same or different. In another embodiment, in formula (I), U and V are present; and U is selected from the group consisting of -0-C (0) NH-, -OC (O) N (alkyl) -, -C (O) -, -C (O) O-, -C (O) NH-, -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= NO-alkyl) -alkyl-; and wherein T is absent or present and when present is selected from the group consisting of -CH2- and phenyl. In another embodiment, in formula (I), U and V are present; and U is selected from the group consisting of -OC (O) NH-, -OC (O) N (alkyl) -, -C (O) -, -C (O) 0-, -C (O) NH- , -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= NO-alkyl) -alkyl-; and wherein V is selected from the group consisting of alkyl, heterocyclyl and cycloalkyl, wherein when each of said V heterocyclyl or cycloalkyl contains two carbon atom radicals adjacent, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, heterocyclyl, aryl or heteroaryl ring of five to eight members; wherein each of the aforementioned V alkyl, heterocyclyl and cycloalkyl, optionally with said cycloalkyl, heterocyclyl, aryl or heteroaryl ring of five to eight members is independently unsubstituted or is substituted with one to four portions R10 which may be the same or different . In another embodiment, in formula (I), U and V are present; and U is selected from the group consisting of -OC (O) NH-, -OC (O) N (alkyl) -, -C (O) -, -C (O) O-, -C (O) NH- , -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= NO-alkyl) -alkyl-; and wherein V is selected from the group consisting of methyl, ethyl, isopropyl, morpholinyl, cyclohexyl, piperidinyl optionally substituted with cyano or phenyl, -CH 2 - substituted with tetrahydrofuranyl and -CH (CH 3) - substituted with phenyl, piperazinyl substituted with methyl, pyrrolidinyl substituted with -CH 2 -phenyl, substituted with cyclopropyl and In another embodiment, in formula (I), U and V are present; and U is selected from the group consisting of -O-C (O) NH-, -OC (O) N (alkyl) -, -C (O) -, -C (O) O-, -C (O) NH-, -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= NO-alkyl) -alkyl-; and where each of Y and Z selected independently of the group consisting of a covalent bond and -O-. In another embodiment, in formula (I), U and V are present; and U is selected from the group consisting of -OC (O) NH-, -OC (O) N (alkyl) -, -C (O) -, -C (O) O-, -C (O) NH- , -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= NO-alkyl) -alkyl-; and where Y is -O- and Z is a covalent bond. In another embodiment, in formula (I), U and V are present; and U is selected from the group consisting of -OC (O) NH-, -OC (O) N (alkyl) -, -C (O) -, -C (O) 0-, -C (O) NH- , -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= N-0-alkyl) -alkyl-; and wherein each of R1 and R2 selected independently of the group consisting of H and alkyl. In another embodiment, in formula (I), U and V are present; and U is selected from the group consisting of -OC (O) NH-, -OC (0) N (alkyl) -, -C (O) -, -C (O) O-, -C (O) NH- , -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= NO-alkyl) -alkyl-; and wherein R1 is alkyl and R2 is H. In another embodiment, in formula (I), U and V are present; and U is selected from the group consisting of -O-C (O) NH-, -OC (O) N (alkyl) -, -C (O) -, -C (O) 0-, -C (O) NH-, -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= NO-alkyl) -alkyl-; and wherein R1 is methyl. In another embodiment, in formula (I), U and V are present; and U is selected from the group consisting of -OC (O) NH-, -OC (O) N (alkyl) -, -C (O) -, -C (O) 0-, -C (O) NH- , -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= NO-alkyl) -alkyl-; and wherein the compound of formula (I) is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or ester thereof. In another embodiment, in formula (I), at least one of T and V is present and each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2 ) nC (O) OH, - (C (R4) 2) nC (O) O-alkyl, - (C (R4) 2) nC (O) NH2, - (C (R4) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (O) N (alkyl) 2, wherein each R4 independently is H or alkyl; and n is 1-3. In another embodiment, in formula (I), at least one of T and V is present and each of -Y-R1 and -Z-R2 is selected independently of the group consisting of cyano, - (C (R4) 2) nC (0) OH, - (C (R4) 2) nC (O) O-alkyl, - (C (R4) 2) nC (O) NH2, - (C (R4) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (0) N (alkyl) 2, wherein each R4 independently is H or alkyl; and n is 1-3; where ring A is selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidyl and each of them being substituted with -Y-R1 and -Z-R2 as shown. In another embodiment, in formula (I), at least one of T and V is present and each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2 ) nC (O) OH, - (C (R4) 2) nC (O) O-alkyl, - (C (R4) 2) nC (O) NH2, - (C (R4) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (O) N (alkyl) 2, wherein each R4 independently is H or alkyl; and n is 1-3; wherein said ring A is phenyl. In another embodiment, in formula (I), at least one of T and V is present and each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2 ) nC (O) OH, - (C (R4) 2) nC (O) O-alkyl, - (C (R4) 2) nC (O) NH2, - (C (R4) 2) nC (O) NH (alkyl) and - (C (R) 2) nC (O) N (alkyl) 2, wherein each R 4 independently is H or alkyl; and n is 1-3; where T or V is aryl which is not substituted or is substituted with one to four portions R10. In another embodiment, in formula (I), at least one of T and V is present and each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2 ) nC (O) OH, - (C (R4) 2) nC (O) O-alkyl, - (C (R4) 2) nC (O) NH2, - (C (R4) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (O) N (alkyl) 2, wherein each R4 independently is H or alkyl; and n is 1-3; wherein said T or V is phenyl which is not substituted or is substituted with one to four portions R10. In another embodiment, in formula (I), at least one of T and V is present and each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2) nC (O) OH, - (C (R) 2) nC (O) 0-alkyl, - (C (R) 2) pC (O) NH2 , - (C (R4) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (O) N (alkyl) 2, wherein each R4 independently is H or alkyl; and n is 1-3; where R10 is fluorine. In another embodiment, in formula (I), at least one of T and V is present and each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2 ) nC (O) OH, - (C (R4) 2) nC (O) O-alkyl, - (C (R4) 2) nC (O) NH2, - (C (R) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (O) N (alkyl) 2, wherein each R4 independently is H or alkyl; and n is 1-3; where only one of T and V is present. In another embodiment, in formula (I), at least one of T and V is present; each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2) nC (O) OH, - (C (R4) 2) nC (O) O -alkyl, - (C (R4) 2) nC (O) NH2, - (C (R4) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (O) N (alkyl) 2, wherein each R4 independently is H or alkyl; and n is 1-3; where U is absent. In another embodiment, in formula (I), at least one of T and V is present; each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R) 2) nC (O) OH, - (C (R4) 2) nC (O) O -alkyl, - (C (R4) 2) nC (O) NH2, - (C (R4) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (O) N (alkyl) 2, wherein each R4 independently is H or alkyl; and n is 1-3, where n is 1. In another embodiment, in formula (I), at least one of T and V is I presented; each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2) nC (O) OH, - (C (R4) 2) nC (O) O -alkyl, - (C (R4) 2) nC (O) NH2, - (C (R4) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (O) N (alkyl) 2, wherein each R4 independently is H or alkyl; and n is 1-3; wherein each of Y and Z selected independently of the group consisting of a covalent bond and -CH2- and each of R1 and R2 selected independently of the group consisting of cyano, -C (O) OH or - C (O) NH2. In another embodiment, in formula (I), at least one of T and V is present, each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2 ) nC (O) OH, - (C (R4) 2) nC (O) O-alkyl, - (C (R4) 2) nC (O) NH2, - (C (R4) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (O) N (alkyl) 2, wherein each R4 independently is H or alkyl; and n is 1-3; where Y is a covalent bond and R1 is H. In another embodiment, in formula (I), at least one of T and V is present; each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2) nC (O) OH, - (C (R4) 2) nC (O) O -alkyl, - (C (R4) 2) nC (O) NH2, - (C (R4) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (O) N (alkyl) 2, wherein each R4 independently is H or alkyl; and n is 1 -3; where Z is a covalent bond and R2 is cyano. In another embodiment, in formula (I), at least one of T and V is present; each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2) nC (O) OH, - (C (R4) 2) nC (O) O -I rent, - (C (R4) 2) nC (O) NH2, - (C (R) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (O) N (alkyl) 2, in wherein each R4 independently is H or alkyl; and n is 1-3; where Z is -CH2- and R2 is -C (O) OH or -C (O) NH2. In another embodiment, in formula (I), at least one of T and V is present; each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2) nC (O) OH, - (C (R4) 2) nC (O) O -alkyl, - (C (R) 2) nC (O) NH2, - (C (R4) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (O) N (alkyl) 2, wherein each R4 independently is H or alkyl; and n is 1-3; wherein the compound of formula (I) is selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, in formula (I), T is aryl or heteroaryl, each of which is optionally substituted with one to four independently selected R10 portions and V is alkynyl which is optionally substituted with one or two R10 independently selected .

In another embodiment, in formula (I), T is aryl or heteroaryl, each of which is optionally substituted with one to four R10 portions independently selected and V is alkynyl which is optionally substituted with one to two R10 portions selected in the form Independent; where ring A is selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidyl and each of them being substituted with -Y-R1 and -Z-R2 as shown. In another embodiment, in formula (I), T is aryl or heteroaryl, each of which is optionally substituted with one to four independently selected R10 portions and V is alkynyl which is optionally substituted with one to two selected R10 portions. Independent; wherein said ring A is phenyl. In another embodiment, in formula (I), T is aryl or heteroaryl, each of which is optionally substituted with one to four independently selected R10 portions and V is alkynyl which is optionally substituted with one or two R10 independently selected; where T is aryl, U is -O- or is absent and V is alkynyl which is unsubstituted or is substituted with one to two R10 portions selected from the group consisting of -OR4, -N (R4) 2 and heteroaryl; wherein when said heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; wherein each R 4 independently is H or alkyl and said R 10 heteroaryl optionally is independently substituted with one to four R 30 portions which may be the same or different. In another embodiment, in formula (I), T is aryl or heteroaryl, each of which is optionally substituted with one to four independently selected R10 portions and V is alkynyl which is optionally substituted with one to two selected R10 portions. Independent; where T is phenyl. In another embodiment, in formula (I), T is aryl or heteroaryl, each of which is optionally substituted with one to four independently selected R10 portions and V is alkynyl which is optionally substituted with one to two selected R10 portions. Independent; wherein said V alkynyl is selected from the group consisting of -CH2-C = C-CH3 and R10 substituted with -C = C- and -CH2-C = C-CH2-. In another embodiment, in formula (I), T is aryl or heteroaryl, each of which is optionally substituted with one to four independently selected R10 portions and V is alkynyl which is optionally substituted with one to two selected R10 portions. Independent; wherein said R10 are selected from the group consisting of -N (alkyl) 2, -OH, -OCH3 and pyridyl.

In another embodiment, in formula (I), T is aryl or heteroaryl, each of which is optionally substituted with one to four independently selected R10 portions and V is alkynyl which is optionally substituted with one to two selected R10 portions. Independent; wherein the compound of formula (I) is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or ester thereof. In another embodiment, in formula (I), at least one of T and V is present, ring A is heteroaryl and V is different from alkynyl. In another embodiment, in formula (I), at least one of T and V is present, ring A is heteroaryl and V is different from alkynyl; where ring A is selected from the group consisting of thiophenyl, pyridyl, pyrimidyl and each of them being substituted with -Y-R1 and -Z-R2 as shown. In another embodiment, in formula (I), at least one of T and V is present, ring A is heteroaryl and V is different from alkynyl; where T is selected from the group consisting of alkyl and halo-substituted aryl. In another embodiment, in formula (I), at least one of T and V is present, ring A is heteroaryl and V is different from alkynyl; where U and V are absent. In another embodiment, in formula (I), at least one of T and V is present, ring A is heteroaryl and V is different from alkynyl; where Y is selected from the group consisting of a covalent bond and -O- and Z is a covalent bond. In another embodiment, in formula (I), at least one of T and V is present, ring A is heteroaryl and V is different from alkynyl; wherein R1 is selected from the group consisting of H and -CH3; and R2 is H. In another embodiment, in formula (I), at least one of T and V is present, ring A is heteroaryl and V is different from alkynyl; where Y is a covalent bond R1 is H. In another embodiment, in formula (I), at least one of T and V is present, ring A is heteroaryl and V is different from alkynyl; where Y is -O-and R1 is -CH3. In another embodiment, in formula (I), at least one of T and V is present, ring A is heteroaryl and V is different from alkynyl; where Z is a covalent bond and R2 is H.

In another embodiment, in formula (I), at least one of T and V is present, ring A is heteroaryl and V is different from alkynyl; wherein the compound of formula (I) is selected from the group consisting of: a pharmaceutically acceptable salt or solvate thereof. In another embodiment, the compound of formula (I) is selected from the group consisting of compounds indicated in the table below (Table 1), or a pharmaceutically acceptable salt, solvate, ester or isomer of the same. This table also indicates the mass spectroscopy data and the Ki index for each compound. These compounds with a Ki value of less than 10 nM (< 10 nM) are identified by the letter "A"; those with a Ki value of 10 to less than 100 nM (10 - <100 nM) are identified by the letter "B"; those with a Ki value of 100 to 1000 nM are identified by the letter "C"; and those with a Ki value greater than 1000 nM (> 1000 nM) are identified with the letter "D". The synthesis and characterization of these compounds are described below in the "EXAMPLES" section of the present application.

TABLE 1 In another embodiment, the compound of formula (I) is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or ester thereof. The specific inhibition activity of TACE (Ki values) of some representative compounds of the present invention is indicated below.

As used above and through this disclosure, the following terms, unless otherwise indicated, should be understood as follows: "Patient" includes both humans and animals. "Mammal" means humans and other mammal animals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and which comprises about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. The most 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 the same or different, each substituent being selected independently from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, - NH (alkyl), -NH (cycloalkyl), -N (alkyl) 2, carboxy and -C (O) O-alkylo. 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 about 2 to about 6 carbon atoms in the chain which may 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 carbon-carbon triple 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, each substituent being selected independently from the group consisting of alkyl, aryl and cycloalkyl. "Aryl" means a monocyclic or multicyclic aromatic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group in optional form may be substituted with one or more "ring system substituents" which may be the same or different and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

"Heteroaryl" means a monocyclic or multicyclic aromatic ring system comprising about 5 to about 14 cyclic atoms, preferably about 5 to about 10 cyclic atoms, wherein one or more of the cyclic atoms is a non-carbon element, e.g. nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 cyclic atoms. The "heteroaryl" may optionally be substituted with one or more "ring system substituents" which may be the same or different and are as defined herein. The prefix aza, oxa or tia prior to the heteroaryl root designation means that at least one nitrogen, oxygen or sulfur atom respectively, is present as a cyclic atom. A nitrogen atom of a heteroaryl can optionally be oxidized to obtain the corresponding N-oxide. "Heteroaryl" can also include a heteroaryl as previously defined, fused to an aril as previously defined. 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, 2,4 -thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo [1,2-ajpyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl , pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" is also refers to partially saturated heteroaryl portions, such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl-alkyl group, wherein aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The binding to the main portion is through alkyl. "Alkylaryl" means an alkyl-aryl group, wherein alkyl and aryl are as previously described. The alkylaryls preferably comprise a lower alkyl group. Non-limiting examples of a suitable alkylaryl group is tolyl. The union to the main portion is through aril. "Cycloalkyl" means a mono or multicyclic nonaromatic 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 cyclic atoms. The cycloalkyl in optional form can be substituted with one or more "ring system substituents" which may be the same or different and are as previously defined. 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, norbornyl, adamantyl and Similar. "Cycloalkenyl" 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 containing at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 cyclic atoms. The cycloalkenyl optionally may be substituted with one or more "ring system substituents" which may be the same or different and are as previously defined. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl and the like. Non-limiting examples of a suitable multicyclic cycloalkenyl is norbornylenyl. "Halogen" (or "halo") means fluorine, chlorine, bromine, or iodine. They are preferably fluorine, chlorine and bromine. "Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system that, for example, replaces a hydrogen available in the ring system. The substituents of the ring system may be the same or different, each being 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), G1G2N-, G ^ N-alkyl-, G? G2NC (O) -, G? G2NSO2- and -SO2NG1G2, where dy G2 can be the same or different and are selected independently from the group consisting of 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 said portions are methylenedioxy, ethylenedioxy, -C (CH3) 2- and the like forming portions such as, for example: and "Heterocyclyl" means a monocyclic or multicyclic saturated non-aromatic ring system comprising about 3 to about 10 cyclic atoms, preferably about 5 to about 10 cyclic atoms, in which one or more of the atoms in the ring system is a different element of carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no non-adjacent oxygen and / or sulfur atoms in the ring system. Preferred heterocyclyls contain about 5 to about 6 cyclic atoms. The prefix aza, oxa or aia prior to "heterocyclyl" root designation means that at least one nitrogen atom, oxygen or sulfur respectively, is present as a cyclic atom. Any -NH in a heterocyclyl ring may be 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 optionally be substituted with one or more "ring system substituents" which may be the same or different and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl may optionally be oxidized to obtain the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone and the like. "Heterocyclyl" can also mean a single portion (e.g., carbonyl) that simultaneously replaces two available hydrogens on the same carbon atom in a ring system. An example of such a portion is pyrrolidone: It should be noted that the tautomeric forms, such as, for example, the portions: and are considered equivalent in certain embodiments of this invention. "Alkynylalkyl" means an alkynyl-alkyl group, wherein the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl group and a lower alkyl group. The binding to the main portion is through alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. "Heteroaralkyl" means a heteroaryl-alkyl- group, wherein heteroaryl and alkyl are as previously described. The heteroaralkyls preferably contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl and quinolin-3-ylmethyl. The binding to the main portion is through alkyl. "Hydroxyalkyl" means an HO-alkyl- group, wherein alkyl is as previously defined. Preferred hydroxyalkyls contain a 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 different groups are as previously described. The binding to the main portion is through the 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 binding to the main portion is through the 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 suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The union to the main portion 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 suitable aryloxy groups include phenoxy and naphthoxy. The union to the main portion 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 union to the main portion 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 union to the main portion 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 union to the main portion is a through sulfur. "Aralkylthio" means an aralkyl-S- group, in which the aralkyl group is as previously described. Non-limiting examples of a suitable aralkylthio group is benzylthio. The union to the main portion is through sulfur. "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The binding to the main portion is through the carbonyl. "Aryloxycarbonyl" means an aryl-O-C (O) - group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The binding to the main portion is through the carbonyl. "Aralkoxycarbonyl" means an aralkyl-O-C (O) - group. Non-limiting examples of suitable aralkoxycarbonyl group is benzyloxycarbonyl. The binding to the main portion is through the carbonyl. "Alkylsulfonyl" means an alkyl-S (O2) - group. Preferred groups are those, in which the alkyl group is lower alkyl. The binding to the main portion is through sulfonyl. "Ariisulfonyl" means an aryl-S (O2) - group. The binding to the main portion is through sulfonyl. The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection of the indicated group, provided that under the present circumstances the normal valence of the designated atom is not exceeded and that the substitution results in a compound stable. The combinations of the substituents and / or variables are allowed only if said combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is strong enough to withstand the isolation in a useful degree of purity of a reaction mixture, and is formulated into an efficient therapeutic agent. "means the optional substitution with the specified groups, radicals or portions The term" isolated "or" in isolated form "refers in the case of a compound to the physical state of said compound, after having been isolated from a synthesis process or a natural source or combination thereof The term "purified" or "in purified form" refers in the case of a compound to the physical state of said compound, after having been isolated from a process or purification processes described herein or those well known to a person skilled in the art, with sufficient purity to allow characterization by standard analytical techniques that are they write here or they are well known to the person skilled in the art. It should also be noted that it is assumed that any carbon, as well as a heteroatom with valences not satisfied in the text, the schemes, the examples and tables, has a sufficient amount of hydrogen atom (s) to satisfy the valences. When a functional group in a compound is referred to as "protected," it means that the group has a modified form to exclude unwanted collateral reactions at the point of protection, when the compound is subjected to a reaction. Those skilled in the art will recognize the appropriate protection groups, as well as refer to them in the usual textbooks, such as, for example, TW Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York When any variable (eg, aryl, heterocycle, R2, etc.) occurs more than once in any constituent or in formula I, its definition in each presentation is independent of its definition in any other case. As used herein, the term "composition" should comprise a product comprising the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from the combination of the specified ingredients in the specified amounts. The prodrugs and solvates of the compounds of the invention are also included herein. The term "prodrug", as used herein, refers to a compound that is a precursor drug, which upon administration to an individual, is subjected to chemical conversion through metabolic or chemical processes, to give a compound of formula I or a salt and / or a solvate thereof. Further details of prodrugs are given in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 4 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 herein by reference. The term "prodrug" means a compound (e.g., a precursor drug) that is transformed in vivo to give a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof of the compound. The transformation can occur through various mechanisms (eg, by metabolic or chemical processes), such as, for example, by hydrolysis in blood. A discussion of the use of prodrugs in T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the 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 pharmaceutically acceptable salt, hydrate or solvate thereof, of the compound contains a carboxylic acid functional group, a prodrug may comprising an ester formed by the replacement of a hydrogen atom of the acid group with a group such as, for example, alkyl (C? -8), alkanoyloxymethyl (C2-C? 2), 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, 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 having from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl) having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N- alkylamino (d-C2) -alkyl (C2-C3) (as well as ß-dimethylaminoethyl), carbamoyl-alkyl (C2), N, N-di-alkylcarbamoyl- (C2-C2) -alkyl (C2) and piperidino-, pyrrolidino- or morpholino-alkyl (C2-C3) and the like. Similarly, if a compound of formula (I) contains an alcohol functional group, a prodrug can be formed by replacing a hydrogen atom of the alcohol group with a group such as, for example, alkanoyloxy (C? -C6) - methyl, 1- ((C? -C6) alkanoyloxy) ethyl, 1-methyl-1- (alkanoyloxy (C-? - C6)) ethyl, alkoxy (CrC6) carbonyloxymethyl, N-alkoxy- (d-C? J-carbonylaminomethyl) , succinoyl, alkanoyl (C Ce), a-amino-alkanoyl (CC), arylacyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl, where each a-aminoacyl group selected independently of natural L-amino acids, P (O) (OH) 2, -P (O) (O-C6 alkyl)) 2 or glycosyl (resulting in the radical of the removal of a hydroxyl group from the hemiacetal form of a carbohydrate) and the like. compound of formula (I) incorporates a functional amino group, a prodrug can be formed by the replacement of a hydrogen atom atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'- carbonyl wherein R and R 'are both independently (C1-C10) alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural a-aminoacyl or a natural a-aminoacyl, - C (OH) C (O) OY1 wherein Y1 is H, (C6) alkyl or benzyl, - C (OY2) Y3 where Y2 is (C4) alkyl and Y3 is (C6) alkyl, carboxy (C6-6) alkyl, amino-alkyl (C C4) or mono-N- or di- N, N-alkylaminoacyl (C C6), - C (Y4) Y5 where Y4 is H or methyl and Y5 is mono- N- or di-N, N-alkylamino (C -? - C6) morpholino, piperidin-1-yl or pyrrolidin-1-yl and the like. "Solvate" means a physical association of a compound of this invention with one or more solvents molecules. This physical association includes different degrees of ionic and covalent bonds, including hydrogen bonding. In certain circumstances, the solvate will have the capacity of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The "solvate" comprises both the phase of the solution and the insoluble solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates and the like. A "hydrate" is a solvate, where the solvent molecule is H2O. "Effective amount" or "therapeutically effective amount" is used to describe an amount of a compound or composition of the present invention that is effective to inhibit TACE, the production of TNF-a, MMPs, ADAEMs or any combination thereof. same, thus producing the desired therapeutic, relieving, inhibiting or preventive effect. The compounds of formula I can form salts that are also within the scope of the present invention. The reference to Formula I herein is meant to include 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.

Further, when a compound of formula I contains a basic portion, such as without limitation, pyridine or imidazole, and an acidic portion, such as without limitation, carboxylic acid, zwitterions ("internal salts") can be formed and they are included within the term "salt (s)" as used herein. Pharmaceutically acceptable salts are preferred (for example: acceptable for physiological, non-toxic use), although other salts are also useful. The salts of the compounds of formula I can be formed, for example, by reacting a compound of formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Acid addition salts include, by way of example, acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphor sulfonates, fumarates, hydrochlorides, hydrobromides, iodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. In addition, acids which are generally considered suitable for the formation of salts useful for pharmaceutical use of basic pharmaceutical compounds are described, for example, in P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Sais. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge ef al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P. Gould, International J. de 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. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, salts of alkaline earth metals 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. Groups containing basic nitrogen can be quaternized with agents such as lower alkyl halides (for example: methyl, ethyl, and butyl chloride, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates) , long chain halides (e.g., decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. All these 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 their salts, solvates and prodrugs, can exist in their tautomeric form (for example: as 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 within the scope of the present invention, in the same way as isomers of position (such as, for example, 4-pyridyl and 3-pyridyl). The individual stereoisomers of the compounds of the invention can, for example, be substantially free of other isomers, or may be mixed, for example, as racemates or with the other stereoisomers, or other selected ones. The chiral centers of the present invention may have the S or R configuration as defined by Recommendations lUPAC 1974, The use of the terms "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, are included in the present invention. The compounds according to the invention possess pharmacological properties, in particular, the compounds of formula I can be inhibitors of the activity of TACE, aggrecanase, TNF-a and / or MMP. In one aspect, the invention provides a composition for pharmaceutical use 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 vehicle acceptable for pharmaceutical use. In another aspect, the invention provides a method for the treatment of disorders associated with TACE, aggrecanase, TNF-a, MMPs, ADAM or any combination thereof, wherein said method comprises administering to the patient in need of such treatment an amount effective of at least one compound of formula (I). In another aspect, the invention provides the use of a compound of formula (I) for the preparation of a medicament for treating disorders associated with TACE, aggrecanase, TNF-a, MMPs, 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 without limitation septic shock, hemodynamic shock, sepsis syndrome, post-ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases related to angiogenesis, autoimmune diseases, skin inflammation diseases, inflammatory bowel diseases such as Crohn's disease and colitis, OA and RA, ankylosing spondylitis, psoriatic arthritis, Still's disease in adults, ureitis, Wegener's granulomatosis , Behcehe's disease, Sjogren's syndrome, sarcoidosis, polymyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, non-insulin-dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, pulmonary fibrosis, diopathic, pulmonary bronchial dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral attack, cerebral ischaemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing alveolitis, psoriasis, rejection to transplants, dermatitis atopic, vasculitis, allergy, allergic rhinitis and stational, reversible obstruction in the respiratory tract, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD), and / or bronchitis. It is contemplated that a compound of the present invention may be useful in the treatment of one or more of the detailed diseases. In another aspect, the invention provides a method for preparing a pharmaceutical composition for the treatment of disorders associated with TACE, aggrecanase, TNF-α, MMPs, ADAMs or any combination thereof, wherein said method comprises bringing into close contact the less a compound of formula (I) and at least one acceptable vehicle for pharmaceutical use. In another aspect, the invention provides a compound of formula (I) which discloses TACE, FNT-α, MMPs, ADAMs or any inhibitory activity of the combination thereof, including enantiomers, stereoisomers, and tautomers of said compounds, and pharmaceutically acceptable salts, solvates or esters of said compound, said compound being selected from the compounds of structures detailed in Table 1 set forth above. In another aspect, the invention provides a pharmaceutical composition for the treatment of disorders associated with TACE, aggrecanase, TNF-a, MMPs, ADAM or any combination thereof in an individual, which comprises administering to the individual 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 condition or disease transmitted by TACE, MMP, TNF-a, aggrecanase, or any combination thereof in an individual comprising: administering to an individual 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 treating a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulcer, solid tumor growth and tumor invasion by secondary metastasis, neovascular glaucoma, inflammatory disease. of intestines, multiple sclerosis and psoriasis in an individual, comprising administering to a 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 condition or disease selected from the group consisting of fever, cardiovascular diseases, haemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, attack, graft versus host, autoimmune disease and HIV infection in an individual, comprising administering to the individual 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 condition or disease selected from the group consisting of septic shock, hemodynamic shock, sepsis syndrome, post-ischemia reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, heart failure. congestive, fibrotic diseases, cachexia, rejection of grafts, cancers such as cutaneous T-cell lymphoma, diseases related to angiogenesis, autoimmune diseases, inflammation diseases of the skin, inflammatory bowel diseases such as Crohn's disease and colitis, osteoatritis and rheumatoid arthritis, spondylitis ankylosing, 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 lesion , periodontal disease, HIV, non-insulin-dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, pulmonary bronchial dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, stroke, cerebral ischemia , nephritis, hepatitis, glomerulone fritis, cryptogenic fibrosing alveolitis, psoriasis, rejection to transplants, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible obstruction in the respiratory tract, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) and bronchitis in a individual, which comprises administering to the individual 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 condition or disease associated with COPD, comprising administering to the individual 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 condition or disease associated with rheumatoid arthritis, which comprises administering to the individual in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, ester or isomers. In another aspect, the invention provides a method for the treatment of a condition or disease associated with Crohn's disease, which comprises administering to the individual in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a of its salts, solvates, ester or pharmaceutically acceptable isomers. In another aspect, the invention provides a method for the treatment of a condition or disease associated with psoriasis, comprising administering to the individual in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, ester or isomers. In another aspect, the invention provides a method for the treatment of a condition or disease associated with ankylosing spondylitis, which comprises administering to the individual 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 condition or disease associated with sciatica, which comprises administering to the individual in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, ester or isomers. In another aspect, the invention provides a method for the treatment of a condition or disease associated with complex regional pain syndrome, which comprises administering to the individual in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, ester or isomers. In another aspect, the invention provides a method for the treatment of a condition or disease associated with psoriatic arthritis, comprising administering to the individual in need of such treatment a therapeutically effective amount of at least one compound of formula (I), or a of its pharmaceutically acceptable salts, solvates, ester or isomers. In another aspect, the invention provides a method for the treatment of a condition or disease associated with multiple sclerosis, which comprises administering to the individual in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, ester or isomers, in combination with a compound selected from the group having Avonex®, Betaserone, 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 with or used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) such as piroxicam, naproxen, indomethacin, ibuprofen and the like; selective cyclooxygenase-2 (COX-2) inhibitors 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 inhibitors of small molecules 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 ZyTAec®. In another aspect, the invention provides a method for the treatment of a condition or disease transmitted by TACE, MMP, TNF-α, aggrecanase, or any combination thereof in an individual, which comprises administering to the individual in need of such treatment a Therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate 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 (BRMs), anti-inflammatory agents and H1 antagonists. In another aspect, the invention provides a method for the treatment of a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulcer, solid tumor growth and invasion of invasive tumor by secondary metastasis, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in an individual, which comprises administering to the individual 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 combination with a therapeutically effective amount of at least one medicament selected from the group having DMARDS, NSAIDs, COX inhibitors -2, COX-1 inhibitors, immunosuppressants, BRMs, anti-inflammatory agents and H1 antagonists, In another aspect, the invention provides a method for the treatment of a condition or disease selected from the group consisting of septic attack, hemodynamic shock, sepsis syndrome, injury by reperfusion post-ischemia, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, rejection of grafts, cancers such as cutaneous T-cell lymphoma, diseases related to angiogenesis, autoimmune diseases, inflammatory diseases of skin, inflammatory bowel diseases such as Crohn's disease and colitis, osteoarthritis 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 iple, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, non-insulin-dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, pulmonary bronchial dysplasia, retinal disease , scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral attack, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing alveolitis, psoriasis, rejection to transplants, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible obstruction in the ways respiratory, syndrome of adult respiratory failure, asthma, chronic obstructive pulmonary disease (COPD), and bronchitis in an individual, which comprises administering to the individual in need of such treatment a therapeutically effective amount of at least one compound of formula (I), one of its pharmaceutically acceptable salts, solvates, ester or isomers in combination with a therapeutically effective amount of at least one medicament selected from the group having DMARDS, NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressants, BRMs, anti-inflammatory agents and antagonists of H1, In another aspect, the invention provides a method for the treatment of RA comprising the administration of 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-aD compound, for example: Enbrel® or Remicade®; a PDE IV inhibitor, or other class of compounds indicated for the treatment of RA. In another aspect, the invention provides a method for the treatment of multiple sclerosis comprising the administration of a compound of formula (I) in combination with a compound selected from the group having Avonex®, Betaserone, Copaxone or other compounds indicated for the treatment of multiple sclerosis. TACE activity is determined by an analysis of the kinetics which measures the percentage increase in fluorescent intensity generated by the catalyzed decomposition of TACE of an internally deactivated peptide substrate (SPDL-3). In the analysis, the purified catalytic region of recombinant human TACE (rhTACEc, Remainder 215 to 477 with two mutations (S266A and N452Q) and one end 6xHis) is used. The expression system of baculovirus / Hi5 cells is purified using affinity chromatography. The substrate SPDL-3 is an internally deactivated peptide (MCA-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Dpa-Arg-NH2), with its sequence obtained from the site of decomposition of the pro -FNTa. 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 CaCl 2, 100 μM ZnCl 2 100 μM, 2% DEMO, 0.04% Methylcellulose, 30 μM SPDL-3, 70 pM rhTACEc and a test compound. The RhTACEc was 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 min. using a fluorospectrometer (GEMINI XS, Molecular Devices). The percentage of enzymatic reaction is shown as units per second. The effect of a test compound is shown as% of TACE activity in the absence of the compound. The pharmaceutical compositions containing an active ingredient may be in a form suitable for oral use, for example, as tablets, pills, aqueous or oily suspensions, powders or dispersible granules, emulsions, hard or soft capsules, or syrups or elixirs. The compositions for oral use can be prepared according to any method known in the art for the preparation of the 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 in order to provide pharmaceutical preparations of elegant presentation and pleasant taste. The tablets contain the active ingredient mixed with pharmaceutically acceptable non-toxic excipients which are suitable for the preparation of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; ligation agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may not be coated or may be coated by known techniques in order to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a retarder material such as glyceryl monostearate or glyceryl distearate may be employed. These can also be coated by means of the technique described in the U.S. Patents. 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 composition in large quantities and the individual dose units composed of more than one (for example: two) pharmaceutically active agent such as, for example, a compound of the present invention and an additional agent selected from lists of the additional agents described herein, together with any pharmaceutically inactive excipients. The composition in large quantities and each unit of individual dose may contain established amounts of "more than one pharmaceutically active agent" mentioned above. The composition in large quantities is material that has not yet been divided into individual dose units. An illustrative dose unit is an oral dose unit such as tablets, similar pills. Similarly, the method described herein for the treatment of a patient by means of administering a pharmaceutical composition of the present invention also encompasses the administration of the above-mentioned large-dose composition and single dose unit. Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with a solid inert diluent, for example, calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules where the active ingredient is mixed with water or a medium of oil, for example peanut oil, liquid paraffin or olive oil.

The aqueous suspensions contain the active material, mixed with suitable excipients for the preparation of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alignate, polyvinyl pyrrolidone, tragacanth gum and acacia gum; Dispersing or wetting agents can be a naturally occurring phosphatide, for example, lecithin, or the condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or the condensation products of ethylene oxide with aliphatic alcohols of long chain, for example, heptadecaethylene-oxicetanol, or the condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or the condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydride, for example, sorbitan polyethylene 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 a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in mineral oils such as liquid paraffin. Oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those listed above, and flavoring agents may be added to provide a palatable oral preparation. The compositions can be preserved 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 mixed with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing agents or humectants and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may 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 naturally occurring phosphatides, for example, soy, lecithin, and partial esters or esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and the condensation products of said partial esters with sodium oxide. ethylene, for example, sorbitan polyoxyethylene monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with agent sweeteners, for example, glycerol, propylene glycol, sorbitol or sucrose. Said formulations may also contain a sweetener, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of an injectable sterile aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing agents or humectants and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or solution in a non-toxic diluent or solvent acceptable for parenteral use, for example, as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and sodium chloride solution. Additionally, conventional sterile fixed oils are used as solvents or suspension media. For this purpose any fixed soft oil can be used including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid are used 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 is liquid at the rectal temperature and thereby melts in the rectum in order 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, topical application should include mouthwash and gargle) The compounds for the present invention can be administered in intranasal form through the topical use of the appropriate intranasal vehicles, or through transdermal routes, using those forms of skin transdermal patches known to those skilled in the art. In order to be administered in the form of the transdermal transfer system, the administration of the dose will, of course, be continuous and not intermittent throughout the dose regimen. The compounds of the present invention can also be transferred as a suppository using bases such as cocoa butter, glycerin-treated gelatin, hydrogenated vegediose oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. The dosage regimen used for the compounds of the present invention is selected according to a variety of factors including type, species, weight, sex and medical condition of the patient.; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof that is employed. An expert doctor or veterinarian can easily determine and prescribe the effective amount of the drug required to prevent, combat, stop or reverse the progress of the condition. The optimal precision to achieve Concentration of the drug within the range that produces efficacy without toxicity requires a regimen based on the kinetics of drug availability to reach the sites. This involves a consideration of the distribution, balance, and elimination of a drug. Preferably, the doses of the compound of formula I useful in the method of the present invention will vary from 0.01 to 1000 mg per day. Most preferably, the doses vary from 0.1 to 1000 mg / day. Even more preferred, doses vary from 0.1 to 500 mg / day. For oral administration, the compositions are preferably supplied in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, in particular 0.01; 0.05; 0.1; 0.5; 1.0; 2.5; 5.0; 10.0; 15.0; 25.0; 50.0; 100 and 500 milligrams of active ingredient for the symptomatic adjustment of the dose for the patient to be treated. An effective amount of the drug is usually delivered at a dose level of between about 0.0002 mg / kg to about 50 mg / kg of body weight per day. The interval is more particularly around 0.001 mg / kg to 1 mg / kg of body weight per day. Conveniently, the active agent of the present invention can be administered in a single daily dose, or the total daily dose can be administered in proportional doses of two, three or four times daily. The amount of active ingredient that can be combined with the materials of the vehicle to produce a single dose form will vary depending on the host to be treated and the particular mode of administration.

It will be understood, however, that the specific dose level for each particular patient will depend on a variety of factors including age, body weight, general health, sex, diet, time of administration, route or administration, elimination percentage, combination of drug and the severity of the particular disease subjected to the therapy. The compounds of the invention can be produced through processes known to those skilled in the art and as shown in the following reaction schemes and in the preparations and examples described below.

EXAMPLES The following abbreviations can be used in the procedures and schemes detailed below: ACN Acetonitrile AcOH Acetic acid Ac Aqueous BOC ter-Butoxycarbonyl BOC2O BOC Anhydride C degrees Celsius CBZCI benzyl chloroformate DBU 1,8-Diazabicyclo [5.4.0] ur DCM Dichloromethane DEAD Diethyl azodicarboxylate (DHQ) 2PHAL 1,4-phthalazinadiidieter hydroquinine DIAD Düsopropylazod carboxylate DIPEA Diisopropylethylamine DMA N, N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DME Dimethoxyethane DMF Dimethylformamide DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro -2 (1 h) -pyrimidinone DEMO dimethyl sulfoxide EDCI 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride The Impact of the electron eq Equivalents EtOAc Ethyl acetate EtOH Ethanol 9 grams h hours hr hours 1H proton HATU N, N, N ', N'-Tetramethyl-O- (7-Azabenzotriazol-1-yl) uronium hexafluorophosphate Hex hexanes HOBT 1 -Hydroxybenzotriazoles HMPA hexamethyl phosphoramide CLAP High pressure liquid chromatography CLAP / EM High pressure liquid chromatography / Mass spectroscopy LC / EM Liquid chromatography / Mass spectroscopy LAH Lithium-aluminum hydrate LDA Lithium diisopropylamide M Molar mmole mmole mCPBA Meflo-chloroperoxybenzoic acid Me Methyl MeCN Acetonitrile MeOH Methanol min Minutes mg Milligrams MHz Megahertz ml Milliliter CLPM Average pressure liquid chromatography NMR Magnetic Resonance Nuclear EM Mass spectroscopy NBS N -Bromosuccinimide NMM N-Methylmorpholine NMP 1-methyl-2-pyrrolidone ON overnight PCC Pyridinium Chlorochromate CCDP Preparative thin layer chromatography PyBrOP bromo-tris-pyrrolidino-phosphonium hexafluorophosphate Pyr Pyridine RT Ambient temperature SEM 2- (Trimethylsilyl) -ethoxymethyl cgs Chromatography on silica gel plates tBOC ter-Butoxycarbonyl TACE tumor necrosis factor-alpha coverting enzyme TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran CCD Thin layer chromatography TR Retention time X-PHOS 2-dicyclohexylphosphin-2 ', 4', 6'-tri-isopropyl-1 ', 1-biphenyl ROUTES OF SYNTHESIS AND EXAMPLES EXAMPLE 1 I A I B C I D General procedures for example 1: In step 1, compound 1A (commercially available or prepared by a process similar to that described by Abdalla, GM and Sowell, JW Journal of Heterocyclic Chemistry, 1987, 24 (2), 297-301) it was treated with an equivalent of Di-tert-butyl dicarbonate in polar solvent, such as DMF, for a period of 30 minutes to 12 hours. The solvent was removed and compound 1B could be used without further purification or without being purified by silica gel chromatography. In step 2, compound 1B was reacted with potassium cyanide and ammonium carbonate in a solution of alcohol and water, at 50 ° C to 90 ° C, for a period of 5 hours to 48 hours. After cooling, water was added and compound 1C could be obtained by filtration. In step 3, compound 1C was stirred with 2 to 20 equivalents of hydrogen chloride in methanol over a period of 5 to 48 hours. Once the ethyl ether was added, compound 1D could be obtained 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 dicarbonate (11.9 g, 54.4 mmol) were stirred in methylene chloride (100 ml) at 25 ° C for 16 hours. Saturated aqueous NaHCO3 (150 mL) was added. The aqueous layer was extracted with CH2Cl2 (100 ml) twice. The organic phase was washed with saline (100 ml) and dried over Na2SO. The solvent was removed by means of the rotary evaporator to obtain 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) 2CO3 (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 obtain compound 2C (7.9 g, 68%).

Step 3 Compound 2C (4.0 g) was suspended in methanol (50 ml) 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 in vacuo for 12 hours to obtain the compound 2D (2.7 g, 84%).

EXAMPLE 3 3C Step 1 Compound 3A (prepared according to the procedure described in Wyrick, SD et al, Journal of Medicinal Chemistry, 1987, 30 (70), 1798-806) (3.33 g, 18.5 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 2 hours. After cooling, the solid was filtered and washed with Et2O (150 ml). The organic solution was then washed with water (50 ml) twice, dried over Na2SO4 or MgSO, filtered, and concentrated by means of the rotary evaporator. The crude product was dried under vacuum to obtain compound 3B which was used without further purification. The 1H-NMR seemed to indicate that approximately 75% of this material was compound 3B.

Step 2 Compound 3B (4.62 mmol), Compound 3C (824 mg, 4.62 mmol), and K2CO3 (1.28 g, 9.24 mmol) were mixed in DMF (30 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 25 ml. The resulting solution was purified through reverse phase MPLC (CH3CN / water, 5% to 90%, containing 0.1% HC02H) to obtain compound 3D (198 mg, 15%).

EXAMPLE 4 Step 1 Compound 4A (20 g, 81.61 mmol), 4B (13.36 mL, 97.93 mmol), Pd (dppf) CI2 (1.0 g, 1.36 mmol), dioxane (350 mL), water (50 mL) were stirred, and Cs2CO3 (22.5 g, 163 mmol) 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 means of cgs (hexane / EtOAc, 10: 1) to obtain 4C (12.1 g, 80%).

Step 2 Compound 4C was converted to compound 4D using a process similar to that described in example 3, EXAMPLE 5 Compound 5A was prepared using chemistry similar to that described in examples 1, 2, 3 and 4, Pasol Compound 5A (1.18 g, 3.36 mmol) and pyridine hydrochloride (2.33 g, 20.17 mmol) were added in a 20 ml microwave reaction tube and reacted at 200 ° C for 1 hour. After cooling, the solid was dissolved in DMF and purified by means of reverse phase chromatography on a C-18 cartridge (CH3CN / water 5% to 90%, with 0.1% HCO2H) to obtain compound 5B (0.87). g, 77%).

Step 2 Compound 5B (0.75 g, 2.22 mmol) was dissolved in DMF (12 mL). SEMCI (0.48 ml, 2.44 mmoles) and DIPEA (0.775 ml, 4.44 were added. mmoles) and the solution was stirred at 25 ° C for 4 hours. The DMF was removed in vacuo and the product was purified by means of cgs (hexane / EtOAc: 3: 1 A 1: 1) to obtain compound 5C (0.81 g, 78%).

EXAMPLE 6 Compound 6A was prepared using chemistry similar to that described in examples 1, 2, 3 4 and 5, Step 1 Compound 6A was resolved by the Chiralcel OD column (Mobile phase: hexane: 2-propanol 4: 1). The first peak was obtained and concentrated to obtain compound 6B.

Step 2 Compound 6B (0.2 g, 0.36 mmole), palladium lysium chloride dimer (3 mg, 0.008 mmol), and DMF (3 ml) were added to a balloon and subjected to the vacuum and nitrogen three cycles times. Tri-tert-butylphosphine (30 microliters of 10% solution in Hexanes-Strem), piperidine (61 mg, 0.7 mmol), and 3-dimethylamino-1-propine were added through the syringe. The reaction was stirred overnight at RT. The next morning, the reaction was stirred for 1 hour at 50 ° C. The resulting material was diluted with EtOAc, washed with water, dried with MgSO, and concentrated to dryness. The crude product was purified through flash chromatography on silica gel using a gradient elution of 70% (5% methanol in EtOAC) in 100% hexanes (5% methanol in EtOAc) to give 55 mg of the compound 6C.

Step 3 Compound 6C (55 mg) was dissolved in 10 ml of 4 M HCl in dioxane (Aldrich) and 10 ml of methanol and the solution was added to a pressure tube. The tube was capped and heated to 90 ° C. The reaction mixture was stirred at 90 ° C for 4 hr, then allowed to cool to room temperature. The reaction mixture was concentrated to dryness. Methanol was added and the reaction mixture was reconcentrated to dryness. Methanol (5 ml) and triethylamine (1 ml) were added and the reaction mixture was stirred at RT for 2 hr. The resulting solution was concentrated to dryness. The crude product was purified on an Isco C-18 cartridge using a gradient (acetonitrile: water (acid formic at + 0.1%)) as the mobile phase to obtain 6D. To prepare compounds 18, 19, 20, 21 and 22 of Table 1, chemistry similar to the processes described in Examples 6, 8, 1, 2, 3, 4, and 5 was used, EXAMPLE 7 7E- R = H Step 1 Compound 4D (16.26 g, 62.77 mmol) was dissolved in 100 mL of DMF and glycine ethyl ester hydrochloride (9.68 g, 69.35 mmol) was added. Diisopropylethylamine (21 ml, 15.6 rnmoles) was added and placed in an oil bath at 70 ° C. The reaction mixture was stirred overnight at 70 ° C. After 17 hr, the reaction mixture was allowed to cool to RT. EtOAc, water, and 5 mL of 1 M aq NaHSO4 were added and the layers were separated. The organic layer was washed with water and saline, dried with MgSO 4, filtered and concentrated to an orange oil (14.8 g). The crude product was purified through flash silica gel chromatography using a gradient EtOAc: hexanes 20% to 60% as the mobile phase to obtain 6.8 g of 7A as product.

Step 2 Compound 7A (6.31 g, 25.3 mmol) was dissolved in dioxane (88 ml). Aqueous 1.0 M aqueous LiOH solution (28 ml, 28 mmol) was added followed by 10 ml of pure ethanol. The reaction mixture was stirred at RT for 3 h, then partially concentrated on a rotary evaporator. Dichloromethane and 1 M aq NaHSO were added and the layers were separated. The ac layer was extracted with CH2Cl2, the combined organic layer was filtered, dried with MgSO4, filtered again, and concentrated to dryness to obtain 4.04 g of 7B.

Step 3 Compound 7B (2.02 g, 9.13 mmol) was suspended in 15 mL of THF. Carbonyldiimidazole was added in one portion. After 10 min, acetonitrile (10 ml) was also added. The reaction mixture was stirred at RT for 1 hr. Magnesium chloride and ethyl potassium malonate were added. The reaction mixture was stirred overnight at room temperature in a drying tube. The reaction mixture was concentrated until almost dried. EtOAc and 1.0 M sodium phosphate pH regulator pH 5.5 were added. The layers were separated. The organic layer was washed with water and saline, dried with MgSO, filtered, and concentrated to dryness. A whitish solid was obtained. The crude product was purified through chromatography of silica gel using a 50% to 100% EtOAc: hexanes gradient as the mobile phase to obtain 1.87 g of 7C.

Step 4 Compound 7C was dissolved in 18 ml of pure ethanol and 8 ml of water. The solution was added to a thick glass wall pressurized bottle and ammonium carbonate (2.21 g, 23.0 mmol) was added. The bottle was capped and the reaction mixture was stirred at RT for 15 min. Potassium cyanide was added, the bottle was capped again, and the reaction mixture was stirred at 70 ° C for 16 hr. The resulting mixture was poured into 250 ml of water and filtered by suction to obtain 7D (1.86 g) as a white solid.

Step 5 Compound 7D (0.83 g, 2.29 mmol) was suspended in 9 ml of dioxane. 1.0 M Ac LiOH (4.6 mL, 4.6 mmol) was added, causing the material to dissolve. The reaction mixture was stirred at RT for 5.5 hr. Additional LiOH (1.0 mL, 1.0 mmol) was added and the reaction mixture was stirred for 1 hr. The reaction mixture was concentrated until almost dried. The resulting mixture was acidified with 1 M NaHSO4 to produce a precipitate. The flask was placed in a bath of ice water and stirred for 30 min. The resulting mixture was suction filtered to obtain 7E (0.70 g) as a white solid.

Step 6 Compound 7E (31 mg, 0.093 mmol) was dissolved in DMF (400 μl). Carbonyldiimidazole (18 mg, 0.11 mmol) was added and the reaction mixture was stirred at RT for 30 min. Pyrrolidine (20 μl) was added and the reaction mixture was stirred at RT for 5 hr. Add 1 M NaHSO4 Ac (7 mL) followed by EtOAc. The layers were separated. The organic layer was dried with MgSO, filtered, and concentrated to dryness. The crude product was purified through reverse phase chromatography (cartridge Isco C-18) using a gradient of acetonitrile: water + (0.1% formic acid) at 10% to 60% as the mobile phase. A white solid was obtained as a product to give a compound 5 of Table 1, which is an embodiment of the class of compounds 7F. The procedures described in Example 7 were used to prepare compounds 1 through 17 of Table 1, EXAMPLE .0 8 8A 8B Compound 8A was prepared using chemistry similar to that described in examples 1, 2, 3 4 and 5, Step 1 Compound 8A was resolved by the Chiralcel OD mobile phase: hexane: 2-propanol 4: 1 column). It was collected and concentrated to obtain compound 8B.

EXAMPLE 9 9A 9B 9C The racemic compound 9A was prepared using chemistry similar to that described in Examples 1, 2, 3, 4 and 5. The enantiomers were resolved by the Chiralcel OD column (mobile phase: hexane / 2-propanol 3: 1) . The first peak was collected and concentrated to obtain compound 9A in its enantiomerically pure form.

Step 1 Compound 9A (1.5 g, 2.73 mmol) and 4-pyridylboronic acid (670 mg, 5.50 mmol) were added to a dry flask. The flask was subjected to vacuum and refilled with nitrogen three times. Pd (dppf) CI2 (220 mg, 0. 30 mmol) and followed with the addition of CH3CN (20 ml) and K2CÜ3 aq. (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 means of cgs (CH2Cl2 / MeOH / NH OH: 20: 1: 0.1) to obtain compound 9B.

Step 2 Compound 9B was dissolved in a mixture of methanol and HCl (4 M in dioxane) (2: 1, 30 ml) and stirred overnight in a pressure-sealed flask at 90 ° C (oil bath). After cooling, the solution was transferred to a 250 ml balloon. 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. Then the solvent was removed and the product was purified by means of C18 reverse phase chromatography (CH3CN / water 5% to 90%, with the addition of 0.1% HCO2H) to obtain compound 9C (815 mg). The chemistry similar to that described in examples 8 and 9 was used to prepare compound 24 of table 1, EXAMPLE 10 Step 1 A mixture of compound 9A (0.3 g, 0.55 mmol), bis (pinacolato) -diboro (10A, 170 mg, 0.65 mmol), potassium acetate (170 mg, 1.70 mmol), and [PdCI2 (dppf)] CH2Cl2 (50 mg, 0.05 mmol) in 1,4-dioxane (10 ml) were passed between the vacuum and argon cycles 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 Celite filter. The filtrate was concentrated in vacuo and the residual material was purified by means of silica gel column chromatography (MeOH al 2% in CH2CI2) to obtain compound 10B (300 mg, yield of 91%).

Step 2 A solution of compound 10B (60 mg, 0.10 mmol), 3-bromoimidazo [1,2-a] pyridine (30 mg, 0.15 mmol), and [PdCI2 (dppf)] CH2Cl2 (8.2 mg, 0.01 mmol) in CH3CN (3 mL) were treated with potassium carbonate (0.6 mL, 0.6 mmol, 1 M in H2O). The mixture was subjected to vacuum and filled 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 Celite filter. The filtrate was concentrated in vacuo and the residual material was purified by preparative CCD (10% MeOH in CH2Cl2) to obtain compound 10C (42 mg, 71% yield).

EXAMPLE 11 HA 23 Compound 11A was prepared by a procedure similar to those described in examples 8 and 10.

Step 1 Compound 11A (53 mg) was dissolved in 2 ml of methanol in a 15 ml pressure tube. HCl (4M in dioxane, 1 ml) was added. The tube was sealed and placed in an oil bath at 80 ° C for 16 hr. After cooling, the solution was transferred to a 100 ml flask and the solvent was removed. NH 3 (7N in methanol, 3 ml) was added and the solution transferred to a 15 ml pressure tube. The tube was sealed and placed in an oil bath at 70 ° C for three hours. After cooling, the solution was transferred to a 100 ml flask and the solvent was removed. The product was purified by means of C18 reverse phase chromatography (CH3CN / water, 5% to 90%, with 0.1% HC02H) to obtain compound 23, Compound 23 was dissolved in methanol, and HCl (4M) was added. in dioxane, 0.5 ml). The solution was stirred at 25 ° C for 30 minutes. The solvent was removed and the product suspended in water. The water was removed by lyophilization to obtain compound 23 (22 mg) in Table 1, The amino-2D hydrochloride (1.13 g, 3.75 mmol) in DMF (30 ml) was treated with thiophenodialdehyde (0.3 g, 1.9 mmol) and the mixture was stirred at room temperature for 1 hr. The reaction was diluted with ethyl acetate (100 ml) and the organics were washed with water (3 X 50 ml) and saline (1 X 50 ml), dried over MgSO 4 and concentrated to obtain a crude oil. The crude product was subjected to silica gel chromatography using CH2Cl2-5% CH3OH / CH2Cl2 as the gradient elution solvent to yield 26 (0.08 g).

The amino-2D hydrochloride (2.7 g, 8 mmol) in DMF (30 ml) was treated with bromoethylester 27A (3.6 g, 15 mmol) and diisopropylethylamine (2.6 ml). The mixture was heated to 55 ° C and stirred for 24 hr. The reaction was diluted with ethyl acetate (200 ml) and the organics were washed with water (3 X 50 ml) and saline (1 X 50 ml), dried over MgSO4 and concentrated to give a crude solid. The product 27 (1.8 g) was isolated by means of recrystallization (ethyl acetate: ether: 2: 1). The product 27A was prepared from commercially available ethyl nicetinate (Aldrich) using the process described in step 1 of example 3. Compound # 25 (table 1) was prepared analogously using the appropriate starting materials.

EXAMPLE 300A ? ? OMe Parle C) ^ Parle D 0 MeO ^ T í - - X r "- - 30c5 f Part A: Compound 300 (20.0 g, 81.61 mmol), trimethylboroxin (13.36 ml, 97.93 mmol), Pd (dppf) CI2 (1.0 g, 1.36 mmol), dioxane (350 ml), water (50 ml), and carbonate of cesium (22.5 g, 163 mmol) were stirred at 110 ° C (oil bath) under nitrogen for 16 hours. After cooling, the solid was removed by filtration. The concentrated solution was purified by means of cgs (10: 1 EtOAc / hexanes) to obtain 301 (12.1 g, 80%).

Part B: Compound 301 (4.4 g, 24.2 mmol) was dissolved in carbon tetrachloride (80 ml) and N-bromosuccinimide (4.48 g, 24.2 mmol) and benzoyl peroxide (276 mg, 1.13 mmol) were added. The reaction mixture was stirred at reflux for 3 hours and then the solids were filtered and washed with ether. The combined organic layers were washed with water, dried over sodium sulfate, and concentrated to obtain the desired product 302 (6.1 g, 98%).

Part C: Compound 302 (32.0 g, 124.0 mmol) was dissolved in 7 M ammonia in MeOH (150 mL) and stirred in a sealed flask at 60 ° C.

° C during the night. The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was suspended in ethyl acetate and stirred for 30 minutes. The solids were filtered and dissolved in chloride methylene. The methylene chloride was washed with water, dried over sodium sulfate, and concentrated to obtain the desired product 303 (13.5 g, 67%).

Part D: Compound 303 (2.2 g, 13.4 mmol) was dissolved in THF (250 mL) and DMPU (40 mL). Sodium t-butoxide (1.55 g, 16.13 mmol) was added and stirred for 5 hours. Chloromethylpivalate (3.0 mL, 20.1 mmol) was added dropwise and stirred overnight. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, saline, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, 25% ethyl acetate / hexanes) yielded the desired product 304 (2.5 g, 67%).

Part E: Compound 304 (288 mg, 1.04 mmol) was dissolved in methylene chloride (5 ml) and cooled in a cold bath. Bromotrimethylsilane (0.3 ml, 2.08 mmol) was added dropwise and stirred in the cold bath for 30 minutes followed by 2 hours at room temperature. The reaction mixture was concentrated and redissolved in methylene chloride (2 ml). Hexanes (8 ml) were added and the solids filtered to yield desired product 305 (218 mg, 83%).

EXAMPLE 400 Part G Part A: The glyoxylic acid monohydrate (20.0 g, 218 mmol) and the methyl carbamate (16.3 g, 218 mmol) were dissolved in diethyl ether (200 ml) and stirred overnight. The solids were filtered to obtain the desired product 306B (32.0 g, 98%).

Part B: Compound 306B (32.0 g, 214 mmol) was dissolved in MeOH (200 mL) and cooled in a cold bath. Concentrated sulfuric acid (8 ml) was added dropwise and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with saline, dried over sodium sulfate, and concentrated to yield compound 306C which was used without purification (27.0 g, 71%).

Part C: Compound 306C (27.0 g, 152 mmol) was dissolved in carbon tetrachloride (700 mL). Phosphoric pentachloride (50 g, 240 mmol) was added and the suspension was stirred for 18 hours (the solution became clear over time). The solvent was removed under reduced pressure and the residue was stirred in petroleum ether (500 ml) overnight. The solids were filtered to yield compound 307 without the need for purification (26.5 g, 96%). The crushing step was repeated if the yield was too high.

Part D: Compound 307 (15.0 g, 82.7 mmol) was dissolved in methylene chloride (140 ml) and cooled in a cold bath. Bis (trimethylsilyl) acetylene (15.0 g, 88.2 mmol) in methylene chloride (20 ml) was added. Aluminum chloride (11.0 g, 82.7 mmol) was added freshly minced in portions for 20 minutes. The reaction mixture was allowed to warm slowly to room temperature and was stirred overnight. The reaction was cooled in a cold bath and deactivated slowly with water. The organic layer was washed several times with water, dried over sodium sulfate, and concentrated. The residue was triturated / recrystallized from hexanes to obtain the desired product 308 (14.8 g, 69%). CLAP-MS tR = 1.84 min (ELSD); mass calculated for the formula C? 0H17NO4Si 243.09, LC / MS m / z 244.1 (M + H) was observed.

Part E: Compound 308 (24.0 g, 98.7 mmol) and compound 305 (25.1 g, 99.0 mmol) were dissolved in THF (300 mL) and cooled to -78 ° C. A 1 M LiHMDS solution (198 ml, 198 mmol) was added dropwise over 30 minutes and the reaction mixture was stirred for 2 hours. The saturated ammonium chloride solution was added slowly and the reaction was allowed to warm to room temperature. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, saline, dried over sodium sulfate, and concentrated. Purification by column chromatography (SiO2, 33% ethyl acetate / hexanes to 50% ethyl acetate / hexanes) yielded the desired product 309 (26.0 g, 63%). CLAP-MS t R = 1.90 min (UV254 nm); mass calculated for the formula C20H26N2O6Si 418.15, LC / MS m / z 419.2 (M + H) was observed.

Part F: The two isomers were separated using a chiral column OD One gram of material was injected into the column and the two peaks were separated by the use of a solvent mixture of hexanes / 85% ethanol. The second isomer was the desired compound 309B (400 mg, 80%).

Part G: Compound 309B (8.0 g, 19.1 mmol) was dissolved in THF (250 mL) and cooled to 0 ° C. Tetrabutylammonium fluoride (1 M in THF, 22.9 ml, 22.9 mmol) was added dropwise and the reaction was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, saturated sodium bicarbonate, saline, dried over sodium sulfate and concentrated to yield compound 400 (5.8 g, 88%). The product was used without purification.

Part H: Compound 400 (75 mg, 0.22 mmol) was combined with 3-bromoquinoline (0.032 ml, 0.24 mmol), Pd (PPh3) 2 Cl2 (3 mg, 0.0044 mmol), Cul (2 mg, 0.009 mmol), diisopropylamine (0.062 mL, 0.44 mmol) in DMF (1 mL) and stirred overnight at 80 ° C. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, saline, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, 50% ethyl acetate / hexane to 80% ethyl acetate / hexane) yielded the desired product 400A (93 mg, 89%). CLAP-MS t R = 1.66 min (UV254 nm); mass calculated for the formula C26H23N3? 6 473.16, LC / MS m / z 474.1 (M + H) was observed.

Part I: Compound 400A (77 mg, 0.16 mmol) was dissolved in 7 M ammonia solution (3 ml) and stirred in a sealed tube under pressure at 90 ° C overnight. The reaction mixture was cooled to room temperature and concentrated to yield compound 400B CLAP-MS tR = 1.41 min (UV254 nm); mass calculated for the formula C 24 H 18 N 4 O 4 426.13, LC / MS m / z 427.0 (M + H) was observed.

EXAMPLE 300E Part A: The sodium pellets (3.6 g, 156 mmol) were dissolved in MeOH (100 ml) at 0 ° C. Compound 320 (3.0 g, 15.6 mmol) was added and stirred at 100 ° C in a pressure sealed flask overnight. The reaction cooled at room temperature and diluted with ethyl acetate and 1 N HCl. The organic layer was dried over sodium sulfate and concentrated to obtain the desired product 321 without the need for purification (2.1 g, 72%).

Part B: Compound 321 (2.1 g, 11.1 mmol) was dissolved in toluene (30 ml) and methanol (30 ml) and cooled in a cold bath. TEM diazomethane (2M in hexanes, 11 ml) was added dropwise until the yellow color persisted. The solvent was evaporated under reduced pressure to obtain the desired product 322 without the need for purification (2.2 g, quant.).

Part C: Compound 322 (1.0 g, 5.0 mmol) was combined with Pd (P-tBu3) (128 mg, 0.25 mmol), Pd (dba) 3 (250 mg, 0.25 mrnol), trimethylboroxin (1.0 ml, 6.5 mmol) ), potassium phosphate monohydrate (3.69 g, 15 mmol) in dioxane (25 ml) and stirred at 90 ° C overnight. The reaction mixture was filtered and the solvent was evaporated under reduced pressure. Purification by column chromatography (SiO 2, 10% ethyl acetate / hexanes) yielded the desired product 323 (0.500 g, 55%).

Part D: Compound 323 (210 mg, 1.16 mmol) was dissolved in carbon tetrachloride (6 ml) and N-bromosuccinimide (228 mg, 1.28 mg) was added. mmoles) and benzoyl peroxide (10 mg). The reaction mixture was stirred at reflux overnight, cooled to room temperature, and filtered (the solids washed with ether). The combined organic layers were washed with water, dried over sodium sulfate, and concentrated to obtain the desired product 324 (0.20 g, 67%).

Part E: Compound 324 (75 mg, 0.29 mmol) and compound 2D (75 mg, 0.29 mmol) were dissolved in DMF (5 ml) and DIEA (0.15 ml, 0.87 mmol) and stirred at 70 ° C during the night. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, saline, dried over sodium sulfate, and concentrated. The residue was purified by reverse phase chromatography to obtain the desired product 325 (24.1 mg, 22%). CLAP-MS t = 1, 269 min (UV254 nm); mass calculated for the formula C? 8H15N4O4F 370.10, LC / MS m / z 371.1 (M + H) was observed.

EXAMPLE 300F 325 326 Part A: Compound 325 (140 mg, 0.378 mmol), chlorotrimethylsilane (226 mg, 1.89 mmol), and sodium iodide (283 mg, 1.89 mmol) were dissolved in acetonitrile (5 mL) and stirred at reflux for 10 minutes . Water (0.3 ml) was added and the reaction refluxed for 3 hours. The reaction mixture was cooled and diluted with ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated. Purification by means of reverse phase chromatography afforded the desired product 326 (7.1 mg, 5%). CLAP-MS t R = 0.855 min (UV25 nm); mass calculated for the formula C17H13N4O4F 356.09, LC / MS m / z 357.1 (M + H) was observed.

EXAMPLE 82 The aryl ether compounds 82 to 90 were prepared from compound 8B using a method based on that described in E. Buck and Z. J. Song in Organic Synthesis Vol 82, p. 69, followed by the standard SEM deprotection sequence. Below is an example.

Compound 8B (0.248 g, 0.442 mmole), 5-Fluoro-2-hydroxypyridine (128 mg, 1.13 mmole), cesium carbonate (374 mg, 1.14 mmole), and copper (I) chloride (48 mg, 0.48 mmole) ) were added to a 10 ml Schlenck tube equipped with a stir bar. The tube was capped with a diaphragm and subjected to vacuum and N2 cycles three times. N-methyl-2-pyrrolidinone (2 ml) was added through a syringe and the Schlenck tube was subjected to vacuum and N2 cycles three times. 2,2,6,6,6-tetramethyl heptane-3,5-dione (33 μl) was added through a syringe. The Schlenck tube was placed in an oil bath at 100 ° C and heated to 150 ° C. The reaction mixture was stirred for 23 hr at 150 ° C. The reaction mixture was allowed to cool to RT, then it was diluted with EtOAc and water. 1% aqueous EDTA was added and the layers separated. The organic layer was washed with 1% EDTA aq, water, and saline. The resulting organic solution was dried with MgSO 4, filtered, and concentrated to dryness. A brown solid was obtained. The crude product was purified through cgs using a Biotage Si02 cartridge and a gradient of MeOH / CH2Cl2 1% -2.5% as the mobile phase. The highest point was collected as a product, giving 0.04 g of compound 8C. Compound 8C (0.04 g) was dissolved in anhydrous (10 ml) acetonitrile and concentrated to dryness on the rotary vacuum evaporator. This step was repeated. The compound was re-dissolved in anhydrous acetonitrile (3 ml) and placed under N2. The flask was cooled in a cold water bath. BF3 etherate (90 μl) was added, the cold bath was removed, and the reaction mre was stirred at RT for 7 hr. The reaction mre was capped and stored in a freezer at 4 ° C during the night. The reaction mixture was cooled in a cold water bath. Diisopropylethylamine (1.5 ml) was added, followed by 3.0 M aq sodium hydroxide. The reaction was stirred for 15 min. The cold bath was removed, and the reaction mixture was stirred for 3 h at RT. Acetic acid was added until the reaction mixture became weakly acidic. The reaction mixture was partially concentrated in a rotary vacuum evaporator. EtOAc and water were added. The layers were separated. The organic layer was washed with water and saline, dried with MgSO 4, filtered and concentrated to dryness. The crude product was purified through reverse phase chromatography using an Isco C-18 cartridge (43 g). The mobile phase was a gradient of CH3CN / H2O at 15% to 80% with 0.1% (volume) formic acid added to both components of the mobile phase. The important peak was isolated as a product giving compound 8D.

EXAMPLE 93A Compound 8B (1.50 g, 2.68 mmol), pinocolat diboron (816 mg, 3.21 mmol), potassium acetate (785 mg, 8.0 mmol), and the palladium dichloride (II) complex (dppf) -CH2CI2 (250 mg , 0.306 mmole) were added to a 100 ml Schlenck flask equipped with a stir bar. He The flask was capped with a diaphragm, then subjected to vacuum and nitrogen cycles four times. Dioxane (20 ml, anhydrous from Aldrich) was added through a syringe. The flask was subjected to the vacuum and nitrogen cycles three times, then placed in an oil bath at 85 ° C. The bath was heated to 100 ° C, then stirred for 1.5 hr. The reaction mixture was allowed to cool to RT and was diluted with EtOAc (80 ml). The resulting mixture was filtered through Celite. The Celite was cleaned with additional EtOAc. The combined filtrate was concentrated until almost dried then re-dissolved in EtOAc. The organic solution was washed with pH buffer of 1.0 M ac sodium phosphate pH 7, water, and saline. After drying with MgSO 4, the organic layer was concentrated to dryness. The crude product was purified through cgs using a 2% -4% MeOH / CH 2 Cl 2 gradient as the mobile phase. A brown solid (1.9 g) was obtained. The solid was dissolved in dioxane (16 ml) and water (11 ml) was added. Sodium perborate (3.0 g, 19.5 mmol) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc and NH CI 1 M aq. The layers separated. The organic layer was washed with water and saline, dried with MgSO 4, filtered and concentrated to dryness to give an off white solid (1.37 g). cgs using a gradient of 25% to 100% (5% methanol in EtOAc) / hexanes as mobile phase yielded 0.25 g of pure 93A and 0.62 g of impure 93A. Compound 93A (0.70 g, 1.40 mmol) was dissolved in 50 ml of 4N HCl Aldrich in dioxane and 50 ml of methanol. The solution was added to a pressure tube equipped with a stirring rod. The tube was covered, placed in an oil bath, and heated up to 95 ° C. The reaction was stirred at 95 ° C for 4 hr, then allowed to cool to RT. The reaction mixture was concentrated to dryness. Methanol was added and the reaction mixture was re-concentrated. Methanol (50 ml) was added, followed by triethylamine (5 ml). The reaction mixture was stirred at RT for 1 hour, then concentrated to dryness. EtOAc and pH buffer of 1.0 M ac sodium phosphate pH 5.5 were added, the layers were separated. The organic layer was washed with water and saline, dried with MgSO, filtered, and concentrated to dryness. The crude product was purified through SiO2 chromatography. The mobile phase was a gradient of 10% to 100% of (100: 10: 1-CH2Cl2: MeOH: NHOH was concentrated) in CH2Cl2 ?. The active UV major peak was isolated as a product giving 0.42 g of compound 93B as a white solid.

EXAMPLE 93 Compound 93A (0.05 g, 0.10 mmol) was dissolved in CH2Cl2 (5 mL). N, N-dimethylcarbamoyl chloride (18 μl) and DMAP (8 mg) were added and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with CH2Cl2 and washed with pH buffer of 1.0 M sodium phosphate Aqueous pH 7.0, water, and saline. The organic layer was dried with MgSO, filtered and concentrated to dryness. The crude product was purified through cgs using a gradient of MeOH / CH2Cl2 from 0.5% to 5% on an Isco S¡O2 cartridge of 40 g. The largest active UV peak was isolated as compound 93C. Compound 93C was converted to compound 93 using the SEM deprotection processes similar to those previously described.

EXAMPLE 401 Part A: Compound 309B (1.26 g, 3.0 mmol) in 7 M ammonia in methanol (20 ml) was heated to 85 ° C in a pressurized bottle overnight. The reaction mixture was concentrated to produce 401 (900 mg, 100%) which was used without further purification. CLAP-MS t R = 1.00 min (UV25 nm); mass calculated for the formula C? 5H13N3O4 299.09, LC / MS m / z 300.1 (M + H) was observed.

EXAMPLE 45 Pasol Compound 401 (100 mg, 0.33 mmol) was combined with compound 45A (80 mg, 0.4 mmol), Pd (PPh 3) 2 Cl 2 (8 mg, 0.012 mmol), Cul (17 mg, 0.1 mmol), diisopropylamino (0.08). ml, 0.58 mmol) in DMF (1 ml) and stirred at 85 ° C for 2 hours. The reaction mixture was purified on CLAP (0-40% acetonitrile in H2O with 0.1% formic acid) Gilson reverse phase, the desired product 45B (18 mg, 13%) was produced.

Step 2 Compound 45B (20 mg, 0.23 mmol) was stirred in MeOH (5 mL) and HCl (1 N, ac, cat.). The reaction was stirred at RT for 2 hours. The solvent was removed, the raw material was purified on CLAP (0-50% acetonitrile in H2O with 0.1% formic acid) Gilson reverse phase, the desired product 45 (20 mg, 99%) was produced.

EXAMPLE 48 Step 1 A mixture of 48A (161 mg, 0.86 mmol), SEMCI (0.17 mL, 0.94 mmol), and diisopropylethylamine (0.22 mL, 1.28 mmol) in CH 2 Cl 2 (3 mL) was stirred at 25 ° C for 2 hr. The mixture was added to an aqueous solution of NaHCO 3 and the organic layers were extracted with CH 2 Cl 2. The combined organic solution was washed with saline, dried (Na 2 SO), and concentrated in vacuo. The residue was purified by means of SiO2 column chromatography (CH2Cl2 / hexane = 2: 1) to yield 48B (200 mg, 74% yield).

Step 2 A mixture of 401 (100 mg, 0.33 mmol), 48B (165 mg, 0.52) mmoles), Pd (PPh3) 2Cl2 (4.9 mg, 7 pmol), Cul (1.9 mg, 10 pmol), and diisopropylethylamine (0.17 ml, 0.99 mmole) in DMF (1.5 ml) was purged with N2 and heated to 70 ° C. After heating for 17 hr, the mixture was cooled to 25 ° C and purified by means of column chromatography on a C-18 reverse phase column (0.01% HCO2H in water / 0.01% HC02H in CH3CN) for produce 48C (78 mg, yield 44%).

Step 3 Compound 48C (78 mg, 0.14 mmol) was dissolved in MeOH (15 mL) and treated with 4 N HCl in dioxane (3 mL). The mixture was heated to 60 ° C in a pressure vessel for 16 hr and cooled to 25 ° C. The mixture was neutralized with NH3-MeOH (7 N solution) and the resulting precipitate was filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative CCD (10% MeOH in CH2Cl2) to yield 48D (25 mg, 40% yield).

Step 4 To a solution of 48 D (12 mg, 0.028 mmol) in EtOH (4 mL) was added NH 2 OH HCl salt (10 mg, 0.14 mmol) and pyridine (34 mL, 0.42 mmol) at 25 ° C. The mixture was heated to reflux for 16 hr and concentrated in vacuo. The residue was purified by preparative CCD (10% MeOH in CH 2 Cl 2) and compound 48 was produced (5 mg, 42% yield).

EXAMPLE 47 Compound 47A (20 mg) was dissolved in pure ethanol (10 ml). The Lindiar catalyst (18 mg) was added and the reaction mixture was placed in a balloon under pressure of hydrogen gas. The reaction mixture was stirred overnight at RT. The reaction mixture was concentrated to dryness. CH2Cl2 was added and the resulting material was loaded onto a SiO2 Sep-Pak of 1g. The product was extracted with CH2Cl2: MeOH 95: 5. The filtrate was concentrated to obtain 457 as a clear oil. Compound 47A was prepared using example 400.

EXAMPLE 41: Part A: Compound 41 B was prepared from compound 41 A according to the procedures described in Example 300D part A and B.

Part B: To a mixture of 41b (7.87 g, 21.7 mmoles) and diisopropylethylamine (7.5 mL, 43.4 mmol) in DMF (80 mL) was added 2-trimethylsilylethoxy 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, saline, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (SiO2, 15% EtOAc / hexane to 30% EtOAc / hexane) to produce 41C as a soft solid (10.2 g, 95%). CLAP-MS t R = 2.17 min (UV254 nm); mass calculated for the formula C23H35N3O7S¡ 493.2, LC / MS m / z 516.1 (M + Na) was observed.

Part C: The two 41C isomers were separated using a chiral AD column. One gram of material was injected into the column and the two peaks were separated using an 80% hexanes / 2-propanol solvent mixture. The second isomer was the desired compound 41 D (400 mg, 80%).

Part D: Compound 41 was repaired from compound 41 D following the procedures that were described in example 2 step 3, example 300E part C and example 8. CLAP-MS tR = 1.32 min (UV25 nm); mass calculated for the formula C 21 H 19 N 3 O 6 409.13, LC / MS m / z 410.2 (M + H) was observed.

EXAMPLE 44 Part A: Compound 44A (670 mg, 3.91 mmol) and iodine (2.10 g, 8.0 mmol) were dissolved in THF (20 ml) and 1 M sodium carbonate (20 ml) and stirred for 4 hours. The reaction was diluted with ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated (1.05 g of inseparable mono- and di-iodinated product mixture). The residue was combined with methyl iodide (1.5 ml) and cesium carbonate (5 g) in DMF (20 ml) and stirred at 60 ° C for 3 hours. The reaction was diluted with water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Column chromatography (2: 1 hexanes / ethyl acetate) yielded mono-iodated methyl ether (460 mg). The methyl ether was dissolved in methylene chloride (7 ml) and 1 M boron tribromide (7 ml) and stirred at room temperature for 5 hours. The reaction was slowly deactivated with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to obtain the desired product (390 mg, 34%). 1 H NMR (400 MHz, CDCl 3) d 8.25 (d, 1 H), 7.85-7.8 (m, 1 H), 7.1 (d, 1 H), 3.0 (s, 3 H).

Part B: Compound 401 (130 mg, 0.43 mmol), compound 44B (130 mg, 0.43 mmol), Pd (PPh3) CI2 (15 mg), Cul (8 mg), and triethylamine (0.4 ml) were dissolved in DMF (3 ml) and stirred at 80 ° C under an inert atmosphere. The solvent was evaporated and the residue was purified by means of reverse phase chromatography to obtain the desired product (112.3 mg, 55%). CLAP-MS tR = 1.2 min (UV25 nm); mass calculated for the formula C22H19N3O7S 469.47, LC / MS m / z 470.0 (M + H) was observed. 1 H NMR (400 MHz, DEMO-d 6) d 11.2 (s, 1 H), 9.0 (s, 1 H), 8.3 (m, 2H), 7.9 (s, 1 H), 7.5 (d, 1H), 7.35 (s, 1 H), 7.2-7.1 (m, 2H), 4.5-4.3 (m, 4 H). 3.8 (s, 3H), 3.2 (s, 3H).

EXAMPLE 46 Step 1 Compound 46A (80 mg, 0.29 mmol) was combined with compound 401 (100 mg, 0.33 mmol), Pd (PPh 3) 2 Cl 2 (5 mg, 0.007 mmol), Cul (12 mg, 0.06 mmol), diisopropylamino ( 0.16 ml, 1.13 mmol) in DMF (1 ml) and stirred at 85 ° C. The reaction mixture was neutralized with acetic acid and purified with the Gilson reverse phase (0-40% acetonitrile in H20 with 0.1% formic acid) the desired product 46B (3 mg, 3%) was produced. Mass calculated for the formula C2oH-? 7N5O 391.13, LC / MS m / z 392.2, (M + H) was observed and compound 46 (22 mg, 15%), mass calculated for formula C25H25N5O6 491.18, CL / was observed. MS m / z 492.2, (M + H) EXAMPLE 49 49A 496 49C 49 Step 1 Commercially available 2,6-dibromo-3-hydroxypyridine compound (588 mg, 2.32 mmol) was dissolved in THF (6 ml) and the solution treated with triethylamine (0.49 ml, 3.48 mmol) and triisopropylsilyl triflate (0.75 ml). ml, 2.78 mmol) at 0 ° C. The mixture was stirred at the temperature for 10 min then added to an aqueous solution of NaHCO3. The organic layers were extracted by means of CH2Cl2 and the combined organic solution was washed with saline, dried (Na2SO4), and concentrated in vacuo to yield a crude compound 49A (1.11 g, quantitative) which was used without further purification.

Step 2 A solution of 49A (100 mg, 0.24 mmole) in toluene (1 ml) was treated with t-BuLi (1.7 M in pentane, 0.32 ml, 0.54 mmole) at -78 ° C. After stirring for 0.5 hr at the temperature, methyl sulfide (65 μl, 0.72 mmol) was added to the mixture slowly and the resulting mixture was stirred for 4.5 hr at -78 ° C to 25 ° C. The mixture was deactivated by MeOH (0.3 ml) and diluted in CH2Cl2 followed by filtration through a SiO2 filter. The clear filtrate was concentrated in vacuo to yield a mixture of 49B and its bromide regioisomer (-1: 1, 62 mg) which was used without further purification.

Step 3 A mixture of 49B and its regioisomer (62 mg, -0.16 mmol) was dissolved in THF and the solution treated with TBAF (1 M in THF, 0.24 mL, 0.24 mmol) at 0 ° C. The mixture was stirred at the temperature for 1 hr and poured into a cold mixture of EtOAc and water. The organic layers were extracted by EtOAc medium and the combined organic solution was washed with saline, dried (Na2SO), and concentrated in vacuo to give a crude mixture of 49C and its bromide regioisomer (-1: 1, 41 mg) which was used without further purification.

Step 4 A mixture of 401 (150 mg, 0.50 mmol), 49C (purity at -50%, 460 mg, -1 mmol), Pd (PPh3) 2 Cl2 (7 mg, 10 pmol), Cul (1.9 mg, 10 pmol ), and diisopropylethylamine (0.43 ml, 2.5 mmol) in DMF (3 ml) was purged with N2 and heated to 60 ° C. After heating for 18 hr, the mixture was cooled to 25 ° C and purified by means of column chromatography on a C-18 reverse phase column (0.01% HCO2H in water / 0.01% HCO2H in CH3CN) for produce a crude compound 49 that was subsequently purified by means of preparative CCD (5% MeOH in CH 2 Cl 2) to yield pure 49 (27 mg, 12% yield).

EXAMPLE 50 A solution of 49 (27 mg, 0.06 mmol) in CH2Cl2 (3 ml) was treated with 3-chloroperbenzoic acid (approximately 70% purity, 30 mg, 0.12 mmol) at 0 ° C. The mixture was stirred at 25 ° C for 1.5 hr. The suspension was dissolved in 10% MeOH-CH 2 Cl 2 and treated with ion exchange resin (Amberlyst, A-21, weakly basic) followed by filtration. The filtrate was concentrated in vacuo and the residue was purified by preparative CCD (10% MeOH in CH 2 Cl 2) to yield compound 50 as a white solid (18 mg, 61% yield).

EXAMPLE 32 Part A To a solution of methyl 4-acetylbenzoate (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 to 60 ° C for 30 min, 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 32A was treated with an equivalent of hexamethylenetetraamine in chloroform for about 1 hour. The product was collected by filtration and then treated with HCl in methanol for 2 hours. The solid was then collected by filtration to obtain compound 32B.

Part C Compound 30 was prepared following the procedures described in Example 2 Steps 1, 2, 3 and in Example 300E Part E: CLAP-MS tR = 1.36 min (UV25 nm); mass calculated for formula C21 H19N3O6 409.1, LC / MS m / z 410.1 (M + H) was observed.

Part D Compound 30 (60 mg, 0.147 mmol) was heated in 5% of KOH in MeOH (2 ml) at 60 ° C overnight, cooled to room temperature and concentrated. The residue was dissolved in water (5 ml), acidified with conc. HCl. and it leaked. The solid was collected and dried to obtain compound 32 (23 mg, 40%): CLAP-MS tR = 1. 04 min (UV254 nm); mass calculated for the formula C20H17N3O6 395.1, LC / MS m / z 396.1 (M + H) was observed.

Part E Compound 30 (39 mg, 0.095 mmol) was heated in pyrrolidine (2 ml) at 60 ° C overnight, cooled to room temperature and concentrated. The residue was purified by means of reverse phase chromatography to obtain 31: CLAP-MS t = 1.19 min (UV25 nm); mass calculated for the formula C 24 H 24 N 4 O 5 448.2, LC / MS m / z 449.2 (M + H) was observed.

Part F A mixture of compound 32 (49 mg, 0.12 mmol), dimethylamino hydrochloride (20 mg, 0.25 mmol), HATU (61 mg, 0.16 mmol), DMAP (2 mg, 0.012 mmol) and diisopropylethylamine (0.065 mL, 0.37 mmoles) was stirred in DMF (2 ml) at room temperature overnight. The mixture was diluted with ethyl acetate, washed with 0.1 N HCl, water and saline, dried over sodium sulfate and evaporated. The residue was purified by means of reverse phase chromatography to obtain 34: CLAP-MS t = 1.09 min (UV254 nm); mass calculated for the formula C22H22N4O5 422.2, LC / MS m / z 423.1 (M + H) was observed.

EXAMPLE 33 Part A Compound 33 was prepared from 33A following the procedures described in example 32 part B and part C: CLAP-MS tR = 1.08 min (UV254 nm); mass calculated for the formula C20H19N3O6S 429.1, LC / MS m / z 430.0 (M + H) was observed.

EXAMPLE 35 Part A A mixture of 5-cyanophthalide (5.0 g, 31.4 mmol) and 1 N NaOH (31.4 ml) was stirred at 100 ° C for 1 hr. The solution was concentrated to dryness with azotropic distillation with toluene. The resulting white solid was dissolved in dry DMF (30 ml). Methyl iodide (5.88 ml, 94.2 mmol) was added slowly, and the reaction mixture was allowed to stir at room temperature for 2 hr. Then it was diluted with H2O and extracted again with EtOAc (30 ml x 4). The EtOAc extracts were combined, washed with saline, dried over Na2SO, and concentrated. Flash column chromatography on silica (EtOAc / hexane 40:60) afforded compound 35A as a white solid (5.5 g, 91%) Part B To a compound 35A (5.5 g, 28.77 mmol) in THF (60 ml) was added carbon tetrabromide (11.45 g, 34.52 mmol). The solution was cooled to 0 ° C in a cold water bath, and triphenylphosphine (9.05 g, 34.52 mmol) was added in portions. The reaction mixture was stirred at room temperature for 3 hr under argon. After removing the precipitate by means of filtration, the solution was concentrated. The residue was dissolved in EtOAc (100 mL), washed with 1 N HCl, H2O, saline, dried over Na2SO4, and concentrated. Flash column chromatography on silica (20:80 EtOAc / hexane) afforded compound 35B as a pale yellow solid (6-8 g, 93%).

Part C Compound 35 was prepared using the methods previously described from 2D and 35B. CLAP-MS tR = 2943 min (UV254 nm), Mass calculated for the formula C19H13FN4O3 364.1, LC / MS m / z 365.0 (M + H) was observed.

EXAMPLE 37 37A 37B 36 Part C Compound 37A was prepared using the procedures described in Example 375, Part A Compound 37A (550 mg, 1.32 mmol) and Pd (f-Bu3P) 2 (34 mg, 0.066 mmol, 5 mol%) in NMP (5 mL) were added with a solution of 2-re? 5 M butoxy-2-oxoethylzinc in THF (10.5 ml, 5.2 mmol) under argon. The reaction mixture was allowed to stir at 90 ° C overnight. After cooling to room temperature, it was diluted with EtOAc, washed with water, saline, dried over Na2SO4, and concentrated. Column chromatography on silica gel (MeOH / DCM, 10:90) yielded 37B as a pale yellow solid (260 mg, 43%). CLAP-MS (5 min) t R = 1.69 min (UV254 nm), Mass calculated for the formula C19H13FN4O3 453.2, LC / MS m / z 454.1 (M + H) was observed.

Part B Compound 37B (40 mg, 0.088 mmol) was treated with TFA in DCM at room temperature to yield compound 36 as a white solid (20 mg, 27%). CLAP-MS t R = 2.64 min (UV25 nm), Mass calculated for the formula C2oH16FN3? 5 397.1, LC / MS m / z 398.0 (M + H) was observed.

Part C Compound 36 (20 mg, 0.05 mmol) in DMF (1 ml) was added with HOBt (14 mg, 0.1 mmol) and EDC (19 mg, 0.1 mmol). After stirring at room temperature for 10 min, NH4CI (20 mg, 0.15 mol) was added, followed by the addition of DIEA (0.026 ml). The reaction mixture was then stirred at room temperature overnight. The same was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO3, and saline, dried over Na2SO4, and concentrated. Recrystallization from EtOAc afforded 37 (7.4 mg, 37%) as a white solid. CLAP-MS tR = 2.64min (UV25 nm), Mass calculated for the formula C20H17FN4O4 396.1, LC / MS m / z 397.1 (M + H) was observed. The following NMR spectral data are provided for some of the above compounds: Compound 50. 1 H NMR (500 Hz, CD3OD) dDD 8.27 (d, 1 H, J = 8.6 Hz), 8.14 (d, 1 H, J = 8.6 Hz), 7.45 (d, 1 H, J = 8.3 Hz), 7.37 (s, 1 H), 7.29 (d, 1H, J = 2.5 Hz), 7.20 (dd, 1 H, J = 8.3 Hz, 2.5 Hz), 4.56 (d, 1 H, J = 8.7 Hz), 4. 53 (d, 1H, J = 8.7 Hz), 4.50 (d, 1H, J = 12.5 Hz), 4.46 (d, 1H, J = 12.6 Hz), 3.87 (s, 3H), 3.30 (s, 3H). Compound 98.1H NMR (400 Hz DEMO-d6) dD (ppm): 11.24 (s, 1H), 8.97 (s, 1H), 8.80 (d, J = 2.01 Hz, 1H), 8.57 (d, J = 2.46 Hz , 1H), 8.17 (s, 1H), 7.60 (s, 1H), 7.49 (d, J = 8.19 Hz, 1H), 7.24 (s, 1H), 7.17-7.14 (m, 2H), 4.46 - 4.25 ( m, 4H), 3.79 (s, 3H). Compound 68.1H NMR (500 Hz, CD3OD) dDD 8.42 (s, 1H), 8.32 (d, 1H, J = 2.1 Hz), 7.79 (d, 2H, J = 8.5 Hz), 7.74 (d, 2H, J = 8.5 Hz), 7.42 (d, 1H, J = 8.4 Hz), 7.28-7.32 (m, 1H), 7.19 (dd, 1H, J = 8.4, 2.5 Hz), 4.32-4.46 (m, 3H), 4.24 (d, 1H, J = 14.2 Hz), 3.87 (s, 3H). Compound 66.1H NMR (500 Hz, CD3OD) dDD 8.88 (d, 1H, J = . 0 Hz), 8.30 (s, 1H), 8.19 (d, 2H, J = 8.5 Hz), 7.88 (d, 2H, J = 8.2 Hz), 7.67 (dd, 1H, J = 5.1, 1.3 Hz), 7.41 (d, 1H, J = 8.6 Hz), 7.31 (d, 1H, J = 2.5 Hz), 7. 19 (dd, 1H, J = 8.2, 2.5 Hz), 4.34 ^ 1.47 (m, 3H), 4.26 (d, 1H, J = 14.7 Hz), 3.87 (s, 3H). Compound 64.1H NMR (500 Hz, CD3OD) dD 8.10 (d, 2H, J = 8. 5 Hz), 7.99 (s, 1H), 7.84 (d, 2H, J = 8.5 Hz), 7.56 (s, 1H), 7.37 (d, 1H, J = 8.2 Hz), 7.27 (d, 1H, J = 2.7 Hz), 7.15 (dd, 1H, J = 8.4, 2.5 Hz), 4.28 ^ .43 (m, 3H), 4. 24 (d, 1H, J = 14.5 Hz), 3.84 (s, 3H), 2.65 (s, 3H), 0.84-0.89 (m, 1H), 0.69-0.74 (m, 2H), 0.49-0.52 (m, 2H). Compound 97.1H NMR (500 MHz, MeOH-d4) dDD 8.19 (s, 1H), 7.83 (s, 1H), 7.66-7.70 (m, 1H), 7.55-7.58 (m, 1H), 7.41-7.44 (m , 1H), 7.29-7.32 (m, 1H), 7.17-7.21 (m, 1H), 7.07 (s, 1H), 4.35-4.55 (m, 4H), 3.87 (s, 3H).

Compound 85. 1 H NMR (500 MHz, MeOH-d 4) dDD 7.70-7.75 (m, 2 H) 7.65-7.70 (m, 1 H), 7.41-7.56 (m, 3 H), 7.28-7.31 (m, 1 H) , 7.17-7.23 (m, 2H), 7.08-7.13 (m, 2H), 4.29-4.47 (m, 3H), 4.15-4.24 (m, 1 H), 3.87 (s, 3H). Compound 84. 1 H NMR (500 MHz, MeOH-d 4) d D 7.80-7.88 (m, 2 H), 7.70-7.78 (m, 2 H) 7.38-7.46 (m, 1 H), 7.26-7.33 (m, 1 H) , 7.16-7.24 (m, 1 H), 7.08-7.15 (m, 2H), 6.98-7.06 (m, 2H), 4.29-4.46 (m, 3H), 4.15-4.26 (m, 1 H), 3.87 ( s, 3H), 2.93 (s, 3H). Compound 43. (400 Hz DEMO-d6) dD 8.99 (s, 1 H), 7.98 (dd, J = 14.8 Hz, 2 Hz, 2H), 7.90 (dd, J = 14.8 Hz, 2 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1 H), 7.14 (m, 2H), 4.26 (m, 3H), 4.08 (m, 1 H), 3.9 (s, 3H), 3.22 (s, 3H). Compound 76. 1 H NMR (500 MHz, DEMO-d 6) d D 10.97 (s, 1 H), 9.00 (d, J = 2.0 Hz, 1 H), 8.39 (d, J = 8.5 Hz, 1 H), 8.22 ( d, J = 7.5 Hz, 1 H), 8.08 (t, J = 7.5 Hz, 1 H), 8.00 (d, J = 7.5 Hz, 1 H), 7.78 (d, J = 8.5 Hz, 1 H), 7.75 (br. S, 1 H), 7.48 (d, J = 8.5 Hz, 1 H), 7.19 (d, J = 2.5 Hz, 1 H), 7.16 (dd, J = 8.5, 2.5 Hz, 1 H) , 4.34 (d, J = 17.5 Hz, 1 H), 4.26 (d, J = 17.5 Hz, 1 H), 4.24 (d, J = 14.5 Hz, 1H), 4.17 (d, J = 14.5 Hz, 1 H ), 3.81 (s, 3H). Those skilled in the art will understand that modifications may be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that the present 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 appended claims. Each document referred to in this invention is incorporated herein as a reference in its entirety for all the ends.

Claims (6)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound represented by formula (I): (or a pharmaceutically acceptable salt, solvate or ester thereof, wherein: ring A is selected from the group consisting of aryl and heteroaryl, each of which is substituted with -Y-R1 and -Z-R2 as shown; X is selected from the group consisting of -S -, - O-, -S (O) 2, -S (O) -, - (C (R3) 2) m- and -N (R3) -, T is absent or present and, if present, T is selected from the group consisting of alkyl, aryl and heteroaryl, wherein when each of said aryl and heteroaryl T contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form an aryl or heteroaryl ring of five to eight members, wherein each of the aforementioned T aryl and heteroaryl, optionally with said aryl or heteroaryl of five to eight members is independently not replaced or substituted with one to four R10 portions that may be the same or different; absent or present and, if present, U is selected from the group consisting of -O-, -OC (O) NH-, -OC (O) N (alkyl) -, -C (O) -, -C ( 0) O-, -C (0) NH-, -C (0) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= NO-alkyl) -alkyl-; V is absent or present and, if present, V is selected from the group consisting of alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and N-oxides of said heterocyclyl and heteroaryl, wherein when each of said V cycloalkyl, heterocyclyl, aryl, heteroaryl and N-oxides of said heterocyclyl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, aryl, heterocyclyl or heteroaryl of five to eight members; wherein each of said alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and heterocyclyl, optionally with said cycloalkyl, aryl, heterocyclyl or heteroaryl of five to eight members independently unsubstituted or substituted with one to four portions R10 which may be same or different; Y is selected from the group consisting of a covalent bond, - (C (R4) 2) n-, -N (R4) -, -C (O) N (R4) -, -N (R4) C (O) -, -N (R4) C (O) N (R4) -, -S (O) 2N (R4) -, -N (R4) -S (O) 2, -0 -, - S-, -C (O) -, -S (O) - and -S (O) 2-; 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 (R) C (O) N (R4) -, -S (O) 2N (R4) -, -N (R4) -S (O) 2-, -0 -, - S-, - C (O) -, -S (O) - and -S (0) 2-; m is 1 to 3; n is 1 to 3; R1 is selected from the group consisting of H, cyano, -C (O) OH, -C (O) O-alkyl, -C (O) NH2, -C (O) NH (alkyl), -C (O) N (alkyl) 2, alkynyl, halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl and heterocyclyl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl ring, aryl, heterocyclyl or heteroaryl of five to eight members; wherein each of the R1 alkyl, alkynyl, aryl, heteroaryl and heterocyclyl, optionally with the unsubstituted or optionally substituted five-or six-membered cycloalkyl, aryl, heterocyclic or heteroaryl ring or in optional form is independently substituted with one to four R20 portions which can be be equal or different; with the proviso that when Y is -N (R4) -, -S- or -O-, then R1 is not halogen or cyano; R2 is selected from the group consisting of H, cyano, -C (0) OH, -C (O) O-alkyl, -C (O) NH2, -C (O) NH (alkyl), -C (O) N (alkyl) 2, alkynyl, halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl and heterocyclyl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl contains two adjacent carbon atom radicals, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members; wherein each of the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, optionally with the unsubstituted or unsubstituted five or six membered cycloalkyl, aryl, heterocyclic or heteroaryl ring is optionally substituted with one to four R20 portions which may be the same or different; with the proviso that when Y is -N (R4) -, -S -o -O-, then R2 is not halogen or cyano; each R3 is equal or different and selected independently from the group consisting of H, alkyl and aryl; each R4 is the same or different and selected independently from the group consisting of H, alkyl, cycloalkyl, haloalkyl, hydroxy, -alkylcycloalkyl, -alkyl-N (alkyl) 2, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members; R10 is selected from the group consisting of hydrogen, cyano, nitro, -C (R4) = N-OR4, -OR4, -SR4, -N (R4) 2, -S (O) R4, -S (O) 2R4 , -N (R4) S (O) 2R4, -N (R4) -C (O) -R4, -N (R4) -C (O) -N (R) 2, -N (R4) -C ( O) -OR4, -OC (O) N (R4) 2, -C (O) N (R4) -S (O) 2R4, -S (O) 2N (R4) -C (0) -R4, - C (O) N (R4) C (O) R4, -C (O) N (R) C (O) NR4, -S (O) 2N (R4) 2, -N (R4) -C (= NR4 ) -N (R4) 2, -N (R4) -C (= N-CN) -N (R4) 2, -haloalkoxy, -C (O) OR4, -C (O) R4, -C (O) N (R4) 2, halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, wherein each of the R10 alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally is independently substituted with one to four R30 portions which may be the same or different; or where two R10 moieties, when attached to the same carbon atom or adjacent carbon atoms, can optionally be taken together with the carbon atom (s) to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl ring , aryl, or heteroaryl; R20 is selected from the group consisting of cyano, nitro, -C (R4) = N-OR4, -OR4, -SR4, -N (R4) 2, -S (O) R4, -S (O) 2R4, -N (R) S (O) 2R4, -N (R4) -C (O) -R4, -N (R4) -C (O) -N (R4) 2, -N (R4) -C (O) -OR4, -OC (O) N (R4) 2, -C (O) N (R4) -S (O) 2R4, -S (O) 2N (R4) -C (0) -R4, -C (O) N (R4) C (O) R4, -C (O) N (R4) C (O) NR4, -S (O) 2N (R4) ) 2, -N (R 4) -C (= NR 4) -N (R 4) 2, -N (R 4) -C (= N-CN) -N (R 4) 2, -haloalkoxy, -C (O) OR 4 , -C (0) R 4, -C (O) N (R 4) 2, halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl; wherein when each of said aryl, heteroaryl, heterocyclyl and cycloalkyl R20 contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, aryl, heterocyclyl ring or heteroaryl of five to eight members; wherein each of said R20 alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, optionally with said unsubstituted or substituted five or eight membered cycloalkyl, aryl, heterocyclic or heteroaryl ring or is substituted with one to four portions independently selected from the group it consists of alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cyano, nitro, -NH2, -NH (alkyl) and -N (alkyl) 2; or when two R20 moieties being attached to the same carbon atom or adjacent carbon atoms can optionally be taken together with the carbon atom (s) to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl ring, aryl, or heteroaryl; R30 is selected from the group consisting of cyano, nitro, -C (R4) = N-OR4, -OR4, -SR4, -N (R4) 2, -S (O) R4, -S (O) 2R4, - N (R4) S (0) 2R4, -N (R4) -C (0) -R4, -N (R4) -C (O) -N (R) 2, -N (R4) -C (O) -OR4, -OC (O) N (R4) 2, -C (O) N (R4) -S (O) 2R4, -S (O) 2N (R4) -C (O) -R4, -C ( O) N (R4) C (O) R4, -C (O) N (R4) C (O) NR4, -S (O) 2N (R4) 2, -N (R4) -C (= NR) -N (R4) 2, -N (R4) -C (= N-CN) -N (R4) 2, -haloalkoxy, -C (0) OR4, -C (O) R 4, -C (O) N (R 4) 2, halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl; wherein when each of said R30 aryl, heteroaryl, heterocyclyl and cycloalkyl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, aryl, heterocyclyl ring or heteroaryl of five to eight members; wherein each of said R30 alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, optionally with said cycloalkyl, aryl, heterocyclic or heteroaryl ring of five or eight members is unsubstituted or is substituted with one to four portions independently selected from the group which consists of alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro, -NH2, -NH (alkyl) and -N (alkyl) 2; or when two R30 moieties when attached to the same carbon atom or adjacent carbon atoms can optionally be taken together with the carbon atom (s) to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl ring, aryl, or heteroaryl; with the proviso that at least one of T, U and V must be present; and further that at least one of the conditions (1) - (5) have been met: (1) at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR 4, -C (0) R 4, -C (O) N (R 4) 2, -C ( O) N (R) C (O) R4, -C (O) N (R) C (O) NR4, -SR4, -S (O) 2R4, -N (R4) -C (O) OR4, - OC (O) N (R4) 2, -N (R4) C (O) N (R4) 2, -N (R4) -C (O) -R4, -S (O) 2N (R4) 2, -S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N (R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R4 cycloalkyl, heterocyclyl , aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from (2) U and V are present and U is selected from the group consisting of -OC (0) NH-, -OC (O) N (alkyl) -, -C (O) -, -C (O) O- , -C (0) NH-, -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= N-0-alkyl) -alkyl-; (3) at least one of T and V is present; and each of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2) nC (0) OH, - (C (R4) 2) nC (O) O-alkyl, - (C (R4) 2) nC (O) NH2, - (C (R) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (O) N (alkyl) ) 2, where each R4 independently is H or I rent; and n is 1-3; (4) T is aryl or heteroaryl, each of which is optionally substituted with one to four independently selected R10 portions and V is alkynyl which is optionally substituted with one to two independently selected R10 portions; and (5) at least one of T and V is present, ring A is heteroaryl and V is different from alkynyl.
2. 2. The compound according to claim 1, further characterized in that X is selected from the group consisting of - (C (R3) 2) m- and -N (R3) -.
3. 3. The compound according to claim 2, further characterized in that X is - (C (R3) 2) m, wherein m is 1 or 2.
4. 4. The compound according to claim 3, further characterized in that m is 1.
5. 5. The compound according to any of claims 1-4, further characterized in that R3 is H.
6. 6. The compound according to claim 1, further characterized in that at least one of T and V is present and V is different from alkynyl; wherein said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (0) OR4, -C (0) R4, -C (O) N (R4) 2, -C ( O) N (R) C (O) R4, -C (O) N (R4) C (0) NR4, -SR4, -S (0) 2R4, -N (R4) -C (0) OR4, - OC (0) N (R4) 2, -N (R4) C (O) N (R4) 2, -N (R4) -C (0) -R4, -S (O) 2N (R4) 2, - S (O) 2N (R4) -C (O) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N ( R4) 2 and -C (R4) = N-OR4, wherein each R4 is independently selected of the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said R 4 cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the atoms of carbon to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; with the proviso that when R10 is -S (O) 2R4, V is different from piperidinyl and when R10 is cyano, the compound of formula (I) is different from 7. The compound according to claim 6, further characterized in that said T or V is substituted with at least one portion R10 selected from the group consisting of cyano, -C (O) OR4, -C (0) R4, -C ( O) N (R4) 2 and -C (R4) = N-OR4. 8. The compound according to claim 6, further characterized in that said T or V is substituted with at least one portion R10 which is cyano. 9. The compound according to claim 6, further characterized in that said T or V is substituted with at least one R10 portion which is -SR4. 10. The compound according to claim 6, further characterized in that said T or V is substituted with at least one portion R10 which is -S (O) 2R4. 11. The compound according to claim 6, further characterized in that said T or V is substituted with at least one portion R10 which is -S (O) 2N (R4) 2. 12. The compound according to claim 6, further characterized in that the ring A is selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidyl and each of them being substituted with -Y-R1 and -Z-R2 as shown. 13. The compound according to claim 12, further characterized in that said ring A is phenyl. 14. The compound according to claim 6, further characterized in that X is selected from the group consisting of - (C (R3) 2) m- and -N (R3) -. 15. The compound according to claim 14, further characterized in that X is - (C (R3) 2) m, where m is 1 or 2. 16. The compound according to claim 15, further characterized in that is 1 17. The compound according to claim 14, further characterized in that R3 is H. 18. The compound according to claim 6, further characterized in that T is selected from the group consisting of alkyl, aryl, heteroaryl, wherein when each one of said T aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals optionally being taken together with the carbon atoms to which they are attached to form an aryl or heteroaryl ring of five to eight members; wherein each of the aforementioned T aryl and heteroaryl, optionally with said five or six membered aryl or heteroaryl independently is unsubstituted or is substituted with one to four R 10 portions which may be the same or different. 19. The compound according to claim 18, further characterized in that T is selected from the group consisting of -CH2-, phenyl, each with the exception of -CH2- is optionally substituted with one to four portions R10 such that the amount of the portions R10 for each T is not greater than four. 20. The compound according to claim 6, further characterized in that U is absent or present and, if present, is selected from the group consisting of -C (O) - and -C (0) O-. 21. The compound according to claim 6, further characterized in that V is absent or present and, if present, is selected from the group consisting of aryl and heteroaryl, wherein when each of said V aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form an aryl or heteroaryl ring of five to eight members; wherein each of the aforementioned V aryl and heteroaryl, optionally with said five or six membered aryl or heteroaryl independently is unsubstituted or is substituted with one to four R 10 portions which may be the same or different. 22. The compound according to claim 21, further characterized in that V is selected from the group consisting of phenyl, pyridyl, pyrazinyl, indazolyl, each of them is optionally substituted with one to four portions R10 which may be the same or different. 23. The compound according to claim 6, further characterized by each of Y and Z selected in the form independent of the group consisting of a covalent bond and -O-. 24. The compound according to claim 23, further characterized in that Y is -O- and Z is a covalent bond. 25. - The compound according to claim 6, characterized in that each of R1 and R2 is selected in the form independent of the group consisting of H and alkyl. 26. The compound according to claim 25, further characterized in that R1 is alkyl and R2 is H. The compound according to claim 26, further characterized in that R1 is methyl. 28. - The compound according to claim 6, selected from the group consisting of: ID of the ._. . . Composite structures or a pharmaceutically acceptable salt, solvate or ester thereof. 29. The compound according to claim 1, further characterized in that U and V are present; and U is selected from the group consisting of -OC (O) NH-, -OC (O) N (alkyl) -, -C (O) -, -C (0) 0-, -C (O) NH- , -C (O) N (alkyl) -, -C (= N-OH) -alkyl- and -C (= NO-alkyl) -alkyl-. 30. The compound according to claim 29, further characterized in that the ring A is selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidyl and each of them being substituted with -Y-R1 and -Z-R2 as shown. 31. The compound according to claim 30, further characterized in that ring A is phenyl. 32. The compound according to claim 29, further characterized in that X is selected from the group consisting of - (C (R3) 2) m- and -N (R3) -. 33. The compound according to claim 32, further characterized in that X is - (C (R3) 2) m, where m is 1 or 2. 34.- The compound according to claim 33, further characterized in that m is 1. 35.- The compound in accordance with claim 32, further characterized in that R3 is H. 36. The compound according to claim 29, further characterized in that T is absent or present and when present, is selected from the group consisting of alkyl and aryl, wherein each of these is not substituted or is substituted with one to four portions R10 which may be the same or different. 37. The compound according to claim 36, further characterized in that T is absent or present and when present is selected from the group consisting of -CH2- and phenyl. 38.- The compound according to claim 29, further characterized in that V is selected from the group consisting of alkyl, heterocyclyl and cycloalkyl, wherein when each of said V heterocyclyl or cycloalkyl contains two radicals on adjacent carbon atoms, said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, heterocyclyl, aryl or heteroaryl ring of five to eight members; wherein each of the aforementioned V alkyl, heterocyclyl and cycloalkyl, optionally with said cycloalkyl, heterocyclyl, aryl or heteroaryl rings of five to eight members are unsubstituted independent or are substituted with one to four portions R10 which may be the same or different. 39.- The compound according to claim 38, further characterized in that V is selected from the group consisting of methyl, ethyl, isopropyl, morpholinyl, cyclohexyl, piperidinyl which is optionally substituted with cyano or phenyl, -CH2- with tetrahydrofuranyl Y -CH (CH 3) - substituted with phenyl, piperazinyl substituted with methyl, pyrrolidinyl substituted with -CH 2 -phenyl, substituted with cyclopropyl and 40. The compound according to claim 29, further characterized by each of Y and Z selected independently from the group consisting of a covalent bond and -O-. 41. The compound according to claim 40, further characterized in that Y is -O- and Z is a covalent bond. 42. - The compound according to claim 29, further characterized in that each of R and R2 selected independently of the group consisting of H and alkyl. 43. The compound according to claim 42, further characterized in that R1 is alkyl and R2 is H. The compound according to claim 43, further characterized in that R is methyl. 45 - The compound according to claim 29, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or ester thereof. 46 - The compound according to claim 1, further characterized in that at least one of T and V is present and each one of -Y-R1 and -Z-R2 selected independently of the group consisting of cyano, - (C (R4) 2) nC (O) OH, - (C (R4) 2) nC (O) O- alkyl, - (C (R4) 2) nC (O) NH2, - (C (R4) 2) nC (O) NH (alkyl) and - (C (R4) 2) nC (O) N (alkyl) 2 , wherein each R4 independently is H or alkyl; and n is 1-3. 47. The compound according to claim 46, further characterized in that the ring A is selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidyl and each of them being substituted with -Y-R1 and -Z-R2 as shown. 48.- The compound according to claim 47, further characterized in that said ring A is phenyl. 49. The compound according to claim 46, further characterized in that X is selected from the group consisting of - (C (R3) 2) m- and -N (R3) -. 50.- The compound according to claim 49, further characterized in that X is - (C (R3) 2) m, where m is 1 or 2. 51.- The compound according to claim 50, further characterized by m is 1. 52. The compound according to claim 49, further characterized in that R3 is H. 53. The compound according to claim 46, further characterized in that T or V is aryl which is not substituted or is substituted with one to four portions R10. 54. The compound according to claim 53, further characterized in that said T or V is phenyl which is not substituted or is substituted with one to four portions R10. 55. The compound according to claim 54, further characterized in that R10 is fluorine. 56. The compound according to claim 55, further characterized in that only one of T and V is present. 57. The compound according to claim 46, further characterized in that U is absent. 58.- The compound according to claim 46, further characterized in that n is 1. 59.- The compound according to claim 46, further characterized in that each of Y and Z is independently selected from the group consisting of a covalent bond and -CH2- and each of R1 and R2 is independently selected from the group consisting of cyano, -C (O) OH or -C (O) NH2. 60. The compound according to claim 55, further characterized in that Y is a covalent bond and R1 is H. 61. The compound according to claim 55, further characterized in that Z is a covalent bond and R2 is cyano. 62 - The compound according to claim 55, further characterized in that Z is -CH2- and R is -C (O) OH or -C (O) NH2. 63.- The compound according to claim 46, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof. 64.- The compound according to claim 1, further characterized in that T is aryl or heteroaryl, each of which is optionally substituted with one to four R10 portions that were independently selected and V is alkynyl which is optionally substituted with one to two R10 portions that were selected independently. The compound according to claim 64, further characterized in that the ring A is selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidyl and each of them being substituted with -Y-R1 and -Z-R2 as shown. 66. The compound according to claim 65, further characterized in that said ring A is phenyl. 67. The compound according to claim 64, further characterized in that X is selected from the group consisting of - (C (R3) 2) m- and -N (R3) -. 68.- The compound according to claim 67, further characterized in that X is - (C (R3) 2) m, where m is 1 or 2. 69.- The compound according to claim 68, further characterized because m is 1. 70.- The compound according to claim 66, further characterized in that R3 is H. 71. The compound according to claim 64, further characterized in that T is aryl, U is -O- or is absent and V is alkynyl which is unsubstituted or is substituted with one to two R10 portions selected from the group consisting of -OR4, -N (R) 2 and heteroaryl; wherein when said heteroaryl contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form an aryl, heterocyclyl, heteroaryl or cycloalkyl ring of five to eight members; wherein each R 4 independently is H or alkyl and said R 10 heteroaryl optionally is independently substituted with one to four R 30 portions which may be the same or different. 72. The compound according to claim 71, further characterized in that T is phenyl. 73. The compound according to claim 71, further characterized in that said V alkynyl is selected from the group consisting of -CH2-C = C-CH3, R10-C = C-substituted and R10 -CH2-C = C- CH2-substituted. The compound according to claim 71, further characterized in that said substituents R10 are selected from the group consisting of -N (alkyl) 2, -OH, -OCH3 and pyridyl. The compound according to claim 64, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or ester thereof. The compound according to claim 1, further characterized in that at least one of T and V is present, ring A is heteroaryl and V is different from alkynyl. 77. The compound according to claim 76, further characterized in that the ring A is selected from the group consisting of thiophenyl, pyridyl, pyrimidyl and each of them being substituted with -Y-R1 and -Z-R2 as shown. 78. The compound according to claim 77, further characterized in that X is selected from the group consisting of - (C (R3) 2) m- and -N (R3) -. 79. The compound according to claim 78, further characterized in that X is - (C (R3) 2) m, where m is 1 or 2. 80.- The compound according to claim 79, further characterized because m is 1. 81. The compound according to claim 78, further characterized in that R3 is H. 82. The compound according to claim 76, further characterized in that T is selected from the group consisting of haloalkyl and aryl. replaced. 83. The compound according to claim 76, further characterized in that U and V are absent. 84. The compound according to claim 76, further characterized in that Y is selected from the group consisting of a covalent bond and -O- and Z is a covalent bond. The compound according to claim 76, further characterized in that R1 is selected from the group consisting of H and -CH3; and R2 is H. 86. The compound according to claim 76, further characterized in that Y is a covalent bond R1 is H. The compound according to claim 76, further characterized because Y is -O- and R1 is -CH3. 88. The compound according to claim 76, further characterized in that Z is a covalent bond and R2 is H. 89. The compound according to claim 76, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof. 90.- A compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or ester thereof. 91.- The compound according to claim 90, selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or ester thereof. 92. The compound according to claim 1 in purified form. 93.- A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof and at least one pharmaceutically acceptable carrier. 94. The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, in the manufacture of a medicament useful for treating disorders associated with TACE, TNF-a, MMPs, aggrecanase, ADAM or any combination thereof. 95.- The use of the pharmaceutical composition of the claim 93, in the manufacture of a medicament useful for treating disorders associated with TACE, FNT-a, aggrecanase, MMPs, ADAM or any combination thereof. The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, in the manufacture of a medicament useful for treating a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis , periodontitis, gingivitis, corneal ulcer, solid tumor growth and tumor invasion due to secondary metastasis, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in an individual. The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, in the manufacture of a medicament useful for treating a condition or disease selected from the group consisting of fever, cardiovascular disease, haemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, attack, graft-versus-host reaction, autoimmune disease and HIV infection in an individual. The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, in the manufacture of a medicament useful for treating a condition or disease selected from the group consisting of septic shock, shock hemodynamic, sepsis syndrome, post-ischemia reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases related to angiogenesis, autoimmune diseases, inflammation diseases of the skin, inflammatory bowel diseases such as Crohn's disease and colitis, osteoatritis and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Still's disease in adults, ureitis, Wegener's granulomatosis, Behcehe's disease , Sjogrep syndrome, sarcoidosis, polymyositis, dermatomyositis , multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, non-insulin-dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, pulmonary bronchial dysplasia, the retina, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral attack, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing alveolitis, psoriasis, rejection to transplants, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible obstruction in the respiratory tract, syndrome of respiratory failure in adults, asthma, chronic obstructive pulmonary disease (COPD) and bronchitis in an individual. The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, in the manufacture of a medicament useful for treating a condition or disease associated with COPD. The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, in the manufacture of a medicament useful for treating a condition or disease associated with rheumatoid arthritis. 101. The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, in the manufacture of a medicament useful for treating a condition or disease associated with Crohn's disease. The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, in the manufacture of a medicament useful for treating a condition or disease associated with psoriasis. 103.- The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, in the manufacture of a medicament useful for treating a condition or disease associated with ankylosing spondylitis. The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, in the manufacture of a medicament useful for treating a condition or disease associated with sciatica. The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, in the manufacture of a medicament useful for treating a condition or disease associated with complex regional pain syndrome. The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or ester thereof, in the manufacture of a medicament useful for treating a condition or disease associated with psoriatic arthritis. 107.- The use of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate or isomer thereof, in combination with a compound selected from the group consisting of Avonex®, Betaserone, Copaxone or other compounds indicated for the treatment of multiple sclerosis, in the manufacture of a medicament useful for treating a condition or disease associated with multiple sclerosis. 108.- The use as claimed in claim 96, wherein the medication is also adapted to be administrable with the less one of the drugs selected from the group consisting of disease modifying antirheumatic drugs (DMARDS), non-spheroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, COX-1 inhibitors, immunosuppressants, modifiers of the biological response (BRM), anti-inflammatory agents and H1 antagonists. 109. The use as claimed in claim 97, wherein the medicament is further adapted to be administrable with at least one of the drugs selected from the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, inhibitors of COX-1, immunosuppressants, BRM, anti-inflammatory agents and H1 antagonists. 110.- The use as claimed in claim 98, wherein the medicament is further adapted to be administrable with at least one of the drugs selected from the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, inhibitors of COX-1, immunosuppressants, BRM, anti-inflammatory agents and H1 antagonists.