MX2008009295A - Hydantoin derivatives 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

COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY DISORDERS FIELD OF THE INVENTION This invention relates in general to new hydantoin derivatives that can inhibit the matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs) and / or the tumor necrosis factor alpha converting enzyme - (TACE) and by doing so avoid release of tumor necrosis factor-alpha (TNF-a), pharmaceutical compositions comprising said compounds and methods of treatment and use of said compounds.

BACKGROUND OF THE INVENTION Osteo arthritis and rheumatoid arthritis (OA and RA, respectively) are destructive diseases of articular cartilage that are characterized by localized erosion of the cartilage surface. Several discoveries have shown that the articular cartilage of the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabelled sulfate with respect to the controls, which suggests that there must be an increased rate of cartilage degradation in OA. (Mankin et al., J. Bone Joint Surg. 52A (1970) 424-434). There are four classes of protein degrading enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteases. The available evidence supports the view that metalloproteases are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in cartilage with OA and the activity is correlated with the severity of the lesion (Mankin et al., Arthritis Rheum, 21, 1978, 761-766, Woessner et al., Arthritis Rheum, 26, 1983). , 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase (a recently identified metalloprotease) has been identified that provides the specific dissociation product of proteoglycan, which is found in patients suffering from RA and OA (Lohmander LS et al., Arthritis Rheum., 36, 1993, 1214-22. ). Metalloproteases (MPs) have been implicated as primordial enzymes in the destruction of cartilage and bone in mammals. It can be expected that the pathogenesis of such diseases should be beneficially modified by the administration of MP inhibitors (see Wahl et al Ann.Rem.Med. Chem. 25, 175-184, AP, San Diego, 1990). MMPs are a family of more than 20 different enzymes that are involved in a variety of important biological processes in the uncontrolled decomposition of connective tissue including proteoglycans and collagens, which leads to the resorption of the extracellular matrix. This is a characteristic of many pathological disorders such as RA and OA, corneal, epidermal or gastric ulceration; metastasis or tumor invasion; periodontal disease and bone diseases. Normally, these catabolic enzymes are tightly regulated at the level of their synthesis as well as in their level of extracellular activity through the action of specific inhibitors such as alpha-2-macroglobulins and TIMPs (tissue inhibitor of MPs), which form inactive complexes with MMPs. Tumor necrosis factor-alpha (TNF-a) is a cell-associated cytokine that is processed from a 26 kDa precursor 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, Yrews RC.'TACE and other ADAM proteases as targets for drug discovery "Drug Discov Today, 2001 April 1; 6 (8): 417-426, each one of which is incorporated herein by reference, TNF-a has been shown to play a key role in immune and inflammatory responses, inappropriate expression or hyper expression of TNF-α is a hallmark of a number of diseases which include RA, Crohn's disease, multiple sclerosis, psoriasis and septicemia.It has been shown that the inhibition of TNF-a production is beneficial in many preclinical models of inflammatory diseases, converting to the inhibition of production or signaling of TNF-a , an attractive target for the development of new anti-inflammatory drugs TNF-a is a basic mediator in the responses to inflammation, fever and acute phases, similar to what was observed during acute infection and shock. It has been shown that an excess of TNF-a is lethal. Blocking the effects of TNF-a with specific antibodies can be beneficial in a variety of disorders including autoimmune diseases such as RA (Feldman, et al., Lancet, (1994) 344, 1105), non-insulin-dependent diabetes mellitus, (Lohmyer LS et al., Arthritis Rheum 36 (1993) 1214-22) and Crohn's disease (Macdonald T. et al., Clin. Exp. Immunol., 81 (1990) 301). The compounds that inhibit the production of TNF-a are therefore of therapeutic importance for the treatment of inflammatory disorders. It has recently been shown that metalloproteases such as TACE are capable of converting TNF-a from its inactive form to an active form (Gearing et al., Nature, 1994, 370, 555). Because it has been observed that the excessive production of TNF-a in various diseases is also characterized by a tissue degradation mediated by MMP, compounds that inhibit both the production of MMPs and TNF-a, may also be particularly advantageous in diseases in which both mechanisms are involved. One way to inhibit the deleterious effects of TNF-a is inhibition of the enzyme, TACE before it can process TNF-a to its soluble form. TACE is a member of the ADAM family of type I membrane proteins and is an intermediary in the ectodomain proteolysis of several signaling and adhesion proteins anchored to membranes. TACE is increasingly important in the study of several diseases, which include inflammatory disease, due to its role in the dissociation of TNF-a from its "conduit" sequence and thus the release of the soluble form of the TNF-a protein (Black RA Int J Biochem Cell Biol 2002 34.1-5). Numerous patents and publications exist that describe inhibitors of MMP based on hydroxamate, sulfonamide, hydantoin, carboxylate and / or lactam. U.S. Patent Nos. 6,677,355 and 6,534,491 (B2), describe compounds that are hydroxamic acid derivatives and MMP inhibitors. U.S. Patent 6,495,565 describes lactam derivatives that are potential inhibitors of MMPs and / or TNF-α. PCT publications WO2002 / 074750, WO2002 / 096426, WO20040067996, WO2004012663, WO200274750 and WO2004024721 describe hydantoin derivatives which are potential inhibitors of MMP. PCT publications WO2004024698 and WO2004024715 describe sulfonamide derivatives that are potential inhibitors of MMP. PCT publications WO2004056766, WO2003053940 and WO2003053941 also describe potential inhibitors of TACE and MMP. PCT publication WO2006 / 019768 refers to hydantoin derivatives which are inhibitors of TACE. There is a need in the art to discover inhibitors of MMPs, ADAMs, TACE, and TNF-a, which may be useful as compounds anti-inflammatory and therapeutic cartilage protectors. The inhibition of TNF-a, TACE and other MMPs can prevent cartilage degradation by these enzymes, thus alleviating the pathological disorders of OA and RA as well as many other autoimmune diseases.

BRIEF DESCRIPTION OF THE INVENTION In its many embodiments, the present invention provides a new class of compounds as inhibitors of TACE, the production of TNF-α, MMPs, ADAMs, aggrecanase, or any combination thereof, methods of preparation of said compounds, pharmaceutical compositions which comprise one or more of said compounds, methods for preparing pharmaceutical formulations comprising one or more of said compounds, and methods of treating, preventing, inhibiting or ameliorating one or more diseases associated with TACE, aggrecanase, TNF-a, MMPs, ADAMs. or any other combination thereof, and use of said compounds or pharmaceutical compositions. In one embodiment, the present application describes a compound represented by Formula (I): or a pharmaceutically acceptable salt, solvate, ester or isomer 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 sample; X is selected from the group consisting of -S-.- O-, -S (O) 2-, S (O) -, - (C (R3) 2) m- and -N (R3) -, T is alkynyl; V is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, and N-oxides of said heteroaryl and heterocyclyl, wherein each of said cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl and N oxides of said heteroaryl and heterocyclyl contain two radicals on the same carbon atoms or on adjacent carbon atoms, and said radicals can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl of five to eight members, where each of said cycloalkyl, above-mentioned cycloalkenyl, aryl, heteroaryl and heterocyclyl, optionally with said cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl of five to eight members, is independently unsubstituted or substituted by one to four R10 moieties which may be the same or different; And it 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-, -O-, -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 (R) -S (O) 2-, -O- -S-, -C (O) -, -S (O) -, and -S (O) 2-; m is 1 to 3: n is 1 to 3; R is selected from the group consisting of H, cyano, 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, alkynyl, aryl, heteroaryl and heterocyclyl, R1, optionally with the five or six membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring, is unsubstituted or is optionally independently substituted with one to four R20 moieties which can be be same or different; with the proviso that whose Y is -N (R4) -, -S -o -O-, then R1 is not halogen or cyano; 2 R is selected from the group consisting of H, cyano, alkynyl, halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, and heterocyclyl, where when each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl contains two carbon atoms adjacent, said radicals may 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 said alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl R2, optionally with the five or six membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring is unsubstituted or is optionally independently substituted with one to four R20 moieties which may be 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 the same or different and is independently selected from the group consisting of H, alkyl, and aryl; 4 each R is the same or different and is independently selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl, hydroxy, -alkylcycloalkyl, -alkyl-N (alkyl) 2, heterocyclyl, aryl, and heteroaryl; R is selected from the group consisting of hydrogen, cyano, nitro, -C (R4) = N-OR4, -OR4, -SR4, -N (R) 2, -S (O) R4, -S (O) 2R4, -N (R4) S (O) 2R4, -N (R4) -C (O) -R4, -C (O) N (R) -S (O) 2R4, -S (O) 2N (R4 ) -C (O) -R4, - C (0) N (R4) C (O) R4, -C (O) N (R4) C (O) NR4 -S (O) 2N (R4) 2, -N (R4) -C (0) OR4 , -OC (O) N (R4) 2, -N (R4) C (O) N (R4) 2, -S (O) 2N (R4) 2, -S (O) 2N (R4) -C ( 0) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N (R4) 2, -haloalkoxy, -C (O ) OR 4, -C (0) R 4, -C (0) N (R 4) 2, halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl, wherein each of the alkyl, aryl, heteroaryl, heterocyclyl, and R10 cycloalkyl is unsubstituted or is optionally independently substituted with one to four R30 moieties which may be the same or different; or wherein two R10 moieties, when attached to the same carbon atom or adjacent carbon atoms, can optionally be taken with the carbon atoms to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl ring; R 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, -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 (0) 2N (R4) 2, -N ( R4) -C (O) OR4, -OC (O) N (R4) 2, --N (R4) C (O) N (R4) 2, -S (0) 2N (R4) 2, -S (O ) 2N (R 4) -C (O) -R 4, -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 adjacent carbon atom radicals, 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; where each of said alkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl R20, optionally with said cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members is unsubstituted or is substituted with one to four moieties 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 moieties when attached to the same carbon atom or adjacent carbon atoms can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl ring; R 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, -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 (O) OR4, -OC (O) N (R) 2, --N (R4) C (O) N (R4) 2, -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 , -haloalkoxy, -C (O) OR 4, -C (O) 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 R30 contains two adjacent carbon atom radicals, said radicals can be taken together with the carbon atoms to which they are attached to form a cycloalkyl, aryl, heterocyclyl or heteroaryl ring from five to eight members; where each of said alkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl R30, optionally with said cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members is unsubstituted or is substituted with one to four moieties 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 bonded to the same carbon atoms or adjacent carbon atoms can be taken together with the carbon atoms to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl ring. In another embodiment, the present application describes a 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 such as it is shown: 3 X is selected from the group consisting of -S-, - 0-, -C (R) 2 -or -N (R) -; T is absent or present, and if present, T is selected from the group consisting of H (with U and V absent), alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl-, and arylalkyl-, where said aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl-, and arylalkyl- are optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, and arylalkyl, wherein each of any of the alkyl groups , aforementioned alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl of T, is unsubstituted or optionally substituted independently with one to four R10 moieties which may be the same or different, wherein each R 0 moiety is independently selected from the group of following R10 residues :; U is absent or present, and if U is present, it is selected from the group consisting of alkynyl, -C (O) -, -C (O) 0-, 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-, wherein said aryl, heteroaryl, heterocyclyl, heterocyclylalkyl- , cycloalkyl, alkylaryl- and arylalkyl- are optionally fused to one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of any of the alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl mentioned above is not substituted or independently is optionally substituted with one to four R10 moieties which may be the same or different, wherein each moiety R0 is independently selected from the group of R10 moieties below; Y is selected from the group consisting of a covalent bond, - (C (R) 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 (0) 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 (O) 2N (R4) -, -N (R4) -S (O) 2-, -0 -, - S-, - C (O) -, -S (O) -, and -S (O) 2-; n is 1 to 3; R is selected from the group consisting of H, -OR4, cyano, -C (O) OR4, -C (0) N (R4) 2, halogen, alkyl, fluoralkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl , wherein each of the alkyl, fluoralkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl groups of R is unsubstituted or optionally independently substituted with one to four R20 moieties which may be the same or different, wherein each R20 moiety is independently selected from the group of R20 residues below, with the proviso 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) OR4, -C (O) N (R4) 2, halogen, alkyl, fluoralkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl , where each of the alkyl, fluoralkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, 2-alkylheteroaryl and arylalkyl groups of R is unsubstituted or is optionally substituted independently with one to four R20 moieties which may be the same or different, wherein each R20 moiety is independently selected from the group of following R20 residues, 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 is independently selected from the group consisting of H, alkyl, and aryl; 4 each R is the same or different and is independently selected from the group consisting of H, alkyl, heterocyclyl, aryl, and heteroaryl; R is selected from the group consisting of cyano, -OR4, -SR4, -N (R4) 2. -S (O) R4-, -S (O) 2R \ -N (R) S (O) 2R4, -S (O) 2N (R4) 2, -O (fluoralkyl), -C (O) OR4, -C (O) N (R4) 2, halogen, alkyl, fluoralkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of the alkyl, fluoralkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and Arylalkyl of R is unsubstituted or is optionally substituted independently with one to four R30 moieties which may be the same or different, wherein each R30 moiety is independently selected from the group of R30 moieties which follow; R is selected from the group consisting of halogen, alkyl, fluoralkyl, -N (R4) 2, and -C (O) N (R4) 2; Y R is selected from the group consisting of halogen, alkyl, fluoralkyl, -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 in the treatment and prevention of diseases associated with TACE, TNF-a, MMPs, ADAMs or any combination thereof.

DETAILED DESCRIPTION OF THE INVENTION In its various 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 the preparation of pharmaceutical formulations comprising one or more of said compounds, and methods for the treatment, prevention or amelioration of one or more of the symptoms of inflammation. In one embodiment, the present invention provides compounds that are represented by structural Formula (I) - (IV) above, or a pharmaceutically acceptable salt, solvate, ester or isomer thereof where the various moieties are as previously described. In another embodiment, the isomer referenced in the preceding paragraph is a stereoisomer.

In one embodiment, the labeled ring A is selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidyl, and each of which is substituted with -Y- R1 and -Z-R2 as shown in Formula (I). In another embodiment, in Formula (I), ring A is phenyl which is substituted with -Y-R1 and -Z-R2 as shown. 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 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), X is - (C (R3) 2) m, where m is 1, and where R3 is H. In another embodiment, in Formula (I), T is -C = C-. In another embodiment, in Formula (I), wherein V is selected from the group consisting of H, aryl, heteroaryl, and N-oxide of said heteroaryl; wherein when each of said aryl, and heteroaryl mentioned above contains two radicals on the same carbon atoms or on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to forming a five or six membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring; wherein said aryl and heteroaryl optionally with said five or six membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring is unsubstituted or optionally substituted with one to four R10 moieties which may be the same or different. In another embodiment, in Formula (I), V is selected from the group consisting of phenyl, naphthyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, benzopyrazolyl, imidazolyl, benzimidazolyl, furazanyl, pyridyl, pyridyl-N-oxide, pyridazinyl, pyrimidinyl. , pyrazinyl, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, pteridinyl, tetrazolyl, oxazolyl, isothiazolyl, thiazolyl, and where each one is optionally not or more residues R10 so that the amount of residues R10 per group V does not exceed four. In another embodiment, in Formula (I), R10 is selected from the group consisting of hydrogen, cyano, nitro, -OR4, -SR4, -N (R) 2, -S (O) 2R4-, -S (O ) 2N (R4) 2, -haloalkoxy, -C (O) OR4, -C (O) R4, -C (O) N (R4) 2, -C (O) N (R4) -S (O) 2R4 , -C (R4) = N-OR, halogen, alkyl, haloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, aryl, heteroaryl, and heterocyclyl is unsubstituted or optionally independently substituted with one to four residues R30 which may be the same or different; or where two R10 moieties, when attached to the same carbon atom, are taken together with the carbon atom to which they are attached to form a heterocyclyl ring; 4 each R is the same or different and is independently selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl, hydroxy, -alkylcycloalkyl, -alkyl-N (alkyl) 2, heterocyclyl, aryl, and heteroaryl; and R is selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, alkoxy, heterocyclyl, -C (R4) = N-OR, -O-alkyl-cycloalkyl, -N (R4) 2, and -C ( O) N (R4) 2, wherein said alkyl R30 is substituted with an -NH2. In another embodiment, in Formula (I), R10 is selected from the group consisting of nitro, alkyl, halogen, haloalkyl, haloalkoxy, alkoxy, cyano, -S (O) 2-alkyl, -NH2, -NH (alkyl), -N (alkyl) 2, cycloalkyl, aryl, heteroaryl, heterocyclyl, -alkyl-heterocyclyl, -cycloalkyl-NH2, -S (0) 2-NH 2, - S (O) 2alkyl, -C (O) NH 2, hydroxy, -C (O) N (H) (cycloalkyl), -C (O) N (H) (alkyl), - N (H ) (cycloalkyl), -C (O) O-alkyl, -C (O) OH, -S (O) 2N (H) (alkyl), -S (O) 2OH, -S-haloalkyl, -S (0 ) 2-haloalkyl, hydroxyalkyl, alkoxyalkyl, -O-alkyl-cycloalkyl, -alkyl-O-alkyl-cycloalkyl, -C (O) alkyl, aminoalkyl, -alkyl-NH (alkyl), -alkyl-N (alkyl) 2 , -CH = NO-alkyl, -C (O) NH-alkyl-N (alkyl) 2, -C (O) -heterocyclyl, and -NH-C (O) -alkyl, wherein each of said aryl and heteroaryl R10 is optionally substituted with 1-2 residues selected from the group consisting of alkyl, -NH2, -NH (alkyl), and -N (alkyl) 2; or where two R10 moieties attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a heterocyclyl ring. In another embodiment, in Formula (I), R10 is selected from the group consisting of hydrogen, nitro, methyl, fluorine, bromine, trifluoromethyl, chlorine, difluoromethoxy, trifluoromethoxy, methoxy, hydroxyl, cyano, -S (0) 2CH3 , -NH2, isopropyl cyclopropyl, -cyclopropyl-NH2, -NH (cyclopropyl), -NH (CH3), -S (O) 2-NH2, -C (O) NH2, -C (O) OCH3, -C (O) OH, S (O) 2N (H) CH 3, -C (O) NH (CH 3), -C (O) NH (cyclopropyl), -S (0) 2 OH, -S-CF 3, S (O) 2-CF 3, ethoxy, hydroxymethyl, methoxymethyl, isopropoxy, -OCH2-cyclopropyl, CH2O-CH2-cyclopropyl, -C (O) CH3, -C (O) CH3, -CH (CH3) OH, -CH2NH2, - CH (CH3) NH2, -CH2NH-CH3, -CH (CH3) OH, -CH2NHCH3, -CH = N-OCH3) -C (CH3) = N-OCH3, -C (O) OCH2CH3, -C (O) NHCH2CH2N (CH3) 2, -NH-C (O) CH3, or where two R10 moieties, when attached to the same carbon atom, are taken together with the carbon atom to which they are attached to form In another embodiment, in Formula (I), Y is selected from the group consisting of a covalent bond and -O-. In another embodiment, in Formula (I), Y is a covalent bond. In another embodiment, in Formula (I), Y is -O-. In another embodiment, in Formula (I), Z is selected from the group consisting of a covalent bond-O-. In another embodiment, in Formula (I), Z is -O-.

In another embodiment, in Formula (I), R1 is selected from the group consisting of hydrogen, cyano, halogen, alkyl, aryl, heteroaryl, haloalkyl, and alkynyl; wherein said alkyl R1 is unsubstituted or is substituted with an aryl, heteroaryl, or heterocyclyl, where when said aryl, heteroaryl, or heterocyclyl contains two adjacent carbon atom radicals, said radicals may optionally be taken together with the carbon atoms. carbon to which they are attached to form a cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members; wherein said aryl, heteroaryl or heterocyclyl substit of said alkyl R1 optionally with said cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members, is unsubstituted or optionally substituted independently with one to four R20 moieties. In another embodiment, in Formula (I), R 2 is selected from the group consisting of hydrogen, cyano, halogen, alkyl, aryl, heteroaryl, haloalkyl, and alkynyl; wherein said alkyl R1 is unsubstituted or substituted with an aryl, heteroaryl, or heterocyclyl, where when said aryl, heteroaryl, or heterocyclyl contains two residues on adjacent carbon atoms, said moieties may optionally be taken together with the carbon atoms at which are joined to form a cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members; wherein said substit aryl, heteroaryl or heterocyclyl of said alkyl R1 optionally with said cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members is unsubstituted or is optionally independently substituted with one to four R20 moieties. In another embodiment, in Formula (I), R1 is halogen or cyano. In another embodiment, in Formula (I), R 1 is fluorine, chlorine, or cyano. In another embodiment, in Formula (I), Y is -O-, and R1 is selected from the group consisting of alkyl, haloalkyl, and alkynyl; wherein said alkyl R1 is unsubstituted or substituted with a heteroaryl, wherein when said 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 of five or six members; wherein said heteroaryl substituent of said alkyl R1, optionally with said five or six membered aryl is substituted with alkyl. In another embodiment, in Formula (I), Y is -O-, and R1 is selected from the group consisting of CH3, -CH2-C = C-CH3, difluoromethyl, In another embodiment, the compound of Formula (I) is represented by the compound of formula (III): wherein in formula (III), X is - (CH2)? 2-, and T, V, Y, R1, and R3 are as set forth in Formula (I). In another embodiment, in Formula (III), X is -CH2-. In another embodiment, the compound of Formula (I) is represented by the compound of formula (IV): where in the formula (IV), X is - (CH2)? - 2-, T, V, Y, R1, and R3 are as stated in Formula (I). In another embodiment, in Formula (IV), X is -CH2-. In another embodiment, the compound of Formula (I) is selected from the group consisting of the compounds listed in the following table, or a pharmaceutically acceptable salt, solvate, ester or isomer thereof. This table also lists the data of mass spectroscopy and Ki evaluation for each compound. Those compounds having a Ki value of less than 5 nM (< 5 nM) are designated with the letter "A"; those with a Ki value from 5 to less than 25 nM (5 - < 25 nM) are designated with the letter "B"; those with a Ki value of from 25 to 100 nM are designated with the letter "C"; and those with a Ki value of more than 100 nM (> 100 nM) are designated with the letter "D". The synthesis and characterization of these compounds will be described below in the "EXAMPLES" section of the present application.

TABLE 1001 Compound ID Structures Mass Mass Observed valuation Exact Ki 1505 429.42 430.5 [M + H] + 1506 415.40 416.4 [M + H] + 1507 394.35 395.4 [M + H] + 1508 429.42 430.4 [M + H] + Compound ID Structures Mass Mass Observed valuation Exact Ki 1514 434.40 435.5 [M + H] + 1515 419.39 420.4 [M + H] + 1516 434.40 435.5 [M + H] + 1517 433.41 434.4 [M + H] + Compound ID Structures Mass Mass Observed valuation Exact Ki 1552 433.14 434.2 [M + H] + 1553 446.16 447.2 [M + H] + 1554 457.14 458.3 [M + H] + 1555 501.16 502.3 [M + H] + In another embodiment, the compounds of Formula (I) are selected from the group consisting of: 15 20 or a pharmaceutically acceptable salt, solvate, or ester thereof. In another embodiment, the compounds of Formula (I) are selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or ester thereof. The TACE-specific inhibitory activity (Ki values) of some representative compounds of the present invention are indicated below.

PICTURE 1002 As used above, and through this description, the following terms, unless otherwise indicated, will be interpreted with the following meanings: "Patient" includes both humans and animals. "Mammal" means humans and other mammalian animals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having from about 1 to about 6 carbon atoms in the chain which may be straight or branched. The alkyl group may be substituted with one or more substituents which may be the same or different, wherein each substituent is independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH (alkyl), -NH (cycloalkyl), -N (alkyl) 2, carboxy and -C (O) O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-to-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 an alkenyl line 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 triple carbon bond carbon 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 approximately 2 to about 6 carbon atoms in the chain that can be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means that the alkynyl group may be substituted with one or more substituents which may be the same or different, wherein each substituent is independently selected from the group consisting of alkyl, aryl and cycloalkyl. "Aryl" means a monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group may be optionally substituted with one or more "ring system substituents" which may be the same or different and which are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Heteroaryl" means a monocyclic or multicyclic aromatic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is a distinct element carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" may be optionally substituted with one or more "ring system substituents" which may be the same or different, as defined herein. The prefix aza, oxa or aia before the root name heteroaryl means that at least one nitrogen atom, oxygen or sulfur respectively, are present as ring atoms. A nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide. "Heteroaryl" can also include a heteroaryl such as defined above fused with an aryl as defined above. 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-a] pyridinyl, imidazo [2,1-bjthiazolyl, benzofurazanyl], indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl portions, such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl-alkyl group in which the 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 link with the main group is through the alkyl. "Alkylaryl" means an alkyl-aryl- group in which the alkyl and the aryl are as previously described. Preferred hire cars they comprise a lower alkyl group. A non-limiting example of an appropriate alkylaryl group is tolyl. The link with the main group is through the aril. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl may be optionally substituted with one or more "ring system substituents" which may be identical or different, and which are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbomyl, adamantyl and the like. "Cycloalkenyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms containing at least one carbon-to-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl may be optionally substituted with one or more "ring system substituents" which may be the same or different, and which are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. A non-limiting example of an appropriate multicyclic cycloalkenyl is norbomilenyl. "Halogen" (or "halo") means fluorine, chlorine, bromine, or iodine. Fluorine, chlorine and bromine are preferred. "Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system which replaces, for example, a hydrogen available in the ring system. The substituents of the ring system may be the same or different, and each is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy , aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C (= N-CN ) -NH2, -C (= NH) -NH2, -C (= NH) -NH (alkyl), G? G2N-, dG? N-alkyl-, G1G2NC (O) -, G1G2NSO2- and -SO2NG1G2, where G ^ and G2 are the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Substituent of the ring system" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) in a ring system.

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

"Heteroaralkyl" means a heteroaryl-alkyl- group in which heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The link with the main group is through the alkyl. "Hydroxyalkyl" means an HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. "Acyl" means a group H-C (O) -, alkyl-C (O) - or cycloalkyl-C (O) -, in which the various groups are as previously described. The link with the main group is through carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl. "Aroyl" means an aryl-C (O) - group in which the aryl group is as previously described. The link with the main group is through carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond with the main group is through the oxygen of the ether.

"Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond with the main group is through the oxygen of the ether. "Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond with the main group is through the oxygen of the ether. "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The link with the main group is through sulfur. "Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The link with the main group is through sulfur. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. A non-limiting example of an appropriate aralkylthio group is benzylthio. The link with the main group is through sulfur. "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The link with the main group is through carbonyl.

"Aryloxycarbonyl" means an aryl-O-C (O) - group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The link with the main group is through carbonyl. "Aralkoxycarbonyl" means an aralkyl-O-C (O) - group. A non-limiting example of an appropriate aralkoxycarbonyl group is benzyloxycarbonyl. The link with the main group is through carbonyl. "Alkylsulfonyl" means an alkyl-S (O 2) - group. Preferred groups are alkyls in which the alkyl group is lower alkyl. The link with the main group is through the sulfonyl. "Arylsulfonyl" means an aryl-S (O 2) - group. The link with the main group is through the sulfonyl. The term "substituted" means that one or more hydrogens in the designated atom are replaced with a selection of the indicated group, with the proviso that the normal valence of the designated atom under the existing circumstances is not exceeded, and that the substitution as a result a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a degree of useful purity from a reaction mixture, and which can be formulated in the form of an effective therapeutic agent.

The term "optionally substituted" means the optional substitution with the radical groups or specified moieties. The term "isolated" or "in isolated form" for a compound refers to the physical state of said compound after having been isolated from a synthesis process or from a natural source or a combination of these. The term "purified" or "in purified form" for a compound refers to the physical state of said compound after it has been obtained from a purification process or processes described herein or that are well known to the person skilled in the art, with sufficient purity to be characterized by conventional analytical techniques such as those described herein or well known to those skilled in the art. It should be noted that any carbon as well as heteroatom with valences not satisfied in the text, schemes, examples and tables given here is considered to have the amount of hydrogen atoms sufficient to satisfy the valences. When a functional group in a compound is called "protected", this means that the group is in a modified form, to avoid any undesirable secondary reaction in the protected site, when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those skilled in the art as well as by references to conventional textbooks such as for example T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.

When any variable (for example, aryl, heterocycle, R2, etc.) occurs more than once in any constituent or in Formula I, its definition each time it occurs is independent of its definition each time it occurs again. As used herein, the term "composition" encompasses a product that comprises the specified ingredients in the specified amounts, as well as any product that is the result, direct or indirect, of the combination of the specified ingredients in the specified amounts. The prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug", as used herein, denotes a compound that is a precursor of a drug which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to provide a compound of Formula I or a salt and / or solvate of this one. A discussion of prodrugs has been provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A. C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, and both are incorporated herein by reference. The term "prodrug" means a compound (ie, a precursor of a drug) that is transformed in vivo to provide a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation can occur by several mechanisms (for example, by metabolic or chemical processes), such as, for example, hydrolysis in the blood. A discussion of the use of prodrugs has been provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of 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 of the compound contains a carboxylic acid functional group, a prodrug may comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, alkyl (C? -8), alkanoyloxymethyl (C2-C12), 1- (alkanoyloxy) ethyl having from 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 from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N-alkylamino (C? -C2) (C2-C3) alkyl (such as ß-dimethylaminoethyl), carbamoyl-alkyl (C? -C2), N, N-di-alkylcarbamoyl (CrC2) -alkyl (C1-C2) and piperidino-, pyrrolidino- or morpholinoalkyl lo (C2-C3), and the like. Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by replacement of the hydrogen atom of the alcohol group with a group such as, for example, alkanoyloxymethyl (C -? - C6), 1 - . 1-methyl-1 - (alkanoyloxy (Cr C6)) ethyl, alkoxycarbonyloxymethyl (C? -C6), N-alkoxycarbonylaminomethyl (C? -C6), succinoyl, alkanoyl (CrC6), a-amino alkanyl (C? -C4) , arylacyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the natural L-amino acids, P (O) (OH) 2, -P (O) (Oalkyl (CrC6 )) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group from the hemiacetal form of a carbohydrate), and the like. If a compound of Formula (I) incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'- carbonyl wherein R and R 'are each independently alkyl (C -? - C? o), cycloalkyl (C3-C7), benzyl, or R-carbonyl is a natural a-aminoacyl or natural a-aminoacyl, - C (OH ) C (O) OY1 where Y1 is H, alkyl (Cr C6) or benzyl, -C (OY2) Y3 where Y2 is alkyl (C? -C4) and Y3 is alkyl (C? -C6), carboxy alkyl (C) C6), aminoalkyl (CrC4) or mono-N- or di-N, N-alkylaminoalkyl (CrC6), -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 solvent molecules. This physical association involves varying degrees of ionic and covalent binding, including hydrogen bonding. In certain cases the solvate will be capable of isolation, for example, when they incorporate one or more solvent molecules in the crystalline lattice of the crystalline solid. "Solvate" covers both solvates in the solution phase and insulables. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate in which the solvent molecule is H2O. "Effective amount" or "therapeutically effective amount" means an amount of compound or a composition of the present invention that is effective to inhibit TACE, the production of TNF-a, MMPs, ADAMS or any combination thereof and thereby produce the therapeutic effect, enhancer, inhibitor or preventive desired. The compounds of Formula I can form salts which are also within the scope of this invention. The reference to a compound of Formula I given here includes reference to salts thereof, unless otherwise stated. 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 both, a basic moiety such as, but not limited to pyridine or imidazole, and an acidic moiety, such as, but not limited to, carboxylic acid, zwitterions ("internal salts") can be formed. and will be included within the term "salt (s)" that is used here. Pharmaceutically acceptable salts (ie, non-toxic, physiologically acceptable) are preferred, although other salts are also useful. The salts of the compounds of Formula I can be formed, for example, by reaction of a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as a medium in which the salt precipitates or in an aqueous medium followed by lyophilization. Examples of acid addition salts include acetates, ascorbates, benzoates, benzensulphonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, bromidrates, iodidrates, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates, etc.) and the like. Additionally, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds have been discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Sales. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food &Drug Administration, Washington, D.C. on their website). These descriptions are incorporated herein by reference. Examples of basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (eg, organic amines) as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. The groups containing basic nitrogen can be quaternized with agents such as lower alkyl halides (for example methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (for example dimethyl, diethyl, and dibutyl sulphates), long-chain halides (for example chlorides, bromides and iodides of decyl, lauplo, and stearyl), aralkyl halides (for example benzyl and phenethyl bromides), and others. All said acid salts and basic salts are pharmaceutically acceptable salts which are 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 the salts, solvates and prodrugs thereof, may exist in their tautomeric form (eg, in the form of an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. All stereoisomers (e.g., geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those that may exist due to asymmetric carbons in various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomers, are contemplated within the scope of this invention, as well as positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). The individual stereoisomers of the compounds of the invention may be, for example, substantially free of other isomers, or may be mixed, for example, as racemates or with all other selected stereoisomers or stereoisomers. The chiral centers of the present invention may have the S or R configuration defined by Recommendations lUPAC 1974. The use of the terms "salt", "solvate", "prodrug" and the like applies equally to salt, solvate and prodrug of 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 have 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 pharmaceutical composition comprising as an active ingredient at least one compound of formula (I).

In another aspect, the invention provides a pharmaceutical composition of formula (I) which additionally comprises at least one pharmaceutically acceptable carrier. In another aspect, the invention provides a method for the treatment of disorders associated with TACE, aggrecanase, TNF-a, MMPs, ADAMs or any combination thereof, wherein said method comprises administering to a patient in need of such treatment an effective amount of at least one compound of formula (I). In another aspect, the invention provides a use of a compound of formula (I) for the manufacture of a medicament for treating disorders associated with TACE, aggrecanase, TNF-α, MMPs, ADAMs or any combination thereof. The compounds of Formula (I) may have anti-inflammatory activity and / or immunomodulatory activity and may be useful in the treatment of diseases including but not limited to septic shock, hemodynamic shock, septicemic syndrome, post-ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, rejection of grafts, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, inflammation diseases of the skin, diseases of intestinal inflammation such 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, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation injuries, hyperoxic alveolar lesions, periodontal disease, HIV, non-insulin dependent diabetes mellitus, lupus erythematosus systemic, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebrovascular accident, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing alveolitis, psoriasis, rejection of transplants, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible obstruction of the respiratory tract, adult respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD) and / or bronchitis. It has been contemplated that a compound of this invention may be useful for the treatment of one or more of the listed 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 intimately contacting at least one compound of formula (I) and at least one pharmaceutically acceptable carrier. In another aspect, the invention provides a compound of formula (I) which exhibits TACE, TNF-α, MMPs, ADAMs or any inhibitory activity, in combination, including enantiomers, stereoisomers and tautomers of said compound, and pharmaceutically acceptable salts, solvates, or esters of said compound, wherein said compound is selected from the compounds of the structures listed in Table 1001 indicated above. In another aspect, the invention provides a pharmaceutical composition for the treatment of disorders associated with TACE, aggrecanase, TNF-α, MMP, ADAM or any combination thereof in a subject, comprising administering to the subject in need of such treatment, a therapeutically effective of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, or isomer thereof. In another aspect, the invention provides a compound of formula (I) in purified form. In another aspect, the invention provides a method for the treatment of a disease or disorder mediated by TACE, MMPs, TNF-α, aggrecanase, or any combination thereof in a subject, comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof. In another aspect, the invention provides a method for the treatment of a disorder or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, growth of solid tumors and invasion of tumors by metastasis. secondary, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in a subject comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt, solvate, ester or isomer of this pharmaceutically acceptable. In another aspect, the invention provides a method for the treatment of a disorder or disease selected from the group consisting of fever, cardiovascular disorders, haemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, reaction of graft versus host, autoimmune diseases and HIV infection in a subject, comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt, solvate, ester, or isomer thereof pharmaceutically acceptable. In another aspect, the invention provides a method for the treatment of a disorder or disease selected from the group consisting of septic shock, hemodynamic shock, septicemic syndrome, post ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure. , fibrotic diseases, cachexia, rejection of the grafts, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, skin inflammation diseases, diseases of intestinal inflammation such as the disease of Crohn's and colitis, osteo and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Still's disease in adults, ureitis, Wegener's granulomatosis, Behcehe's disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, pain syndrome complex regional, radiation injuries, hyperoxic alveolar lesions, periodontal disease, HIV, non-insulin-dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction , cerebrovascular accident, cerebral ischaemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing alveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible obstruction of the respiratory tract, adult respiratory distress syndrome (ARDS) ), asthma, enf chronic obstructive pulmonary disease (COPD) and bronchitis, in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof . In another aspect, the invention provides a method for the treatment of a disorder or disease associated with COPD, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt, solvate, ester or isomer thereof pharmaceutically acceptable.

In another aspect, the invention provides a method for the treatment of a disorder or disease associated with rheumatoid arthritis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt , solvate, ester, or pharmaceutically acceptable isomer thereof. In another aspect, the invention provides a method for the treatment of a disorder or disease associated with Crohn's disease, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof. In another aspect, the invention provides a method for the treatment of a disorder or disease associated with psoriasis., comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, or isomer thereof. In another aspect, the invention provides a method for the treatment of a disorder or disease associated with ankylosing spondylitis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt , solvate, ester or isomer thereof pharmaceutically acceptable.

In another aspect, the invention provides a method for the treatment of a disorder or disease associated with sciatica, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt, solvate, ester or isomer thereof pharmaceutically acceptable. In another aspect, the invention provides a method for the treatment of a disorder or disease associated with complex regional pain syndrome, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, or isomer thereof. In another aspect, the invention provides a method for the treatment of a disorder or disease associated with psoriatic arthritis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I), or a salt, solvate, ester, or pharmaceutically acceptable isomer thereof. In another aspect, the invention provides a method for the treatment of a disorder or disease associated with multiple sclerosis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt , solvate, ester or isomer thereof pharmaceutically acceptable, in combination with a compound selected from the group consisting of Avonex®, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis. Additionally, a compound of the present invention can be co-administered or used in combination with disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, azathioprine, leflunomide, pencillinamine, gold salts, mycophenolate mofetil, cyclophosphamide and other similar drugs. They can also be co-administered with or used in combination with non-spheroidal anti-inflammatory drugs (NSAIDs) such as piroxicam, naproxen, indomethacin, ibuprofen and the like; selective inhibitors of cycloxygenase-2 (COX-2) such as Vioxx® and Celebrex®; immunosuppressants such as steroids, cyclosporin, Tacrolimus, rapamycin and the like; biological response modifiers (BRMs) such as Enbrel®, Remicade®, IL-1 antagonists, anti-CD40, anti-CD28, IL-10, anti-adhesion molecules and the like; and other anti-inflammatory agents such as p38 kinase inhibitors, PDE4 inhibitors, other chemically different TACE inhibitors, chemokine receptor antagonists, Thalidomide, and other small molecule inhibitors of pro-inflammatory cytokine production. Also, a compound of the present invention can be co-administered or used in combination with an H1 antagonist for the treatment of seasonal allergic rhinitis and / or asthma. Suitable H1 antagonists can be, for example, Claritin®, Clarinex®, Allegra®, or Zyrtec®.

In another aspect, the invention provides a method for the treatment of a disorder or disease mediated by TACE, MMPs, TNF-α, aggrecanase, or any combination thereof in a subject, comprising: administering to the subject in need of such treatment an amount Therapeutically effective of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate or isomer thereof in combination with a therapeutically effective amount of at least one medicament selected from the group consisting of anti-rheumatic drugs modifying the disease (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 disorder or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, growth of solid tumors and invasion of tumors by secondary metastases., neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in a subject, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or an acceptable salt, solvate, ester , or isomer thereof pharmaceutically in combination with a therapeutically effective amount of at least one medicament selected from the group consisting of inhibitors of DMARDS, NSAIDs, COX-2, inhibitors of COX-1, immunosuppressants, BRMs, anti-inflammatory agents and H1 antagonists. In another aspect, the invention provides a method for the treatment of a disorder or disease selected from the group consisting of septic shock, hemodynamic shock, septicemic syndrome, post ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure. , fibrotic diseases, cachexia, rejection of the grafts, cancers such as cutaneous T-cell lymphoma, diseases that involve angiogenesis, autoimmune diseases, inflammation diseases of the skin, diseases of intestinal inflammation such as Crohn's disease and colitis, osteo arthritis and rheumatoid, ankylosing spondylitis, psoriatic arthritis, Still's disease in adults, ureitis, Wegener's granulomatosis, Behcehe's disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation injuries, alveol lesions hyperoxic ares, periodontal disease, HIV, non-insulin dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebrovascular accident, cerebral ischaemia, nephritis , hepatitis, glomerulonephritis, cryptogenic fibrosing alveolitis, psoriasis, rejection of transplants, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible obstruction of the respiratory tract, adult respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD) and bronchitis in a subject, which comprises administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester or isomer thereof in combination with a therapeutically effective amount of at least one medicament selected from the group consisting of inhibitors of DMARDS, NSAIDs, COX-2, COX-1 inhibitors, immunosuppressants, BRMs, anti-inflammatory agents and H1 antagonists. In another aspect, the invention provides a method for the treatment of RA comprising administering a compound of Formula I in combination with a compound selected from the class consisting of a COX-2 inhibitor for example Celebrex® or Vioxx®; a COX-1 inhibitor for example Feldene®; an immunosuppressant for example methotrexate or cyclosporin; a spheroid for example β-metasone; and an anti-TNF-α compound, for example Enbrel® or Remicade®; an inhibitor of PDE IV, or other classes of compounds indicated for the treatment of RA. In another aspect, the invention provides a method for the treatment of multiple sclerosis comprising administering a compound of Formula (I) in combination with a compound selected from the group consisting of Avonex®, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis.

The activity of TACE is determined by a kinetic assay that measures the rate of increase of the fluorescent intensity generated by the TACE catalyzed dissociation of an internally quenched peptide substrate (SPDL-3). The purified catalytic domain of recombinant human TACE (rhTACEc, Residue 215 to 477 with two mutations (S266A and N452Q) and a 6xHis tail) was used in the assay. It was purified from the baculovirus / Hi5 cell expression system using affinity chromatography. The SPDL-3 substrate is an internally quenched peptide (MCA-Pro-Leu-Ala-GIn-Ala-Val-Arg-Ser-Ser-Ser-Dpa-Arg-NH2), with its sequence derived from the dissociation site. TNFa. MCA is (7-Methoxycoumarin-4-yl) acetyl. Dpa is N-3- (2,4-Dnitrophenyl) -L-2,3-diaminopropionyl. A 50 μl assay mixture contains 20 mM HEPES, pH 7.3, 5 mM CaCl 2, 100 μM ZnCl 2, 2% DMSO, 0.04% Methylcellulose, 30 μM of SPDL-3, 70 pM of rhTACEc and a test compound. The RhTACEc is pre-incubated with the test compound for 90 minutes at 25 ° C. The reaction is initiated by the addition of the substrate. Fluorescent intensity (excitation at 320 nm, emission at 405 nm) was measured every 45 seconds for 30 minutes using a fluorescetrometer (GEMINI XS, Molecular Devices). The speed of the enzymatic reaction is shown as units per second. The effect of a test compound is shown as the percentage of TACE activity in the absence of the compound. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, in form of tablets, lozenges, aqueous or oily suspensions, powders or dispersible granules, emulsions, hard or soft capsules, or syrups or elixirs. The compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and said compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and agents present / Adores to provide pharmaceutically pleasing and tasty preparations. The tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture 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; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action for a longer period of time. For example, a delayed release material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in US Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release. The term "pharmaceutical composition" also encompasses both the bulk composition and the individual dosage units comprising more than one (eg, two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the list of additional agents described herein together with any pharmaceutically inactive excipient. The bulk composition and each individual dosage unit may contain fixed amounts of the aforementioned "more than one pharmaceutically active agent". Mass composition is a material that has not yet been formed in individual dosage units. An illustrative dosage unit is an oral dose unit such as tablets, pills and the like. Similarly, the method described herein for the treatment of a patient by administration of a pharmaceutical composition of the present invention also encompasses the administration of the aforementioned bulk composition and of the individual dosage units. Formulations for oral use can also be presented in the form of hard gelatin capsules wherein the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or with soft gelatine capsules in which the Active ingredient is mixed with water or in an aqueous medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active material mixed with excipients suitable for the manufacture of aqueous suspensions. Said excipients are suspending agents, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and acacia gum; the dispersing or wetting agents may be natural phosphatides, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, example, heptadecaethylene-oxicetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan 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 oil such as liquid paraffin. Oily suspensions may contain a thickening agent for example, beeswax, hard paraffin or alcohol cetyl Sweetening agents such as those indicated above, and flavoring agents can be added to provide a tasty oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent such as a suspending agent and one or more preservatives. The dispersing agents or wetting agents and suspending agents are exemplified by those that have already been mentioned above. Additional excipients may also be present, for example, sweetening, flavoring and coloring agents. The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures thereof. Suitable emulsifying agents may be natural phosphatides, for example, soy beans, lecithin, and partial esters or esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of said partial esters with sodium oxide. ethylene, for example, polyoxyethylene monooleate sorbitan. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Said formulations may also contain a demulgent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known techniques employing suitable dispersing or wetting agents and suspending agents, which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable solvent or diluent, for example, in the form of a solution in 1,3-butane diol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixative oils are conventionally used as a solvent or suspension medium. For this purpose, any soft fixative oil including synthetic mono- or diglycerides can be employed. In addition, fatty acids such as oleic acids are useful in the preparation of injectables. The compounds of the invention can also be administered in the form of suppositories for rectal administration of the drug. The compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at normal temperatures but is liquid at rectal temperature and therefore it melts in the rectum to release the drug. These materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc. are used, which contain the compounds of the invention. (For the purposes of this application, topical application will include mouthwash and gargle.) The compounds of the present invention can be administered by intranasal form through topical use of appropriate intranasal vehicles or transdermal routes using those forms of transdermal patch for skin that are well known to those skilled in the art. For administration in the form of a transdermal delivery system, the administration of the dose will, of course, be continuous rather than intermittent throughout the dosage regimen. The compounds of the present invention can also be released in the form of suppositories using bases such as cocoa butter, glycerin gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. The dosage regimen using the compounds of the present invention is selected according to a variety of factors including the type, species, weight, sex and health status of the patient.; the severity of the disease that must be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound that is used. A doctor or veterinarian with common experience they can easily determine and prescribe the effective amount of drug required to prevent, counteract, stop or reverse the progress of the disease. The optimal precision to achieve drug concentration within the range that provides efficacy without toxicity requires a regimen based on the kinetics of the drug's affordability at the target sites. This involves a consideration of the distribution, balance and elimination of a drug. Preferably, the doses of the compound of Formula I that are useful in the method of the present invention are in a range of from 0.01 to 1000 mg per day. More preferably, the doses are in a range of from 0.1 to 1000 mg / day. More preferably, the doses are in a range of from 0.1 to 500 mg / day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01 to 1000 milligrams of active ingredient, particularly 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 the active ingredient for the symptomatic adjustment of the dose for the patient to be treated. An effective amount of the drug is commonly delivered at a dosage level of from about 0.0002 mg / kg to about 50 mg / kg of body weight per day. The range is more particularly from about 0.001 mg / kg to 1 mg / kg of body weight per day. Advantageously, the active agent of the present invention can be administered in a single daily dose or the total daily dose can be administered in divided doses of two, three or four times per day.

The amount of active ingredient that can be combined with the carrier materials to produce the single dosage form will vary depending on the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including age, body weight, health, sex, diet, time of administration, route of administration , the excretion regimen, the combination of the drug and the severity of the particular disease submitted to therapy. The compounds of the invention can be produced by methods known to those skilled in the art as shown in the following reaction schemes and in the preparations and examples described below.

EXAMPLES The following abbreviations can be used in the procedures and schemes: ACN Acetonitrile AcOH Acetic acid Aq Aqueous BOC ter-Butoxycarbonyl BOC2O BOC anhydride C degrees Celsius CBZCI Benzylchloroformate DBU 1, 8-Diazabicyclo [5,4,0] undec-7-ene DCM Dichloromethane DEAD Diethyl azodicarboxylate (DHQ) 2PHAL 1,4-Ftalazinediyl hydroquinine di-ether DIAD Diisopropylazodicarboxylate 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 DMSO Dimethyl sulfoxide EDCI 1- (3-dimethylaminopropyl) hydrochloride 3- Ethylcarbodiimide The ionization of electrons Eq Equivalents EtOAc Ethyl acetate EtOH Ethanol 9 grams h hours hr hours 1H proton HATU Hexafluorophosphate N, N, N ', N'-Tetramethyl-O- (7 azabenzotriazol-1 -yl) Uronium Hex hexanes HOBT 1 -Hydroxybenzotriazole HPLC High pressure liquid chromatography LAH Lithium aluminum hydride LDA Lithium diisopropylamide M Molar mmol millimolar mCPBA Mefa-chloroperoxybenzoic acid Me Methyl MeCN Acetonitrile MeOH Methanol min Minutes mg Milligrams MHZ Megahertz mL Milliliter MPLC Liquid pressure liquid chromatography NMR Nuclear magnetic resonance EM NBS mass spectroscopy N-Bromosuccinimide NMM N-Methylmorpholine NMP 1-methyl-2-pyrrolidone ON during the night PCC Pyridinium chlorochromate PTLC Thin-layer chromatography p PiBrOP Bromine-tris-pir hexafluorophosphate Pir Pyridine RT Ambient temperature sgc Silica gel chromatography 60 tBOC ter-Butoxycarbonyl TACE Enzyme converter TNF-alpha TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography EXAMPLE 300A 303 305 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 (in an oil bath) under nitrogen for 16 hours. After cooling, the solid was removed by filtration. The solution was concentrated and purified by sgc (10: 1 EtOAc / hexanes) to provide 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 provide 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 under pressure at 60 ° C overnight. 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 methylene chloride. The methylene chloride was washed with water, dried over sodium sulfate, sodium, and concentrated to provide 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. Chloromethyl pivalate (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, brine, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, 25% ethyl acetate / hexanes) gave 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 an ice bath. Bromotrimethylsilane (0.3 mL, 2.08 mmol) was added dropwise and stirred in an ice 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 provide the desired product 305 (218 mg, 83%).

EXAMPLE 300B Part A: Compound 307 was prepared from compound 306 using the procedure found in Tetrahedron 1975, 31, 863-866. Part B: Compound 308 was prepared from compound 307 using the procedure found in J. Med. Chem. 1981, 24, 16-20. HPLC-MS tR = 1839 min (ELSD); mass calculated for the formula C? 0H? NO4S 243.09, LCEM observed m / z 244.1 (M + H). Part C: Diisopropylamine (0.80 mL, 5.8 mmol) and HMPA (2.3 mL) were dissolved in THF (10 mL) and cooled to -78 ° C. A solution of n-BuLi (2.5 M, 2.0 mL, 5 mmol) was added to the reaction by dropping and stirred for 20 minutes. Compound 308 (425 mg, 1.66 mmol) was dissolved in THF (5 mL) and added dropwise. After 20 minutes, compound 305 (470 mg, 1.83 mmol) in THF (10 mL) was added dropwise and the reaction was stirred for 2 hours at the same temperature. A saturated solution of ammonium chloride was slowly added 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, brine, dried over sodium sulfate, and concentrated. Purification by column chromatography (SiO2, 33% ethyl acetate / hexanes to 50% ethyl acetate / hexanes) gave the desired product 309 (0.360 g, 52%). HPLC-MS t R = 1904 min (UV254 nm); mass calculated for the formula C20H26N2O6Si 418.15, LCEM observed m / z 419.2 (M + H). Part D: Compound 309 (100 mg, 0.23 mmol) was dissolved in THF (5 mL) and cooled to 0 ° C. Tetrabutylammonium fluoride (1 M in THF, 0.3 mL, 0.3 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, brine, dried over sodium sulfate and concentrated to provide compound 310 (70 mg, 88%). The product was used without purification. Part E: Compound 310 (627 mg, 1.87 mmol) was combined with 3-iodopyridine (561 mg, 2.8 mmol), Pd (dppf) CI2 (76 mg, 0.093 mmol), X-PHOS (88 mg, 0.186 mmol) , piperidine (321 mg, 3.74 mmol) in acetonitrile (20 mL) and stirred overnight at 80 ° C. The reaction mixture was cooled to room temperature and concentrated. Purification by column chromatography (SiO2, ethyl acetate up to 2% methanol / ethyl acetate) gave the desired product 311 (0.630 g, 80%). HPLC-MS tR = 1389 min (UV254"m); mass calculated for the formula C22H2? N3? 6 423.14, LCEM observed m / z 424.1 (M + H). Part F: Compound 311 (60 mg, 0.14 mmol) was dissolved in 7 M ammonia in a methanol solution (5 mL) and stirred in a closed tube under pressure at 90 ° C overnight. The reaction mixture was cooled to room temperature and concentrated. Trituration with ethyl acetate gave the desired product 312 (49.5 mg, 93%). HPLC-MS t R = 1086 min (UV254 nm); mass calculated for the formula C20H? 6N O4 376.11, LCEM observed m / z 377.0 (M + H).

EXAMPLE 300C 305 Part A: Compound 313 was prepared using the procedure found in J. Org. Chem. 1990, 55, 4657-4663.

Part B: Compound 314 was prepared using the procedure found in Part C of Example 300B. Part C: Compound 314 (100 mg, 0.23 mmole) was dissolved in 7 M ammonia in a methanol solution (5 mL) and stirred in a closed tube under pressure at 90 ° C overnight. The reaction mixture was cooled to room temperature and concentrated. Trituration with ethyl acetate gave the desired product (57 mg, 63%). HPLC-MS tR = 1533 min (UV254 nm); mass calculated for the formula C2-? H16N3? 4F 393.1, LCEM observed m / z 394.1 (M + H).

EXAMPLE 400 3-9 3-9 B 3D5 Í0Q-, (DDB Part A: Glyoxylic acid monohydrate (20.0 g, 218 mmol) and methyl carbamate (16.3 g, 218 mmol) were dissolved in diethyl ether (200 mL) and stirred overnight. The solids were filtered to provide 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 an ice 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 brine, dried over sodium sulfate, and concentrated to provide 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). Phosphorus pentachloride (50 g, 240 mmol) was added and the suspension was stirred for 18 hours (the solution cleared 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 provide compound 307 without the need for purification (26.5 g, 96%). The grinding step was repeated if the yield of the dough was too high.

Part D: Compound 307 (15.0 g, 82.7 mmol) was dissolved in methylene chloride (140 mL) and cooled in an ice bath. Bis (trimethylsilyl) acetylene (15.0 g, 88.2 mmol) in methylene chloride (20 mL) was added. Freshly ground aluminum chloride (11.0 g, 82.7 mmol) was added in portions over 20 minutes. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction was cooled in an ice bath and quenched 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 provide the desired product 308 (14.8 g, 69%). HPLC-MS t R = 1.84 min (ELSD); mass calculated for the formula C10H? 7NO Si 243.09, LCEM observed m / z 244.1 (M + H). 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 solution of LiHMDS (198 mL, 198 mmol) was added dropwise over 30 minutes and the reaction mixture was stirred for 2 hours. A saturated solution of ammonium chloride was slowly added 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, brine, dried over sodium sulfate, and concentrated. Purification by column chromatography (Si? 2, 33% acetate) ethyl / hexanes at 50% ethyl acetate / hexanes) gave the desired product 309 (26.0 g, 63%). HPLC-MS t R = 1.90 min (UV254"m); mass calculated for the formula C20H26N2O6Si 418.15, LCEM observed m / z 419.2 (M + H). The synthesis for compound 305 was described in Example 300A Part F: The two isomers were separated using a chiral OD column. One gram of material was injected into the column and the two peaks were separated using a solvent mixture of 85% hexanes / 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, brine, dried over sodium sulfate and concentrated to provide compound 400 (5.8 g, 88%). The product was used without purification.

Part H: Compound 400 (500 mg, 1.45 mmol) was combined with 3-iodopyridine (434 mg, 2.16 mmol), Pd (PF3) 2 Cl2 (50 mg, 0.072 mmol), (14 mg, 0.072 mmol), diisopropylamine (0.4 mL, 2.9 mmol) in DMF (5 mL) and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, 2% ethyl acetate methanol / ethyl acetate) gave the desired product 400A (0.520 g, 84%). HPLC-MS t R = 1.39 min (UV254 nm); mass calculated for the formula C22H21N3O6 423.14, LCEM observed m / z 424.1 (M + H). Part I: Compound 400A (480 mg, 1.13 mmol) was dissolved in a 7 M ammonia solution (5 mL) and stirred in a closed tube under pressure at 90 ° C overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was treated with 1 M HCl (2 mL) and then diluted with acetonitrile (10 mL) and water (3 mL). The solvent was removed by lyophilization to provide compound 400B in the form of the HCl salt (437.4 mg, 93%). HPLC-MS t R = 1.09 min (UV254 nm); mass calculated for the formula C20H16N O4 376.11, LCEM observed m / z 377.0 (M + H).

EXAMPLE 401 Part A: Compound 309B (1.26 g, 3.0 mmol) in 7 M ammonia in methanol (20 mL) was heated at 85 ° C in a bottle under pressure overnight. The reaction mixture was concentrated to provide 401 (900 mg, 100%) which was used without further purification. HPLC-MS R = 1.00 min (UV25 nm); mass calculated for the formula C15H13N3O4 299.09, LCEM observed m / z 300.1 (M + H).

EXAMPLE 402 Part A: To 6-bromoindazole (402A) (5.0 g, 25.4 mmol) in THF (50 mL) was added sodium hydride (95%, 672 mg, 26.6 mmol) with cooling in an ice bath. The mixture was stirred for 30 minutes. Methyl iodide (6.36 mL, 102 mmol) was added at room temperature. The reaction mixture was quenched with a solution of ammonium chloride and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, ethyl acetate / hexane gradient) provided 1-methyl-6-bromoindazole (402B) (2.71 g, 51%) in the form of a yellow oil and 2-methyl-6-bromoindazole (402C) (2.28 g, 43%) as a yellow crystalline solid. 402B: HPLC-MS t R = 1.69 min (UV254 nm); mass calculated for the formula C8H7BrN2 209.98, LCEM observed m / z 211.0 (M + H). 402C: HPLC-MS t R = 1.54 min (UV25 nm); mass calculated for the formula C8H7BrN2 209.98, LCEM observed m / z 211.0 (M + H).

EXAMPLE 403 403A 403B 403C Part A: Using the procedure described in Example 402, 403B (53%) and 403C (39%) were prepared. 403B: HPLC-MS t R = 1.69 min (UV254 nm); mass calculated for the formula C8H7BrN2 209.98, LCEM observed m / z 211.0 (M + H). 403C: HPLC-MS t R = 1.46 min (UV254 nm); mass calculated for the formula C8H7BrN2 209.98, LCEM observed m / z 211.0 (M + H).

EXAMPLE 409 400 Part A: Compound 409 (545 mg, 2.3 mmol) was combined with 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H- pyrazole (526 mg, 2.53 mmol), PdCI2dppf.CH2CI2 (94 mg, 0.11 mmol) and K3PO4 (1.46 g, 6.9 mmol) in 1,4-dioxane (10 mL) and heated overnight at 80 ° C. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The organic filtrate was concentrated and purified by column chromatography (SiO2, 50% to 80% ethyl acetate / hexane to ethyl acetate) to provide the desired product 409A (0.250 g, 46%) as a yellow solid . HPLC-MS t R = 1.24 min (UV254 nm); mass calculated for the formula C9H8BrN3 236.99, LCEM observed m / z 238.1, 240.0 (M + H, isotope Br). Part B: Compound 409B was prepared using the procedures described in Example 400, part H. Purification by column chromatography (SiO2, 5% ethyl acetate methanol / ethyl acetate) provided the desired product 409B (0.1 g , 59%). HPLC-MS t R = 1.38 min (UV254 nm); mass calculated for the formula C26H25N5? 6 503.18, LCEM observed m / z 504.2 (M + H). Part C: Compound 409C was prepared using the procedures described in Example 400, Part I. Purification by reverse phase prepLC gave the desired product 409C (46 mg, 50%). HPLC-MS R = 1.14 min (UV254 nm); mass calculated for the formula C 24 H 20 N 6 O 4 456.15, LCMS observed m / z 457.1 (M + H).

EXAMPLE 410 Part A: According to a modification of a Xue procedure, C-B et. to the. (WO 2006/004741) a mixture of compound 410 (1.0 g, 3.52 mmol), pyrrolidine (0.31 mL, 3.7 mmol), Cul (67 mg, 0.35 mmol), K3PO4 (1.57 g, 7.4 mmol) and ethylene glycol (0.4 mL, 7.04 mmol) in isopropanol (10 mL) was heated at 85 ° C in a sealed tube for 60 hours. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The Ifiltrado The organic was concentrated and purified by column chromatography (SiO2, 10% to 30% ethyl acetate / hexane) to provide the desired product 41AA (0.39 g, 49%) as a white solid. HPLC-MS t R = 1.26 min (UV254 nm); mass calculated for the formula C9HnBrN2 226.01, LCMS observed m / z 227.1, 229.1 (M + H, isotope Br).

Part B: Compound 410B was prepared using the procedures described in Example 400, Part H. Purification by reverse phase prepLC yielded the desired product 410B (54 mg, 24%). HPLC-MS t R = 1.1 1 min (UV2 nm); mass calculated for the formula C24H23N5O 445.18, LCMS observed m / z 446.2 (M + H).

EXAMPLE 412 412C 412D Part A: Compound 412 (500 mg, 1.92 mmol) was dissolved in methylene chloride (15 mL) and triethylamine (0.53 mL, 3.84 mmol). Methylamine hydrochloride (186 mg, 2.3 mmol) was added and the solution was stirred for two hours. The reaction mixture was washed with water and the organic layer was dried over sodium sulfate and concentrated to provide compound 12A (430 mg, 77%). Part B: Compound 412A (430 mg, 1.47 mmol) was dissolved in acetic acid (10 mL) and bromine (0.091 mL, 1.76 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The solvent was removed and the residue was dissolved in ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated to provide the desired product (230 mg, 43%). HPLC-MS t R = 1.53 min (UV254 nm); mass calculated for the formula C8H7IN2S 290.12, LCMS observed m / z 291.0 (M + H). Part C: See Example 400, Part H for a similar experimental procedure. HPLC-MS R = 1.47 min (UV254 nm); mass calculated for the formula C25H24N4O6S 508.55, LCMS observed m / z 509.1 (M + H). Part D: See Example 400, Part I for a similar experimental procedure. HPLC-MS R = 1.19 min (UV254 nm); mass calculated for the formula C23H19N5? 4S 461.49, LCMS observed m / z 462.1 (M + H).

Part A: Compound 413 (3.5 g, 20.7 mmol) was dissolved in methylene chloride (100 mL) and m-CPBA (4.95 g) was added., 28.9 mmol). The reaction mixture was stirred for two hours and then quenched with saturated sodium carbonate and dried overnight. The organic layer was dried over sodium sulfate and concentrated to give a yellow solid (3.8 g). The solid was placed under argon and trifluoroacetic anhydride (15 mL) was slowly added. The reaction was stirred for 30 minutes at room temperature and then refluxed for 30 minutes. The reaction was cooled to room temperature and quenched slowly with saturated sodium bicarbonate. Methylene chloride was added and the organic layer was washed, dried over sodium sulfate and concentrated. Column chromatography (2 to 1 ethyl acetate / hexanes) provided the desired product (3.0 g, 78%). 1 H NMR (400 MHz, CDCl 3) d 8.65 (d, 1 H), 7.8 (m, 1 H), 7.2 (d, 1 H), 4.7 (s, 2 H).

Part B: Compound 413A (500 mg, 2.7 mmol) was dissolved in methylene chloride (5 mL) and cooled in an ice bath. Thionyl chloride (480 mg, 4.05 mmol) was added dropwise and stirred at room temperature for 3 hours. The reaction was quenched with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated to provide the desired product (510 mg, 92%). Part C: Compound 413B (255 mg, 1.25 mmol) was dissolved in DMF (8 mL) and cesium carbonate (812 mg, 2.5 mmol) and pyrrolidine (108 mg, 1.5 mmol) were added. The reaction mixture was stirred at 80 ° C for one hour. The reaction was diluted with ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated to provide the desired product (250 mg, 81%). 1 H NMR (400 MHz, CDCl 3) d 8.6 (d, 1 H), 7.8 (m, 1 H), 7.35 (d, 1H), 3.75 (s, 2H), 2.55 (m, 2H), 1.8 (m, 2H). Part D: Compound 401 (100 mg, 0.334 mmol), 413C (104 mg, 0.43 mmol), Pd (PPh3) 2 Cl2 (15 mg, 0.021 mmol), Cul (8 mg, 0.041 mmol), diisopropylamine (0.1 mL) and DMF (1 mL) were stirred overnight at 80 ° C. The solvent was evaporated and the residue was washed with ethyl acetate and water. The remaining residue was purified by reverse phase HPLC to provide the desired product (50 mg, 32%). HPLC-MS t R = 0.981 min (UV254 nm); dough calculated for the formula C25H25N5O 459.50, LCMS observed m / z 460.2 (M + H).

EXAMPLE 414 Part A: Compound 414 (1.0 g, 5.46 mmol) was suspended in diethyl ether (30 mL) and cooled to -78 ° C. Titanium (IV) isopropoxide (1.7 mL, 6.01 mmol) was added dropwise and stirred for 5 minutes. Ethyl magnesium bromide (3M in diethyl ether, 4.0 mL) was added dropwise and stirred for 30 minutes at the same temperature and for 1 hour at room temperature. Boron trifluoride diethrate (1.55 g, 10.92 mmol) was added dropwise and the reaction was stirred for 2 hours. The reaction was quenched with 1 M hydrochloric acid and the aqueous layer was washed with diethyl ether. The aqueous layer was basified (pH = 10) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Chromatography in column (1: 1 hexanes / ethyl acetate) provided the desired product (350 mg, 30%). 1 H NMR (400 MHz, CDCl 3) d 8.5 (d, 1 H), 7.7 (m, 1 H), 7.3 (d, 1 H), 1.25 (m, 2 H), 1.15 (m, 2 H). Part B: See Example 413, Part D for a similar experiment. HPLC-MS t R = 0.85 min (UV25 nm); mass calculated for the formula C23H21N5O 431.44, LCMS observed m / z 432.1 (M + H).

EXAMPLE 555 Part A: Compound 555B was prepared according to a modification of a process described in WO-9846609. A mixture of 2-hydroxy-4-methylpyridine 555A (1.50 g, 13.7 mmol), iodine (3.68 g, 13.7 mmol) and sodium carbonate (3.06 g, 28.9 mmol) in water (70 mL) was heated to 70 ° C. overnight. The mixture was acidified with concentrated HCl to pH = 3, and the resulting tan solid residue was washed twice with ethyl acetate and then taken up in hot ethanol. The solid that did not dissolve (by-product diiodo) was removed by filtration and the ethanol filtrate was concentrated to provide the desired product 555B as a white solid (0.67 g, 21%); HPLC-MS t R = 1 min (UV25 nm); mass calculated for the formula C6H6INO 234.95, LCMS observed m / z 236.0.

EXAMPLE 1039 Step 1 mCPBA (3.49 g, 77%, 15.6 mmol) was added to an ice-cooled solution of Compound 1039A (1 g, 3.9 mmol) in CH2Cl2 (19 mL). The reaction sample was allowed to warm to room temperature and stirred overnight. The mixture was diluted with CH2Cl2 and washed consecutively with saturated sodium bicarbonate and brine. The organic solution was dried over MgSO 4, filtered and concentrated. The resulting crude product was purified by sgc (0-50% EtOAc-hexanes gradient) to provide Compound 1039B (787 mg, 70%). Step 2 Compounds 1039B and 400 were converted to Compound 1039 by applying the procedure described for Examples 300A and 300B.

EXAMPLE 1055 1055A 105SB 1055 Step 1 A solution of compound 1055 A (300 mg, 1.28 mmol) in DMF (4.3 mL) was treated with solid cesium carbonate (835 mg, 2.56 mmol) followed by iodomethane (0.09 mL, 218 mg, 1.54 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc, and then washed consecutively with water (3x) and brine. The organic layer was dried over anhydrous MgSO 4, filtered, and concentrated. The residue was purified by sgc (0-50% EtOAc-hexanes gradient) to provide Compound 1055B (150 mg). Step 2 Compounds 1055B and 400 were converted to Compound 1055 by applying the procedure described for Examples 300A and 300B. Compounds 1046, 1050, 1057, 1058, and 1059 were prepared using the same procedure as for compound 1055.

EXAMPLE 1061 1061A 1061B 1061 Step 1 Compound 1061 A (620 mg, 3.02 mmol) was dissolved in methanol (30 mL) and the solution was cooled to 0 ° C. Solid sodium borohydride (230 mg, 6.04 mmol) was added in small portions. The resulting cloudy reaction mixture was stirred at 0 ° C for 40 minutes. The reaction was quenched by dropwise addition of glacial acetic acid (0.4 mL). The solvents were removed under reduced pressure and the resulting white solid was partitioned between EtOAc (100 mL) and water (50 mL). The aqueous layer was extracted once more with EtOAc (-25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous MgSO, filtered and concentrated to provide a colorless oil. The crude product was purified by sgc (10-40% EtOAc-hexanes gradient) to provide Compound 1061 B (591 mg, 95%) as a clear, colorless oil.

Step 2: Compounds 1061B and 400 were converted to Compound 1061 by application of the procedure described for Examples 300A and 300B. The same procedure was used for the preparation of Compounds 1075, 1078 and 1079.

EXAMPLE 1070 1070A 1070B 1061 Step 1 HCl (17 mL, 4 M in dioxane, 68 mmol) was added to an ice-cooled solution of Compound 1070A in CH2Cl2 (27 mL). The reaction mixture was stirred at 0 ° C for 30 minutes, and at room temperature for 18 hours. The solvent was concentrated to dryness to provide Compound 1070B as an off-white solid (1.51 g). Step 2 Compounds 1070B and 400 were converted to Compound 1070 by applying the procedure described for Examples 300A and 300B EXAMPLE 1071 1071A 1071B 1071 Step 1: Net bromine (1.4 mL, 28 mmol, 1.1 eq) was added dropwise to a stirred solution of Compound 1071 A (3.0 g, 26 mmol) in dioxane (8 mL) at 0 ° C. Upon completion of the addition, the reaction mixture was heated at 60 ° C for 18 hours. The reaction mixture was diluted with Et2O (50 mL), and washed consecutively with saturated aqueous sodium bicarbonate (50 mL) and brine (-50 mL). The organic phase was dried over anhydrous MgSO 4, filtered, and concentrated. The desired product, Compound 1071 B, was separated from the crude product by sgc (0-10% EtOAc-hexanes). Yield: 0.987 g, 15% yield. Step 2 Compounds 1071B and 400 were converted to Compound 1071 by application of the procedure described for Examples 300A and 300B EXAMPLE 1077 1077 A 1077B 1077 Step 1 A solution of Compound 1077A (200 mg, 0.68 mmol) in DMF (3 mL) was treated with sodium hydride (41 mg, 60% dispersion in oil, 0.82 mmol) followed by iodomethane (0.05 mL, 117 mmol) . The reaction mixture was stirred for 3 days. The reaction mixture was diluted with EtOAc and washed consecutively with water and brine. The organic layer was dried over MgSO 4, filtered and concentrated to dryness to provide an intermediate (191 mg). This intermediate was re-dissolved in CH2Cl2 and treated with a solution of HCl (0.78 mL). The solution was stirred at room temperature overnight, then concentrated to provide the desired product (152 mg, 100% yield (HCl salt)), which was used without further purification. Step 2 Compounds 1077B and 400 were converted to Compound 1077A by application of the procedure described for Examples 300A and 300B EXAMPLE 1080 1080 to 1080B 1080 Net bromine (0.8 mL, 24 mmol, 0.9 eq) was added dropwise over -20 min to a stirred solution of Compound 1080A (2.00 g, 0.026 mmol) in carbon tetrachloride (4 mL) at 0 ° C. Upon completion of the addition, the reaction mixture was heated at 60 ° C for 18 hours. The reaction mixture was diluted with Et2O (50 mL), and washed consecutively with saturated aqueous sodium bicarbonate (50 mL) and brine (-50 mL). The organic phase was dried over anhydrous MgSO 4, filtered, and concentrated. The desired product 1080B was purified by sgc (100% hexanes, isocratic) to provide Compound 1080B as a clear, colorless liquid (1.78 g, 53%) Step 2 Compounds 1080B and 400 were converted to Compound 1080 by application of the procedure described for Examples 300A and 300B EXAMPLE 1081 1081A 1081B 1081 Step 1 A pressure tube containing a mixture of Compound 1081 A (500 mg, 2.7 mmol), hydroxylamine hydrochloride (375 mg, 5.40 mmol), and sodium acetate (443 g, 5.6 mmol) in absolute ethanol (10 mL) ) was heated with stirring at 80 ° C for 18 hours. The mixture was allowed to cool after which the solvent was removed. The residue was redissolved in EtOAc, and then washed with water and brine. The organic layer was dried over anhydrous MgSO 4, filtered and concentrated. The product was purified by PTLC (5% EtOAc-hexanes) to provide Compound 1081 B (504 mg, 93%). Step 2 Compounds 1081B and 400 were converted to Compound 1081 by application of the procedure described for Examples 300A and 300B. Analogous procedures were used for the preparation of Compounds 1082, 1083, 1084, 1085, 1086, 1089, 1090, and 1091.

EXAMPLE 1095 Step 1 A solution of Compound 1095A in DMF (2 mL) was treated consecutively with sodium hydride (28 mg, 60% dispersion in oil, 0.70 mmol) and iodomethane (0.04 mL, 80 mg, 0.56 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was quenched with water, diluted with EtOAc, and washed consecutively with water and brine. The organic phase was dried over anhydrous MgSO 4, filtered and concentrated to provide crude Compound 1095B (37 mg, 68%), which was used without further purification.

Step 2 Compounds 1095B and 400 were converted to Compound 1095 by application of the procedure described for Examples 300A and 300B EXAMPLE 973 973A 973B CHJCIJ Et-N / D AP Stage 1 962 973 Step 1 To a solution of 973A (320 mg, 1.62 mmol) in CH2Cl2 (10 mL) at room temperature was added E.3N (0.45 mL, 3.2 mmol), 973B (375 mg, 1.78 mmol) and DMAP (cat.) . After 30 minutes, the The solvent and the crude material was purified by column chromatography (SiO2, 40% EtOAc / Hexanes) to give 973C (520 mg, 43%). Step 2 Compound 400 (100 mg, 0.29 mmol) was combined with Compound 973C (133 mg, 0.34 mmol), Pd (PPh 3) 2 Cl 2 (2.2 mg, 0.003 mmol), Cul (5.5 mg, 0.03 mmol), diisopropylamine (0.05 mmol). mL, 0.36 mmol) in DMF (1 mL) was stirred overnight at 85 ° C. The reaction mixture was concentrated and the crude material was purified with TLC plates (SiO2, 10% 7N NH3 in methanol / CH2Cl2) which yielded the desired product 973D (20 mg, 15%) and 973E (20 mg, 14% ). Step 3 Compound 973D (20 mg, 0.042 mmol) was dissolved in 7 M NH 3 in a MeOH solution (2 mL) and stirred in a sealed tube under pressure at 90 ° C overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was purified with preparative TLC (SiO2, 10% 7N NH3 in methanol / CH2Cl2) which gave the desired product 962 (12 mg, 67%). Step 4 Compound 973E (20 mg, 0.04 mmol) was dissolved in a 7 M ammonia solution (2 mL) and stirred in a sealed tube under pressure at 90 ° C overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative TLC (SiO2, % 7N NH 3 in methanol / CH 2 Cl 2) to provide the desired 973 product (12 mg, 60%).

EXAMPLE 1221 Compound 1221A (1.0 g, 4.22 mmol), cyclopropyl boronic acid (326 mg, 3.80 mmol) and [PdCI2 (dppf)] CH2Cl2 (150, 0.21 mmol) in CH3CN (15 mL) was treated with potassium carbonate (5 mL , 5 mmoles, 1 M in H2O). The mixture was subjected to vacuum and replenished three with Nitrogen. The reaction mixture was stirred at 80 ° C (oil bath) for 3 days. Additional [PdCI2 (dppf)] CH2CI2 (150 mg) was added on the second day. After cooling, the water layer was separated and extracted once with EtOAc (20 mL). The organic layers were combined, filtered through a pad of Celite, and concentrated. The product was purified by silica gel chromatography (Hexane / EtOAc, 1: 0 to 10: 1 to 5: 1) to provide compound 1221B (280 mg, 33.5%) EXAMPLE 1250 1250A 1250B Compound 1250 A (5.0 g, 20.3 mmol) was dissolved in thionyl chloride (40 mL) and stirred at reflux for two hours. After cooling, the thionyl chloride was removed with a rotary evaporator. The residue was dissolved in CH2Cl2 and added to NH3-H2O (50 mL conc.) Slowly with stirring. The solid was collected by filtration, washed with water, dried in vacuo overnight to provide Compound 1250B.

EXAMPLE 1251 Step 1 Compound 1251A (2.0 g), MeOH (20 mL), and H2SO4 (conc., 2 mL) were stirred at room temperature for three days. Hexane (50 mL) was added. The organic layer was washed with water, dried over Na 2 SO 4, concentrated by rotary evaporator. The product was purified by sgc (Hexane / EtOAc 10: 1) to provide compound 1251 B (1219 g) Step 2 Compound 1251B (1219 g, 5.32 mmol) was dissolved in CCI4 (30 mL). NBS (947 mg, 5.32 mmol) and benzoyl peroxide (66 mg, 0.27 mmol) were added. The solution was stirred at 85 ° C for 2 hours. After cooling, the solid was filtered and the organic layer was washed with water (10 mL). The organic layer was dried over Na 2 SO 4, concentrated by rotary evaporator, dried in vacuo. The residue was then dissolved in NH3-MeOH (7N, 10 mL) and transferred to a 75 mL pressure bottle. The solution was stirred at 90 ° C overnight. The product was purified by C18 chromatography (CH3CN / water: 5% to 90%, with addition of 0.1% HCO2H) to provide compound 1251C (800 mg, 71%).

EXAMPLE 1254 1254A 1254B Compound 1254A (5.0 g, 17.61 mmol), 4-pyridine boronic acid (2.06 g, 16.73 mmol), and Pd (dppf) CI2-CH2Cl2 (644 mg, 0.88 mmol) were placed in a 500 mL flask. The vial was emptied for 1 minute and then It was filled with N2. This procedure was repeated twice. CH3CN (200 mL) and K2CO3 (1 M, 100 mL) were added. The solution was stirred at 35 ° C for two days. On the second day additional Pd (dppf) CI2-CH2CI2 (400 mg) was added. The aqueous layer was separated and extracted with EtOAc (50 mL) once. The organic layers were combined, washed with brine (100 mL) and dried over Na2SO4. The solution was concentrated and purified by sgc (Hexane / EtOAc 3: 1 to 2: 1) to provide compound 1254B (3.1g, 74.9%).

EXAMPLE 1256 Compound 1256A (5.00 g, 20.3 mmol), KCN was placed (1.59 g, 24.4 mmoles), and (NH) 2CO3 (7.80 g, 81.3 mmoles) in a 150 mL pressure bottle. EtOH (30 mL) and water (30 mL) were added. The bottle was sealed and stirred at 80 ° C in an oil bath overnight. A white solid appeared. After cooling, 30 mL of water was added and the solid was collected by filtration. The solid was washed with water (20 mL) twice, dried under vacuum at 50 ° C overnight to provide compound 1256B (6.18 g, 96.2%).

EXAMPLE 1555 1555A 1555B Compound 1555A (1.0 g, 3.16 mmol) was dissolved in anhydrous DMF (20 mL). Methyl iodide (0.236 mL, 3.80 mL) and DIPEA (1.1 mL, 6.32 mL) were added and the solution was stirred at room temperature for 2 days. More methyl iodide (0.472 mL, 7.6 mL) was added on the second day. The solvent was removed by rotary evaporator. The product was purified by sgc (Hexane / EtOAc: 3: 1 to 1: 1) to provide compound 1555B (766 mg, 73.4%).

EXAMPLE 1566 1566A 1566B Compound 1566A (200 mg, 1.02 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 459 μL, 3.06 mmol) were dissolved in DMF (2 mL) in a two-neck flask. The mixture was subjected to vacuum and the atmosphere was filled with CO2 supplied by the evaporation of dry ice at 23 ° C in a separate flask through the vacuum adapter. The mixture was left under stirring at 23 ° C overnight and the CO2 atmosphere was gradually allowed to escape through a hole in a septum. The solvent was removed and the remaining yellow oil was redissolved in THF (2 mL). 2M HCl (5 mL) was added dropwise with stirring. A cloudy white precipitate formed which was briefly sonicated. The solid was filtered, washed with THF (10 mL), and dried under reduced pressure to provide compound 1566B (206.3 mg, 84.0%) as a white solid.

EXAMPLE 925 Stage! Compound 401 (130 mg, 0.43 mmol) was combined with compound 925B (112 mg, 0.52 mmol), Pd (PPh 3) 2 Cl 2 (6 mg, 0.009 mmol), Cul (12 mg, 0.06 mmol), diisopropylamine (0.1 mL). , 0.71 mmole) in DMF (1 mL) and stirred at 85 ° C for 2 hours. The reaction mixture is purified on Gilson reverse phase HPLC (0-40% acetonitrile with 0.01% Formic acid in H2O with 0.01% formic acid) which yielded the desired 924 product (107 mg, 57%). Step 2. Compound 924 (100 mg, 0.23 mmol) was stirred in MeOH (5 mL) and LiOH (1 N, aq., 5 mL) was added. The reaction was stirred at room temperature for 2 hours. The solvent was removed and the crude material was purified by Gilson reverse phase HPLC (0-40% acetonitrile in H2O with 0.1% formic acid) which yielded the desired product 925 (40 mg, 41%).

EXAMPLE 2000 Step 1 To a solution of 2000A (1 g, 4.6 mmol) in EtOH (12 mL) was added hydrazine (0.22 mL, 6.9 mmol) at 25 ° C and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled to 0 ° C and the resulting precipitate was filtered and washed with cold EtOH to provide 2000B (0.86 g, 86% yield). Stage 2 To a suspension of 2000B (300 mg, 1.39 mmol) and triethylamine (0.39 mL, 2.78 mmol) in CH2Cl2 (9 mL) was added acetic anhydride (0.15 mL, 1.53 mmol) at 25 ° C. After stirring at the temperature for 1.5 hours, the mixture was poured into cold water and the resulting precipitate was collected by filtration. The white solid was washed with water and dried under reduced pressure to provide 2000C (323 mg, 90% yield). Step 3 A suspension of 2000C (120 mg, 0.47 mmol) in CH 3 CN (3 mL) and CH 2 Cl 2 (3 mL) was treated with triethylamine (0.39 mL, 2.82 mmol) and TsCI (94 mg, 0.49 mmol) at 25 ° C. The mixture was stirred at the temperature for 5 hours and added to a solution of aqueous NaHC 3. The organic layers were extracted with CH2Cl2 and the combined organic solution was washed with a brine solution, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by SiO2 column chromatography (0 to 5% MeOH in CH2Cl2) to provide 2000D (80 mg, 71% yield). Step 4 A suspension of 2000B (100 mg, 0.46 mmol) in MeOH (3 mL) and 1,4-dioxane (1.5 mL) was treated with BrCN (3 M solution in CH2Cl2, 0.17 mL, 0.51 mmol) per drop to 25 mL. ° C. After stirring for 1 hour at that At room temperature, NaHCO3 (80 mg, 0.95 mmol) was added and the resulting suspension was stirred for 18 hours. The white precipitate formed was filtered, washed with water and dried in air to provide 2000E (95 mg, 86% yield). Step 5 A suspension of 2000B (100 mg, 0.46 mmol) in CH2Cl2 (6 mL) was treated with ethyl isocyanate (0.04 mL, 0.50 mmol) at 0 ° C and the mixture was stirred at 25 ° C for 6 hours. To this suspension, triethylamine (0.32 mL, 2.2 mmol) and TsCI (95 mg, 0.50 mmol) were added and the mixture was added. stirred at the temperature for 18 hours followed by addition to an aqueous solution of NaHCO3. The organic layers were extracted with CH2Cl2 and the combined organic solution was washed with a brine solution, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 column chromatography (0 to 5% MeOH in CH2Cl2) to provide 2000F (102 mg, 82% yield).

EXAMPLE 2001 jp. MeOzC 2001 A 2001 B 2001C Stage 2 400 2001E Etapal A solution of 2001A (11.7 g, 48 mmol) and 2001B (10.3 g, 40 mmol) in THF (400 mL) was cooled to -7 ~ 8 ° C treated with NaH (dispersion at 60%, 6 g, 150 mmol) per parts. The mixture was stirred for 2 hours at the temperature and quenched by slow addition of acetic acid (15 mL). The mixture was poured into a mixture of cold aqueous NaHC 3 solution and EtOAc.

After stirring for 0.5 hours, the organic layers were extracted with EtOAc and the combined organic solution was washed with a brine solution, dried (Na2SO4), and concentrated in vacuo. The oily residue was solidified in EtOAc / hexane (1: 1 mixture) to provide racemic 2001 C (8.5 g) as a white solid after filtration. The filtrate was concentrated and the residue was purified by SiO2 column chromatography.

(EtOAc: hexane = 1: 2) to provide 2001 C (1.5 g, combined yield 60%). The active chiral isomer 2001 C (0.32 g of racemic 0.8 g per charge) was obtained by HPLC separation using a preparative chiral OD column (EtOH: hexane = 1: 4). Step 2 A solution of 2001 C (3 g, 7.16 mmol) in THF (30 mL) was treated with TBAF (1 M solution in THF, 10 mL, 10 mmol) at 0 ° C. The mixture was stirred for 1.5 hours at room temperature and poured into a mixture of ice water and EtOAc. The organic layers were extracted with EtOAc and the combined organic solution was washed with brine solution, dried (Na2SO), and concentrated in vacuo to provide 400 crude. The 400 crude oil was placed in a pressure vessel and dissolved in ammonia in MeOH (7 N solution, 60 mL). The solution was heated at 80 ° C for 14 hours and cooled to 25 ° C followed by concentration. The residue was treated with CH2Cl2 in an ice bath and the resulting solid was filtered to give 2001 E (1.38 g) and the filtrate was concentrated and the residue was solidified in CH2Cl2 and hexane to provide 2001 E (0.24 g, 76% yield). combined performance).

EXAMPLE 2002 Etapal A mixture of 2001 E (52 mg, 0.17 mmol), 2000 F (68 mg, 0.26 mmol), Pd (PPh 3) 2 Cl 2 (2.4 mg, 3.4 μmol), Cul (3.2 mg, 17 μmol), and diisopropylethylamine (65 μL) , 0.37 mmole) in DMF (1.5 ml) was purged with N2 and heated to 70 ° C. After heating for 17 hours, the mixture was cooled to 25 ° C and purified by column chromatography on a reverse phase C-18 column (0.01% HCO2H in water / 0.01% HCO2H in CH3CN) to provide compound 1502 ( 47 mg, 57% yield).

EXAMPLE 2003 Compound 2003A (400 mg, 2.0 mmol) was dissolved in 10 mL of THF and reacted with sodium methoxide (4 mL, 2.0 mmol). After 30 minutes, iodomethane (0.5 mL, 8.0 mmol) was added. The reaction mixture was stirred for 4 hours at room temperature and then added to ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. All the organic layers were combined, washed with a brine solution and dried over sodium sulfate. The solvent was removed by rotary evaporator and further purified by SiO2 column chromatography to provide 2003B (105 mg, 25% yield), 2003C (110 mg, 26% yield) and 2003D (106 mg, 25% yield) .

EXAMPLE 2004 Compound 2004A (1 g, 5.07 mmol) was dissolved in 20 mL of THF and reacted with sodium methoxide (10 mL, 5.07 mmol). After 30 minutes, iodomethane (1.3 mL, 20.3 mmol) was added. The reaction mixture was stirred for 5 hours at room temperature and then added to ethyl acetate and water. The aqueous layer was extracted with ethyl acetate twice. All the organic layers were combined, washed with a brine solution and dried over sodium sulfate. The solvent was removed by rotary evaporator and further purified by SiO2 column chromatography to provide 2004B (470 mg, 44% yield) and 2004C (450 mg, 42% yield).

EXAMPLE 2005 Compound 2005A (400 mg, 2.03 mmol) was dissolved in 10 mL of THF and reacted with sodium methoxide (4 mL, 2.03 mmol). After 30 minutes, iodomethane (0.5 mL, 8.12 mmol) was added. The reaction mixture was stirred for 3 hours at room temperature and then added to ethyl acetate and water. The aqueous layer was extracted with ethyl acetate twice. All the organic layers were combined, washed with a brine solution and dried over sodium sulfate. The solvent is stirred by rotary evaporator and further purified by SiO2 column chromatography to provide 2005B (200 mg, 47% yield), 2005C (150 mg, 35% yield).

EXAMPLE 2007 Compound 2007A (200 mg, 1.01 mmol) was dissolved in 10 mL of CH2Cl2 and reacted with DIPEA (0.5 mL, 3.04 mmol), followed by addition of MEMCI (0.15 mL, 1.31 mmol). The reaction mixture was stirred for 5 hours at room temperature and then added to an aqueous solution of CH2Cl2 and sodium bicarbonate. The organic layers were extracted with CH2CI2, combined and dried over sodium sulfate. The solvent was removed by rotary evaporator to provide compound 2007B (205 mg, 71% yield).

EXAMPLE 2008 Compound 2008A (200 mg, 1.02 mmol) was dissolved in 10 mL of CH2Cl2 and reacted with DIPEA (0.53 mL, 3.03 mmol), followed by addition of MEMCI (0.15 mL, 1.31 mmol). The reaction mixture was stirred for 16 hours at room temperature and then added to an aqueous solution of sodium bicarbonate and CH2Cl2. The organic layers were extracted with CH2CI2, combined and dried over sodium sulfate. The solvent was removed by rotary evaporator to provide compound 2008B (210 mg, 72% yield).

EXAMPLE 2009 Compound 2009A (20 mg, 0.04 mmol) was stirred in 2 mL of MeOH-CH 2 Cl 2 (1: 1 mixture) and reacted with trifluoroacetic acid (0.4 ml). The reaction mixture was stirred for 3 days at room temperature and then at 40 ° C for 20 hours. The solvent was removed by rotary evaporator and the residue was purified by preparative TLC to provide compound 1522 (2 mg, yield 12%).

EXAMPLE 943 to 6 Step 1. 943A (0.35 g, 2.35 mmol) was treated in 5 mL of NMP with CS2CO3 (1.15 g, 3.5 mmol). The flask was equipped with an ice-cold acetone trap and difluor chlorine methane gas was bubbled in for 2 hours. To another portion of Cs2CO3 (2.68 g, 8.2 mmol) was added excess difluor chlorine methane gas which was allowed to bubble before stopping the bubbling, and the reaction was stirred overnight. To another portion of Cs 2 CO 3 (2.68 g, 8.2 mmoles) was added added difluor chlorine methane gas in excess which was allowed to bubble and the reaction was stirred at room temperature for 3 hours. The reaction was diluted with 15 mL of CH2Cl2 and washed with water (2x15 mL) and brine (1x15 mL). The organics were dried and concentrated to provide a crude which was purified by preparative silica gel plate using 3: 1 ethyl acetate: hexane to provide 230 mg of the pure product 943B. Step 2. Compound 943B (600 mg, 3.01 mmol) was dissolved in THF (40 mL) and DMPU (6 mL) and potassium r -butoxide (406 mg, 3.61 mmol) were added and stirred at room temperature for 2 hours. hours. Chloride pivalate (0.656 mL, 4.52 mmol) was added dropwise and stirred at room temperature for 2 hours. The reaction was quenched with NH CI-H2O and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were dried and concentrated to provide a crude which was purified by preparative silica gel chromatography using 1: 3 ethyl acetate: hexane to provide 700 mg of the pure product 943C. Step 3. Compound 943C (1.4 g, 4.47 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to 0 ° C. TMS bromide (1.13 mL, 8.58 mmol) was added dropwise. The reaction was stirred at 0 ° C for 2 hours and then slowly warmed to room temperature. The solvent was removed and dried under vacuum to provide compound 943D (1.2g, 92%). Step 4. Compound 308 (1.05 g, 4.3 mmole) and compound 943D (1.1 g, 3.76 mmol) were dissolved in THF (40 mL) and cooled to -30 ° C. NaH (518 mg, 12.95 mmol) was added in portions and the reaction mixture was stirred for 2 hours at -12 ° C. Acetic acid was added slowly and the 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, brine, dried over sodium sulfate, and concentrated. Purification by column chromatography (SiO2, 30% ethyl acetate / hexanes to 50% ethyl acetate / hexanes) provided the desired product 943E (1.3 g, 76%). Step 5 The two isomers were separated using a chiral AD column. One gram of material was injected into the column and the two peaks were separated using a solvent mixture consisting of 90% hexanes / 2-propanol. The first isomer was the desired compound 943F (400 mg, 80%). Step 6: Compound 943F (450 mg, 1 mmol) was dissolved in THF (10 mL) and cooled to 0 ° C. Tetrabutylammonium fluoride (1 M in THF, 1.5 mL, 1.5 mmol) was added dropwise and the reaction was stirred for 20 minutes at 0 ° C. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to provide compound 943G (380 g, 99%). The product was used without purification. Step 7 Compound 943G (50 mg, 0.13 mmol) was combined with 3-iodopyridine (40 mg, 2.0 mmol), Pd (PPh 3) 2 Cl 2 (1 mg, cat.), Cul (2.5 mg, cat.), Diisopropylamine ( 0.04 mL, 0.29 mmol) in DMF (5 mL) and stirred at 70 ° C for 1 hour. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, 66% EtOAc / Hexanes) gave the desired product 943H (46 mg, 77%). Step 8. Compound 943H (46 mg, 0.1 mmol) was dissolved in a 7 M ammonia solution (2 mL) and stirred in a closed tube under pressure at 90 ° C overnight. The reaction mixture was cooled to room temperature and concentrated. The crude material was treated with EtOEt and the solid was collected by suction filtration to provide compound 943 (28 mg, 68%).

EXAMPLE 2014 Q 2014G Etapal A solution of 2001 A (515 mg, 2.12 mmol) and 2014A (730 mg, 2.54 mmol) in THF (15 mL) was cooled to -5 ° C and treated with NaH (dispersion at 60%, 370 mg, 9.25 mmoles) per portions. The mixture was stirred for 8 hours at the temperature and poured into the mixture of cold aqueous NH 4 Cl solution and EtOAc. After stirring for 0.5 h, the organic layers were extracted with EtOAc and the combined organic solution was washed with a brine solution, dried (Na2SO), and concentrated in vacuo. The residue was purified by SiO2 column chromatography (1 to 7% MeOH in CH2Cl2) to provide 2014B (600 mg, 72% yield). Step 2 A solution of 2014B (600 mg, 1.51 mmol) in THF (10 mL) was treated with TBAF (1 M solution in THF, 1.8 mL, 1.8 mmol) at 0 ° C. The mixture was stirred for 3 hours at room temperature and poured into a mixture of ice water and EtOAc. The organic layers were extracted with EtOAc and the combined organic solution was washed with a brine solution, dried (Na2SO), and concentrated in vacuo. The residue was purified by SiO2 column chromatography (30% EtOAc in hexane) to provide 2014C (329 mg, 73% yield). Step 3 A mixture of 2014C (168 mg, 0.56 mmol), 2005C (124 mg, 0.58 mmol), Pd (PPh3) 2CI2 (4.0 mg, 6 μmol), Cul (21 mg, 110 μmol), and diisopropylethylamine (0.39 mL) , 0.24 mmole) in DMF (4 ml) was purged with N2 and it was heated to 70 ° C. After heating for 17 h, the mixture was cooled to 25 ° C and then the mixture was poured into ice water. The organic layers were extracted with EtOAc and the combined organic solution was washed with brine solution, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 column chromatography (1 to 5% MeOH in CH2Cl2) to provide racemic 2014D (183 mg, 76% yield). The active enantiomer of 2014D was separated by chiral HPLC on a chiral OD column (IPA / hexane = 1: 3) to provide the active isomer 2014D (50 mg). Stage 4 2014D (49 mg, 0.11 mmol) was placed in a vessel under pressure and dissolved in ammonia in MeOH (7 N solution, 7 mL). The solution was heated at 80 ° C for 18 h and cooled to 25 ° C followed by concentration. The residue was purified by preparative TLC (7% MeOH in CH 2 Cl 2) to provide hydantoin 2014E (not shown, 35 mg, yield 84%). The 2014E (34 mg, 0.089 mmol) was dissolved in 10% MeOH in CH2Cl2 (3 mL) and treated with 4 N HCl in dioxane (0.3 mL). The mixture was stirred at 25 ° C for 18 hours and concentrated in vacuo to provide 2014F (34 mg, quant.). Step 5 A mixture of 2014F (18 mg, 0.055 mmol), 2014G (18 mg, 0. 06 mmole), and diisopropylethylamine (48 μL, 0.28 mmole) in DMF (0.5 mL) was heated at 60 ° C. The mixture was stirred for 16 hours at the temperature and concentrated in vacuo. The residue was dissolved in EtOAc and washed with water, brine solution, dried (Na2SO), and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH in CH 2 Cl 2) to provide 1533 (7 mg, 28% yield).

EXAMPLE 2015 Step 1 A solution of 2014B (193 mg, 0.52 mmol) in CH2Cl2 (3 mL) was treated with trifluoroacetic acid (0.3 mL) at 25 ° C. The mixture was stirred for 2 hours at the temperature and concentrated in vacuo to provide 2015A (280 mg, quant.). Stage 2 A mixture of 2015A (580 mg, 1.2 mmol), 2015B (435 mg, 1. 22 mmol), and diisopropylethylamine (0.85 mL, 4.88 mmol) in DMF (7 mL) was heated at 80 ° C. The mixture was stirred for 48 hours at the temperature and concentrated in vacuo. The residue was dissolved in EtOAc and washed with water, brine solution, dried (Na2SO), and concentrated in vacuo. The residue was purified by SiO2 column chromatography (0 to 5% MeOH in CH2Cl2) to provide racemic 2015C (180 mg, 28% yield). The active enantiomer of 2015C was separated by chiral HPLC on a chiral OD column (IPA / hexane = 1: 3) to provide the active isomer 2015C (68 mg). Step 3 A solution of 2015C (68 mg, 0.12 mmol) in THF (2 mL) was treated with TBAF (1 M solution in THF, 0.16 mL, 0.16 mmol) at 0 ° C. The mixture was stirred for 1.5 hours at the temperature and poured into a mixture of ice water and EtOAc. The organic layers were extracted with EtOAc and the combined organic solution was washed with a brine solution, dried (Na2SO), and concentrated in vacuo to provide the desilylated compound after column separation with S¡O2 (0 to 5%). of MeOH in CH2Cl2). The desilylated compound (48 mg, 0.098 mmol) was placed in a vessel under pressure and dissolved in ammonia in MeOH (7 N solution, 10 mL). The solution was heated at 70 ° C for 18 hours and cooled to 25 ° C followed by concentration to provide crude 2015D (39 mg, 82% yield in 2 steps). Step 4 A mixture of 2015D (39 mg, 0.089 mmol), 3-iodopyridine (37 mg, 0.18 mmol), Pd (PPh3) 2 Cl2 (1.4 mg, 9 μmol), Cul (1.4 mg, 2 Dmol), and diisopropylethylamine ( 0.027 mL, 0.20 mmol) in DMF (1 mL) was purged with N2 and heated to 70 ° C. After heating for 3 hours, the mixture was cooled at 25 ° C and purified by column chromatography on a reverse phase C-18 column (0.01% HCO2H in water / 0.01% HCO2H in CH3CN) to provide 1534 (27 mg, 59% yield).

EXAMPLE 2016 °? Yw - «= • Xy8F > "_ =. < J CT" ~ M.O? 8F, H OH Br 2016A 2016B 2016C 2016D Step 1 To a suspension of 2016A (1.46 g, 9.73 mmol) and K2CO3 (4.03 g, 29.2 mmol) in DMF (35 mL) in a 100 mL, 3-neck flask equipped with dry ice condenser, gas was bubbled CF2CIH and the mixture was heated to 70 ° C. After 16 h of stirring at that temperature, the mixture was cooled to 25 ° C and diluted with EtOAc. The organic solution was washed with water, brine solution, dried (Na2SO), and concentrated in vacuo. The residue was purified by SiO2 column chromatography (CH2Cl2) to provide 2016B (900 mg, 46% yield). Step 2 A suspension of 2016B (428 mg, 2.14 mmol) in water (2.5 mL) was treated with a solution of 1 N NaOH (2.14 mL, 2.14 mmol) and the mixture was stirred at 100 ° C for 2 hours. The mixture was cooled and concentrated in vacuo. The residual solid was dried by azeotropic distillation with toluene and dissolved in DMF (2.5 mL). The solution was treated with iodomethane (0.4 mL, 6.42 mmol) at 25 ° C for 4 hours followed by addition to the ice water. The organic layers were extracted with EtOAc and the combined organic solution was washed with a brine solution, dried (Na2SO) and concentrated in vacuo. The residue was purified by SiO2 column chromatography (CH2Cl2) to give 2016C (326 mg, 66% yield). Stage 3 A solution of 2016C (50 mg, 0.22 mmole) in THF (1 mL) with tribromophosphine (20 μL, 0.22 mmol) at 25 ° C. The reaction mixture was stirred at that temperature for 20 hours and added to an aqueous solution of NaHCO3. The organic layers were extracted with CH2Cl2 and the combined organic solution was washed with a brine solution, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SiO2 column chromatography (CH2Cl2 / hexane = 1: 1) to give 2016D (16 mg, 25% yield).

EXAMPLE 2017 Stage 1 2014C (73 mg, 0.24 mmol) was placed in a vessel under pressure and ammonia dissolved in MeOH (7 N solution, 5 mL). The solution is heated at 80 ° C for 18 hours and cooled to 25 ° C followed by concentration. The residue was purified by SiO2 column chromatography (1 to 10% MeOH in CH2Cl2) to give 2017A (20 mg, 33% yield). Step 2: 2017A (20 mg, 0.08 mmol) in MeOH (2 mL) was treated with 4 N HCl in dioxane (1 mL) at 25 ° C. The mixture was stirred at that temperature for 20 hours and concentrated in vacuo to give crude 2017B (19.6 mg). Stage 3 A mixture of 2017B (19.6 mg, 0.103 mmol), 2016B (37 mg, 0. 12 mmol), and diisopropylethylamine (0.11 mL, 0.6 mmol) in DMF (0.5 mL) was heated at 60 ° C. The mixture was stirred for 48 hours at that temperature and concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH in CH 2 Cl 2) to give 2017C (11 mg, 32% yield).

EXAMPLE 1087 Stage 7 10871 1087 Step 1 Net ethyl chloroformate (12.5 mL, 14.3 g, 132 mmol) was added dropwise in ~ 10 minutes to a stirred, ice-cooled solution of compound 1087A (18.9 g, 125 mmol) and triethylamine (18.2 mL, 13.3 g, 132 mmol) in CH2Cl2 (400 mL). The solution was stirred at 0 ° C for 1.5 h, after which the solvents were removed by evaporation. The resulting liquid was dissolved in EtOAc (-400 mL) and the resulting solution was washed consecutively with water (2 x 100 mL) and brine (-100 mL). The organic layer was dried over anhydrous MgSO 4, filtered, and concentrated to provide compound 1087B in the form of a pale yellow liquid (26.9 g, 96%). Step 2 The transformation of compound 1087B to compound 1087C was carried out following the procedure of Sali and Grunewaid, in Sali, D.J .; Grunewaid, G.L. J. Med. Chem. 1987, 30, 2208-2216. Step 3 The conversion of compound 1087C to compound 1087D was carried out following the procedure given in Example 300A, Step D. Step 4 The conversion of compound 1087D to compound 1087E was carried out following the procedure given in Example 300A, Step E. Step 5 Compounds 1087F (2.45 g, 10.1 mmol) and 1087E (2.86 g, 10.6 mmol) were mixed. Dry THF (80 mL) was added and the resulting solution was cooled to -78 ° C and stirred for 30 minutes. A solution of LHMDS (20 mL, 1 M in THF, 20 mmol) was added dropwise over 15 minutes. The reaction mixture was stirred at -78 ° C for 2 hours. A solution of saturated aqueous ammonium chloride (100 mL) was added to the reaction mixture, followed by EtOAc (250 mL), and the temperature was allowed to rise to room temperature. The organic layer was separated and the layer aqueous was extracted with EtOAc (200 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, and concentrated. The resulting crude product was purified by sgc (10-100% EtOAc-hexane gradient) to provide compound 1087G (2.70 g, 62%) as a beige solid. Steps 6, 7, 8 Compound 1087G was converted to compound 1087 in a three step sequence following the procedure given in Example 300B, Steps D to F.

EXAMPLE 1099 1099G 109SF 1099E Step 7 Compound 1099 was prepared following the procedure given in Example 1087, but from 4-methoxyphenethylamine commercially obtainable (Compound 1099 A) in place of 3-methoxyphenethylamine (Compound 1087A).

EXAMPLE 1570 1570A 1570 Compound 1570A was prepared from Compound 400 and 4-iodobenzoic acid by consecutive application of the procedures given in Parts H and I in Example 400. Solid carbonyl diimidazole (19 mg, 0.12 mmol) was added in one portion. Time to a stirred solution of Compound 1570A in THF (200 μL). The solution was stirred at 70 ° C for 1.5 hours, and allowed to cool subsequently to room temperature. Solid cyclopropanesulfonamide (17 mg) was added consecutively, 0.14 mmole) and DBU (43 μL, 43 mg, 0.29 mmole) and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in DCM (50 mL). The solution was washed consecutively with 0.1N aqueous hydrochloric acid (-25 mL), water (-25 mL) and brine (-25 mL). The organic phase was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an off white solid. The crude product was purified by PTLC (3: 1 EtOAc-hexanes + 1% HCO2H) to provide the Compound 1570 desired (24 mg, yield 48%) as a beige solid. The spectral data of Proton NMR for some of the Compounds are indicated below: Compound 400B 1 H NMR (400 Hz, DMSO-d 6) d D 11.2 (s, 1 H), 8. 8 (s, 1 H), 8.6 (m, 2H), 8.0 (d, 1 H), 7.6 (m, 2H), 7.2 (m, 2H), 4.6 (m, 2H), 4.05 (m, 2H) , 3.8 (s, 3H). Compound 417C. 1 H NMR (400 Hz, DMSO-d 6) d D 12.05 (s, 1 H), 11.14 (s, 1 H), 8.84 (d, J = 1.6 Hz, 1 H), 6.63 (m, 1 H), 7.27 (m , 2H), 7.18 (m, 2H), 6.19 (m, 1 H), 4.59 (dd, J = 6.4 Hz, 16.8 Hz, 2H), 4.02 (m, 2H), 3.80 (s, 3H) Compound 424. 1 H NMR (400 Hz, DMSO-d 6) d D 11.22 (s, 1 H), 8.90 (d, 1 H, J = 1.0 Hz), 8.38 (s, 1 H), 7.72 (m, 2 H), 7.55 (d, 1 H, J = 8.4 Hz), 7.19 (m, 2H), 6.97 (m, 1 H), 4.60 (m, 2H), 4.18 (s, 3H), 4.12 (m, 2H), 3.83 (s, 3H) ). Compound 447. 1 H NMR (400 Hz, DMSO-d 6) d D 8.85 (br s, 1H), 7.02 (br s, 1 H), 7.91-7.88 (m, 2H), 7.77-7.74 (m, 1 H), 7.61 (t, J = 8.20 Hz, 1 H), 7.55 (d, J = 8.53 Hz, 1H), 7.23 - 7.17 (m, 2H), 4.64 - 4.5 (m, 2H), 4. 15 - 4.01 (m, 2H), 3.82 (s, 3H). Compound 494. 1 H NMR (400 Hz, DMSO-d 6) dD 11.2 (s, 1 H), 8. 9 (s, 1 H), 8.7 (bs, 1 H), 7.8 (s, 1 H), 7.5 (d, 1 H), 7.4-7.3 (m, 2H), 7.2-7.1 (m, 2H), 4.5 (dd, 2H, J = 17 Hz, 33 Hz), 4.05 (dd, 2H, J = 14 Hz, 20 Hz), 3.8 (s, 3 H).

Compound 507. 1 H NMR (400 Hz, DMSO-d 6) d D 11.2 (s, 1 H), 8.9 (s, 1 H), 7.8 (d, 1 H), 7.5 (m, 1 H), 7.4 (s, 1 H), 7.2-7.1 (m, 3H), 4.6 (dd, 2H, J = 17 Hz, 26 Hz), 4.05 (dd, 2H, J = 14 Hz, 30 Hz), 3.8 (s, 3H), 3.0 (s, 3H). Compound 554. 1 H NMR (400 Hz, DMSO-d 6) d D 11.27 D (s, 1 H), 8.93 (d, 1 H, J = 1.2 Hz), 7.96 (bs, 2 H) 7.52 (d, 1 H, J = 8.4 Hz ), 7.23 (m, 2H), 1.17 (m, 1H), 4.54 (m, 2H), 4.07 (m, 2H), 3.8 (s, 3H). Compound 555. 1 H NMR (400 Hz, DMSO-d 6) d D 11.73 (s, 1 H), 11.14 (s, 1 H), 8.79 (s, 1 H), 7.54 (m, 2 H), 7.17 (m, 2 H), 6.20 (s, 1H), 4.52 (dd, J = 25.6 Hz, 17.6 Hz, 2H), 4.03 (m, 2H), 3.79 (s, 3H), 2.03 (s, 3H). Compound 516. 1 H NMR (400 MHz, DMSO-d 6) d D 8.91 (s, 1H), 7. 49 (m, 3H), 7.30 (m, 1H), 7.20 (m, 3H), 4.55 (dd, J = 36.8 Hz, 17.2 Hz, 2H), 4.07 (s, 2H), 3.80 (s, 3H). Compound 490.1H NMR (400 MHz, DMSO-d6) d 10.9 (bs, 1H), 8.95 (s, 1H), 7.6 (m, 1H), 7.5 (d, 1H), 7.4 (m, 1H), 7.2- 7.1 (m, 3H), 4.5 (m, 2H), 4.05 (s, 2H), 3.8 (s, 3H). Compound 442. 1 H NMR (400 MHz, DMSO-d 6) 5 D 11.36 (s, 1H), 9.74 (s, 1H), 9.08 (d, 1h, J = 1.7 Hz), 8.66 (d, 1H, J = 6.1 Hz), 8.45 (d, 1H, J = 8.5 Hz), 8.29 d, 1H, J = 6.3 Hz), 8.19 (dd, 1H, J = 0.9, 7.2 Hz), 7.89 (dd, 1H, J = 7.6, 8.2 Hz), 7.55 (d, 1H, J = 8.0 Hz), 7.25 - 7.10 (m, 2H), 4.63 (m, 2H), 4.29 (d, 1H, J = 14.0 Hz), 4.15 (d, 1H, J = 13.9 Hz), 3.82 (s, 3H) Compound 930. 1 H NMR (500 Hz, MeOH-d 4) d D 7.95 (d, 1 H, J D = 4 Hz), 7.67 (dd, 1 H, J = 10 Hz, 1.5 Hz), 7.48 (d, 1H, J = 8.5Hz), 7.33 (d, 1H, J = 2.5 Hz), 7.22 (dd, 1H, J = 2.5Hz, 8.5 Hz), 6.67 ( dd, 1H, J = 8 Hz, 5 Hz), 4.67 (q, 2H, J = 17 Hz), 4.36 (d, 1H, J = 14 Hz), 4.15 (d, 1H, J = 14.5 Hz), 3.88 (s, 3H). Compound 943.? NMR (500Hz, MeOH-d4) d 8.630 (s, 1H), 8.568 (dd, J = 2.0Hz, 5.1Hz, 1H), 7.925 (dt, J = 1.5Hz, 8.2Hz, 1H), 7.648 (d, J = 8.8Hz, 1H), 7.57 (s, 1H), 7.452 (m, 2H), 6.940 (t, J = 73.1Hz, 1H), 4.731 (dd, J = 16.4Hz, 56.7Hz, 2H), 4.267 (dd, J = 23.1Hz, 14.2Hz, 2H). Compound 960.1H NMR (500Hz, MeOH-d4) d 8,492 (s, 2H), 8,137 (d, J = 2.2Hz, 1H), 7,490 (d, J = 8.5Hz, 1H), 7,337 (d, J = 2.8 Hz, 1H), 7,217 (dd, J = 8.5Hz, 2.5Hz, 1H), 4,673 (dd, J = 55.2Hz, 17.3Hz, 2H), 4,280 (dd, J = 37.8Hz, 14.2Hz, 2H), 3,877 (s, 3H). Compound 972.? NMR (500Hz, MeOH-d4) d 9.319 (s, 1H), 8. 159 (s, 1H), 8.083 (d, J = 8.5Hz, 1H), 7.547 (dd, J = 2.3Hz, 8.6Hz, 1H), 7.482 (d, J = 8.8Hz, 1H), 7.334 (d, J = 2.5Hz, 1H), 7.209 (dd, J = 8.5Hz, 2.5Hz, 1H), 4. 669 (dd, J = 59.9Hz, 16.7Hz, 2H), 4277 (dd, J = 29.6Hz, 14.8Hz, 2H), 3871 (s, 3H). Compound 1003. 1 H NMR (500 MHz, DMSO-d 6) dD 11.32 (s, 1H), 9.01 (s, 1H), 8.59 (d, 1H, J = 4.5 Hz), 8.07 (d, 1H, J = 7.5 Hz), 7.55 (d, 1H, J = 8 Hz), 7.50 (t, 1H, J = 5.5 Hz), 7.21 (m, 2H), 4.62 (d, 1H, J = 17 Hz), 4. 56 (d, 1H, J = 17 Hz), 4.18 (d, 1H, J = 14 Hz), 4.09 (d, 1H, J = 14 Hz), 3.83 (s, 3H), 2.58 (s, 3H). Compound 1256. 1 H NMR (500 MHz, DMSO-d 6) d D 11.23 (s, 1 H), 10.84 (s, 1 H), 8.91 (s, 1 H), 8.66 (s, 1 H), 7.55 (H, J = 8 Hz ), 7.50 (d, 1H, J = 9 Hz), 7.48 (d, 1H, J = 9 Hz), 7.23 (d, 1H, J = 2.5 Hz), 7.20 (dd, 1H, J = 8, 2. 5 Hz), 4.62 (d, 1H, J = 17 Hz), 4.54 (d, 1H, J = 17 Hz), 4.11 (d, 1H, J = 15 Hz), 4.07 (d, 1H, J = 15 Hz ), 3.83 (s, 3H), 1.65 (s, 3H). Compound 1009. 1 H NMR (500 MHz, DMSO-d 6) dD 12.63 (bs, 1H), 11.24 (s, 1H), 8.90 (S, 1H), 8.57 (bs, 1H), 7.55 (d, 1H, J = 8 Hz), 7.40 (bs, 1H), 7.33 (bs, 1H), 7.27 (m, 2H), 7.20 (d, 1H, J = 8.5 Hz), 4.62 (d, 1H, J = 16.5 Hz), 4.56 (d, 1H, J = 16.5 Hz), 4.15 (d, 1H, J = 14.5 Hz), 4.06 (d, 1H, J = 14.5 Hz), 3.84 (s, 3H). Compound 1012. NMR (500 MHz, DMSO-d6) dD 11.27 (s, 1H), 8.94 (s, 1H), 7.89 (s, 1H), 7.79 (d, 1H, J = 8.5 Hz), 7.56 (d, 1H, J = 8.5 Hz), 7.50 (d, 1H, J = 8.5 Hz), 7.26 (d, 1H, J = 2.5 Hz), 7.20 (dd, 1H, J = 9, 2.5 Hz), 4.64 (d, 1H, J = 17.5 Hz), 4.58 (d, 1H, J = 17.5 Hz), 4.18 (d, 1H, J = 14.5 Hz), 4.09 (d, 1H, J = 14.5 Hz), 3.84 (s, 3H). Compound 1253. NMR (500 MHz, DMSO-d6) d 11.27 (s, 1H), 8.95 (s, 1H), 8.72 (s, 1H), 7.67 (d, 1H, J = 8 Hz), 7.63 (s, 1H), 7.55 (d, 1H, J = 8 Hz), 7.53 ( d, 1H, J = 8 Hz), 7.25 (d, 1H, J = 2.5 Hz), 7.20 (dd, 1H, J = 8, 2. 5 Hz), 4.63 (d, 1H, J = 17.5 Hz), 4.56 (d, 1H, J = 17.5 Hz), 4.41 (s, 2H), 4.15 (d, 1H, J = 14 Hz), 4.09 (d, 1H, J = 14 Hz), 3.84 (s, 3H). Compound 1015. 1 H NMR (500 MHz, DMSO-d 6) dD 11.27 (s, 1H), 8.84 (s, 1H), 8.21 (s, 1H), 7.88 (d, 1H, J = 8 Hz), 7.56 (d, 1H, J = 8 Hz), 7.48 (d, 1H, J = 7.5 Hz), 7.25 (d, 1H, J = 2 Hz), 7.20 (dd, 1H, J = 8, 2 Hz), 7.14 (d, 1H, J = 7.5 Hz), 4.65 (d, 1H, J = 17.5 Hz), 4.61 (d, 1H, J = 17.5 Hz), 4.30 (d, 1H, J = 14 Hz), 4.15 (d, 1H, J = 14 Hz), 3.83 (s, 3H).

Compound 1155. 1 H NMR (500 MHz, MeOH-d 6) d D 8.90 (bs, 1H), 8.51 (d of d, 1H, J = 8 Hz, J = 2 Hz), 7.94 (d, 1H, 8 Hz), 7.49 (d, 1H, 9 Hz), 7.31 (d, 1H, J = 2 Hz), 7.23 (d of d, 1H, J = 9 Hz, 2 Hz), 4.69 (d, 1H, J = 17 Hz), 4.60 (d, 1H, J = 17 Hz), 4.35 (d, 1H, J = 14 Hz), 4.22 (d, 1H, 14 Hz), 3.88 (s, 3H). Compound 1152.? NMR (500 MHz, MeOH-d6) dD 7.46-7.51 (m, 3H), 7.31 (s, 1H), 7.20 (d, 1H, J = 9 Hz), 6.66 (bs, 1H), 4.68 (d, 1H , J = 17 Hz), 4.57 (d, 1H, J = 17 Hz), 4.30 (d, 1H, J = 14 Hz), 4.23 (d, 1H, J = 14 Hz), 3.87 (s, 3H). Compound 1129. 1 H NMR (500 MHz, MeOH-d 6) dD 7.67 (s, 1H), 7.51-7.46 (m, 1H), 7.39-7.26 (m, 3H), 7.24-7.13 (m, 2H), 6.46 (s, 1H), 4.74 (d, 1H, J = 17 Hz), 4.61 (d, 1H, J = 17 Hz), 4.25 (s, 2H), 3.88 (s, 3H). Compound 1133. NMR (500 MHz, MeOH-d6) dD 7.90-7.84 (m, 1H), 7.57-7.46 (m, 3H), 7.35-7.32 (m, 1H), 7.25-7.20 (m, 1H), 4.70 (d, 1H, J = 17 Hz), 4.60 (d, 1H, J = 17 Hz), 4.28 (d, 1H, J = 15 Hz), 4.22 (d, 1H, J = 15 Hz), 3.88 (s) , 3H). Compound 1134. 1 H NMR (500 MHz, MeOH-d 6) d D 7.97 (s, 1 H), 7.93-7.88 (m, 1 H), 7.66-7.61 (m, 1 H), 7.52-7.47 (m, 2 H), 7.33 ( s, 1H), 7.24-7.19 (m, 1H), 4.71 (d, 1H, J = 17 Hz), 4.60 (d, 1H, J = 17 Hz), 4.28 (d, 1H, J = 15 Hz), 4.23 (d, 1H, J = 15 Hz), 3.88 (s, 3H). Compound 1136. NMR (500 MHz, MeOH-d6) dD 7.88-7.83 (m, 2H), 7.55-7.45 (m, 3H), 7.34-7.29 (m, 1H), 7.23-7.15 (m, 3H), 4.69 (d, 1H, J = 17 Hz), 4.59 (d, 1H, J = 17 Hz), 4.28 (d, 1H, J = 14 Hz), 4.21 (d, 1H, J = 14 Hz), 3.87 (s, 3H). Compound 1146. 1 H NMR (400 MHz, MeOH-d 6) d D 7.50-7.48 (m, 2 H), 7.42 (d, 2 H, J = 8 Hz), 7.37-7.33 (m, 1 H), 7.30-7.24 (m, 2H), 7.18-7.14 (m, 1H), 5.48 (s, 1H), 4.69 (d, 1H, J = 17 Hz), 4.55 (d, 1H, J = 17Hz), 4.23 (d, 1H, J = 14 Hz), 4.20 (d, 1H, J = 14 Hz), 3.83 (s, 3H). Compound 1132. 1 H NMR (500 MHz, MeOH-d 6) d D 7.47-7.41 (m, 2 H), 7.34-7.28 (m, 2 H), 7.22-7.13 (m, 2 H), 7.10-7.04 (m, 1 H), 6.55-6.52 (m, 1H), 4.73 (d, 1H, J = 17 Hz), 4.60 (d, 1H, J = 17 Hz), 4.30 (d, 1H, J = 15 Hz), 4.27 (d, 1H , J = 15 Hz), 3.86 (s, 3H). Compound 1091.? NMR (500 MHz, CD3OD) dD 8.09 (s, 1H), 7.60 (d, 2H, J = 8 Hz), 7.44-7.51 (m, 3H), 7.33 (d, 1H, J = 2H), 7.22 (dd) , 1H, J = 8 Hz, 2 Hz), 4.70 (d, 1H, J = 17 Hz), 4.59 (d, 1H, J = 17 Hz), 4.27 (d, 1H, J = 14.5 Hz), 4.21 ( d, 1H, J = 14.5 Hz), 3.88 (s, 3H). Compound 1063. 1 H NMR (500 MHz, CD3OD) dD 7.48 (d, 1H, J = 8.5 Hz), 7.33 (d, 1H, J = 2.5 Hz), 7.28 (bs, 1H), 7.20-7.30 (m, 2H), 7.11-7.19 (m, 1H), 4.70 (d, 1H, J = 17 Hz), 4.58 (d, 1H, J = 17 Hz), 4.28 (d, 1H, J = 14.5 Hz), 4.21 (d, 1H, J = 14.5 Hz), 3.88 (s, 3H). Compound 1070. NMR (500 MHz, CD3OD) dD 7.68 (s, 1H), 7.48 (d, 1H, J = 8.5 Hz), 7.32 (d, 1H, J = 2 Hz), 7.22 (dd, 1H, J = 8.5 Hz, 2 Hz), 7.17 (s, 1H), 4.67 (d, 1H, J = 16.5 Hz), 4.57 (d, 1H, J = 16.5 Hz), 4.16-4.28 (m, 4H), 3.88 (s) , 3H).

Compound 1090.? NMR (500 MHz, CD3OD) dD 7.48 (d, 1H, J = 8.5 Hz), 7.33 (d, 1H, J = 2.5 Hz), 7.18-7.23 (m, 3H), 4.69 (d, 1H, J = 17 Hz), 4.57 (d, 1H, J = 17 Hz), 2.24 (d, 1H, J = 14.5 Hz), 2.21 (d, 1H, J = 14.5 Hz), 3.88 (s, 3H). Compound 1092. 1 H NMR (500 MHz, DMSO-d 6) d D 8.80 (s, 1H), 8.62 (bd, 1H, J = 12 Hz), 7.89 (dt, 1H, J = 8.3 Hz, 2 Hz), 7.83 (d, 1H, J = 8.3 Hz), 7.43-7.47 (m, 1H) , 6.91 (dd, 1H, J = 8 Hz, 2.5 Hz), 6.86 (d, 1H, J = 2.5 Hz), 4.14 (d, 1H, J = 13.5 Hz), 4.02 (d, 1H, J = 13.5 Hz ), 3.81 (s, 3H), 3.68-3.74 (m, 1H), 3.60-3.67 (m, 1H), 2.88-3.01 (m, 2H). Compound 1098. 1 H NMR (500 MHz, DMSO-d 6) d D 8.91 (s, 1H), 8.21 (bs, 1H), 7.55 (d, 1H, J = 6 Hz), 7.17-7.26 (m, 2H), 4.63 (d, 1H, J = 17 Hz), 4.57 (d, 1H, J = 17 Hz), 4.17 (d, 1H, J = 13.5 Hz), 4.08 (d, 1H, J = 13.5 Hz), 3.83 (s, 3H), 2.47 (s, 3H). Compound 1069. NMR (500 MHz, CD3OD) dD 7.47 (d, 1H, J = 8.5 Hz), 7.32 (d, 1H, J = 2.5 Hz), 7.21 (dd, 1H, J = 8.5 Hz, 2.5 Hz), 7.15 (dd, 1H, J = 8 Hz, 1 Hz), 7.12 (d, 1H, J = 1 Hz), 7.01 (d, 1H, J = 8 Hz), 4.70 (d, 1H, J = 17 Hz) , 4.59 (d, 1H, J = 17 Hz), 4.26 (d, 1H, J = 14 Hz), 4.20 (d, 1H, J = 14Hz), 3.84 (s, 3H). Compound 1099.? NMR (500 MHz, DMSO-d6) dD 11.2 (s, 1H), 8.83 (s, 1H), 8.71 (s, 1H), 8.66 (bd, 1H, J = 4 Hz), 7.99 (dt, 1H, J = 8 Hz, 2 Hz), 7.52-7.56 (m, 1H), 7.40 (d, 1H, J = 3 Hz), 7.24 (d, 1H, J = 8.5 Hz), 7.08 (dd, 1H, J = 8.5 Hz, 3 Hz), 4.17 (d, 1H, J = 14 Hz), 4.07 (d, 1H, J = 14 Hz), 3.78 (s, 3H), 3.69-3.75 (m, 1H), 3.61-3.67 ( m, 1H), 2.84-2.96 (m, 2H).

Compound 1502. NMR (500 MHz, DMSO-d6) dD 11.31 (s, 1H), 8.98 (s, 1H), 8.71 (s, 1H), 8.01 (m, 2H), 7.56 (d, 1H, J = 8.2 Hz), 7.24 (d, 1H, J = 2.6 Hz), 7.21 (dd, 1H, J = 8.2 Hz, 2.6 Hz), 4.63 (d, 1H, J = 17.1 Hz), 4. 57 (d, 1H, J = 17.1 Hz), 4.16 (d, 1H, J = 13.9 Hz), 4.11 (d, 1H, J = 13.9 Hz), 3.84 (s, 3H), 3.30 (m, 2H), 1.19 (t, 3H, J = 7.2 Hz). Compound 1505. NMR (500 MHz, DMSO-d6) dD 11.25 (s, 1H), 8.93 (s, 1H), 8.76 (s, 1H), 7.69 (s, 1H), 7.56 (d, 1H, J = 8.5 Hz), 7.45 (d, 1H, J = 9.4 Hz), 7.25 (d, 1H, J = 2.6 Hz), 7.21 (dd, 1H, J = 8.5 Hz, 2.6 Hz), 7.13 (dd, 1H, J = 9.4 Hz, 1.6 Hz), 4.63 (d, 1H, J = 17.1 Hz), 4.55 (d, 1H, J = 17.1 Hz), 4.13 (d, 1H, J = 14.2 Hz), 4.08 (d, 1H, J = 14.2 Hz), 3.83 (s, 3H), 2.33 (s, 3H). Compound 1513. NMR (500 MHz, DMSO-d6) d 11.31 (s, 1H), 8.98 (s, 1H), 8.68 (s, 1H), 8.20 (s, 1H), 8.06 (dd, 1H, J = 8.2 Hz, 1.9 Hz), 8.04 (d, 1H, J = 8.2 Hz), 7.78 (brs, 1H), 7.56 (d, 1H, J = 8.5 Hz), 7.24 (d, 1H, J = 2.4 Hz), 7.21 (dd, 1H, J = 8.5 Hz, 2.4 Hz), 4.63 (d, 1H, J = 17.1 Hz), 4.57 (d, 1H, J = 17.1 Hz), 4.17 (d, 1H, J = 13.9 Hz), 4.11 (d, 1H, J = 13.9 Hz), 3.84 (s, 3H). Compound 1519.? NMR (500 MHz, DMSO-d6) dD 11.18 (s, 1H), 8.85 (d, 1H, J = 1.2 Hz), 7.91 (d, 1H, J = 2.6 Hz), 7.55 (d, 1H, J = 8.3 Hz), 7.20 (m, 3H), 4.60 (d, 1H, J = 17.0 Hz), 4.51 (d, 1H, J = 17.0 Hz), 4.05 (s, 2H), 3.83 (s, 3H), 3.42 ( s, 3H), 1.97 (s, 3H). Compound 1520.? NMR (500 MHz, DMSO-d6) dD 11.28 (s, 1H), 8.97 (d, 1H, J = 1.2 Hz), 8.06 (m, 2H), 7.57 (d, 1H, J = 8.5 Hz), 7.41 ( dd, 1H, J = 8.7 Hz, 1.6 Hz), 7.25 (d, 1H, J = 2.4 Hz), 7.21 (dd, 1H, J = 8.5 Hz, 2.4 Hz), 4.64 (d, 1H, J = 17.1 Hz), 4.57 (d, 1H, J = 17.1 Hz), 4.31 (s, 3H), 4.16 (d, 1H, J = 13.8 Hz), 4.12 (d, 1H, J = 13.8 Hz), 3.84 (s, 3H). Compound 1523. 1 H NMR (500 MHz, CD 3 OD) d 8.08 (s, 1 H), 7.92 (d, 1 H, J = 1.0 Hz), 7.53 (d, 1 H, J = 8.4 Hz), 7.48 (d, 1 H, J = 8.4 Hz), 7.43 (dd, 1H, J = 8.6 Hz, 1.4 Hz), 7.34 (d, 1H, J = 2.6 Hz), 7.21 (dd, 1H, J = 8.2 Hz, 2. 6 Hz), 4.71 (d, 1H, J = 17.1 Hz), 4.62 (d, 1H, J = 17.1 Hz), 4.30 (d, 1H, J = 14. 2 Hz), 4.19 (d, 1H, J = 14.2 Hz), 3.88 (s, 3H). Compound 1220B. 1 H NMR (500 Hz, dmso-d 6) d D 8.9 (bs, 1 H,), 7.95 (d, 2 H, J = 5 Hz), 7.64 (d, 2 H, J = 5 Hz), 7.6 (d, 1 H, J = 3 Hz), 7.28 (s, 1H), 7.2 (d, 1H, J = 3Hz), 4.6 (dd, 2H, J = 16Hz, 9 Hz), 4.15 (dd, 2H, J = 16 Hz, 9 Hz), 3.82 (s, 3H). Compound 1206. 1 H NMR (500 Hz, dmso-d 6) d D 8.9 (bs, 1 H,), 7.52 (d, 1 H, J = 5 Hz), 7.2 (m, 2 H), 4.6 (dd, 2 H, J = 8 Hz , 28 Hz), 4.2 (s, 2H), 3.81 (s, 3H), 212 (s, 3H).

Compound 1201. NMR (500 Hz, dmso-d6) d D 8.92 (s, 1H,), 7. 64 (d, 1H, J = 6Hz), 7.2-7.42 (m, 4H), 7.4 (d, 1H, J = 6 Hz), 6.72 (bs, 1H), 4.62 (d, 1H, J = 8Hz), 4.58 (d, 2H, J = 8 Hz), 4.05 (m, 2H), 3.88 (s, 3H). Compound 1200.? NMR (500 Hz, dmso-d6) d D 8.92 (s, 1H,), 8. 65 (m, 2H), 7.4-7.75 (m, 5H), 4.66 (dd, 2H, J = 16 Hz, 24 Hz) .4.15 (m, 2H). Compound 1220. NMR, (500Hz, dmso-d6), 8.449 (s, 1H), 7.93 (s, 1H), 7.73 (t, 1H, J = 1.892 Hz), 6.55 (d, 1H, J = 2.522 Hz) 6.69 (d, 1H, J = 8.512Hz), 6.41 (dd, 1H, J = 2.52Hz, J = 8.51Hz), 4.46-4.40 (m, 1 H), 3.87 (dd, 2H, J = 17.02Hz, J = 54.85Hz), 3.48 (dd, 2H, J = 14.187Hz, J = 51.703Hz), 3.067 (s, 3H), 0.92 (d, 6H, J = 6.62Hz). Compound 1552. 1 H NMR (500 Hz, CD3OD) d D 8.11 (s, 1 H), 7.49 (d, 1 H, J = 8.5 Hz), 7.33 (d, 1 H, J = 2 Hz), 7.11-7.25 ( m, 3H), 4.72 (d, 1 H, J = 17 Hz), 4.60 (d, 1 H, J = 17 Hz), 4.31 (d, 1 H, J = 14.5 Hz), 4.23 (d, 1 H) , J = 14.5 Hz), 3.88 (s, 3H), 2.24 (s, 3H). Compound 1562. 1 H NMR (500 MHz, MeOH-d 6) dD 7.63-7.61 (m, 2H) (bs, 1H), 7.57-7.55 (m, 2H), 7.48 (d, 1 H, 9 Hz), 7.32 (d, 1 H, J = 3 Hz), 7.22 (d of d, 1 H, J = 9 Hz, 3 Hz), 4.69 (d, 1 H, J = 18 Hz), 4.58 (d, 1 H, J = 18 Hz), 4.27 (d, 1 H, J = 15 Hz), 4.21 (d, 1 H, 15 Hz), 3.88 (s, 3 H), 3.89-3.86 (m, 1 H), 3.40-3.37 (m, 1 H). Compound 1576. 1 H NMR (500 MHz, DMSO-d 6) dD 11.23 (s, 1H), 10.83 (s, 1 H), 8.91 (s, 1H), 8.46 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.35 (br, s, 1 H), 7.32 (d , J = 8.5 Hz, 1 H), 7.24 (d, J = 2.5 Hz, 1 H), 7.20 (m, 2 H), 4.63 (d, J = 17 Hz, 1 H), 4.54 (d, J = 17 Hz, 1 H), 4.11 (d, J = 14 Hz, 1 H), 4.07 (d, J = 14 Hz, 1 H), 3.83 (s, 3H), 2.98 (m, 2H), 2.54 (m, 1 H), 2.16 (m, 1 H). Those skilled in the art will appreciate that changes may be made to the embodiments described above without departing from the broad concept of the invention. It is therefore understood that this invention is not limited to the particular embodiments described, but that it is desired to cover the modifications that are within the spirit and scope of the invention as defined in the appended claims.

Each document mentioned here is incorporated as reference in its entirety for all purposes.

Claims (51)

NOVELTY OF THE INVENTION CLAIMS

1. A compound represented by Formula (I): or a pharmaceutically acceptable salt, solvate, ester or isomer 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 sample; X is selected from the group consisting of -S -, - 0-, -S (O) 2-, 3 3 S (O) -, - (C (R) 2) m- and -N (R) -, T is alkynyl; V is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, and N-oxides of said heteroaryl and heterocyclyl, wherein when each of said cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, and N oxides of said heteroaryl and heterocyclyl contain two radicals on the same atom or on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, cycloalkenyl, aryl ring, heterocyclyl or heteroaryl of five to eight members, wherein each of the aforementioned cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl, optionally with said cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl is unsubstituted independently or substituted with one to four R10 residues that may be the same or different; And it 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 (R4) C (O) -, -N (R4) C (O) N (R4) -, -S (O) 2N (R4) -, -N (R) -S (O) 2-, -0 -, - S-, - C (O) -, - S (O) -, and -S (O) 2-; m is 1 to 3: n is 1 to 3; R is selected from the group consisting of H, cyano, 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 may 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, alkynyl, aryl, heteroaryl, and heterocyclyl R1, optionally with the five or six membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring is unsubstituted or is optionally substituted independently with one to four R20 moieties which may be be the same or different; with the proviso that when Y is -N (R4) -, -S - or - O-, then R1 is not halogen or cyano; R is selected from the group that consists of H, cyano, alkynyl, halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, and heterocyclyl, where when each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl contains two adjacent carbon atom radicals, said radicals may 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 R2, optionally with the five or six membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring, is unsubstituted or optionally independently substituted with one to four R20 moieties which can be 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 the same or different and 4 is independently selected from the group consisting of H, alkyl, and aryl; each R is the same or different and is independently selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl, hydroxy, -alkylcycloalkyl, -10 alkyl-N (alkyl) 2, heterocyclyl, aryl, and heteroaryl; R is selected from the group consisting of hydrogen, cyano, nitro, -C (R4) = N-OR4, -OR4, -SR4, -N (R) 2, -S (O) R4, -S (O) 2R4 , -N (R4) S (O) 2R4, -N (R4) -C (O) -R4, -C (0) N (R4) -S (0) 2R4, -S (O) 2N (R4) -C (O) -R4, -C (O) N (R4) C (O) R4, -C (O) N (R) C (O) NR4 -S (0) 2N (R4) 2, -N (R) -C (O) OR 4, -OC (O) N (R 4) 2, -N (R 4) C (O) N (R 4) 2, -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, -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 alkyl , aril, heteroaryl, heterocyclyl, and cycloalkyl R10 is unsubstituted or is optionally substituted independently with one to four R30 moieties 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 atoms to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl ring; R is selected from the group consisting of cyano, nitro, -C (R4) = N-OR4, -OR4, -SR4, -N (R4) 2, -S (0) R4, -S (O) 2R4, - N (R) S (O) 2 R 4, -N (R 4) -C (O) -R 4, -C (O) N (R 4) -S (O) 2 R 4, -S (O) 2 N (R 4) -C (O) -R4, -C (O) N (R4) C (O) R4, -C (O) N (R4) C (O) NR4 -S (O) 2N (R4) 2, -N (R ) -C (O) OR4, -OC (O) N (R4) 2, -N (R4) C (O) N (R4) 2, -S (O) 2N (R4) 2, -S (O) 2N (R4) -C (0) -R4, -N (R4) -C (= NR4) -N (R4) 2, -N (R4) -C (= N-CN) -N (R4) 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 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 ring or heteroaryl of five to eight members; wherein each of said alkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl R20, optionally with said cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members is unsubstituted or is substituted with one to four residues independently selected from the group consisting of in alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cyano, nitro, -NH2, - NH (alkyl), and -N (alkyl) 2; or when two R20 moieties when attached to it or to adjacent carbon atoms can optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl ring; 30 AR is selected from the group consisting of cyano, nitro, -C (R) = N-OR, - OR4, -SR4, -N (R4) 2, -S (O) R4, -S (O) 2R4 , -N (R4) S (O) 2R4, -N (R4) -C (O) -R4, -C (O) N (R4) -S (O) 2R4, -S (O) 2N (R4) -C (O) -R4, -C (0) N (R4) C (O) R4, C (O) N (R4) C (O) NR4 -S (O) 2N (R4) 2, -N (R4) -C (O) OR4, -OC (O) N (R4) 2, - N ( R) C (O) N (R4) 2, -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, -haloalkoxy, -C (O) OR4, -C (O) R4, -C (O) N (R4) 2, halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl; wherein when each of said aryl, heteroaryl, heterocyclyl and cycloalkyl R30 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 ring or heteroaryl of five to eight members; wherein each of said alkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl R30, optionally with said cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members is unsubstituted or substituted with one to four moieties 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 the same or adjacent carbon atoms can optionally be taken as together with the carbon atoms to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl ring.

2. The compound according to claim 1, further characterized in that said isomer is a stereoisomer.

3. The compound according to claim 1, further characterized in that ring A is selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidyl, and each of which is substituted with -Y-R1 and -Z-R2 as shown.

4. The compound according to claim 3, further characterized in that said ring A is phenyl which is substituted with -Y-R1 and -Z-R2 as shown.

5. 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) -.

6. The compound according to claim 5, further characterized in that X is - (C (R3) 2) m, where m is 1 or 2.

7. The compound according to claim 6, further characterized because m is 1

8. The compound according to claim 1, 6, or 7, further characterized in that R3 is H.

9. The compound according to claim 1, further characterized in that T is -C = C-.

The compound according to claim 1, further characterized in that V is selected from the group consisting of H, aryl, heteroaryl, and N-oxide of said heteroaryl; wherein when each of the aforementioned aryl, and heteroaryl contains two radicals on the same or on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a cycloalkyl ring, aryl , heterocyclyl or heteroaryl of five or six members; wherein said aryl and heteroaryl optionally with said five or six membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring is unsubstituted or optionally substituted with one to four R10 moieties which may be the same or different.

The compound according to claim 9, further characterized in that V is selected from the group consisting of phenyl, naphthyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, benzopyrazolyl, imidazolyl, benzimidazolyl, furazanyl, pyridyl, pyridyl N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, pteridinyl, tetrazolyl, oxazolyl, isothiazolyl. thiazolyl, > Each of which is optionally substituted with one or more residues R10 so that the amount of residues R10 per group V does not exceed four.

12. The compound according to claim 1, further characterized in that R10 is selected from the group consisting of hydrogen, cyano, nitro, -OR4, -SR4, -N (R4) 2, -S (0) 2R4-, - S (O) 2N (R 4) 2, -haloalkoxy, -C (O) OR 4, -C (O) R 4, -C (O) N (R 4) 2, -C (0) N (R 4) -S ( 0) 2R4, -C (R4) = N-OR, halogen, alkyl, haloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, aryl, heteroaryl, and heterocyclyl is unsubstituted or optionally substituted independently with each other four R30 residues that may be the same or different; or where two R10 moieties, when attached to the same carbon atom, are taken together with the carbon atom 4 to which they are attached to form a heterocyclyl ring; each R is the same or different and is independently selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl, hydroxy, -alkylcycloalkyl, -alkyl-N (alkyl) 2, heterocyclyl, aryl, and heteroaryl; and R is selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, alkoxy, heterocyclyl, -C (R4) = N-OR, -O-alkyl-cycloalkyl, -N (R4) 2, and -C (O ) N (R) 2, wherein said alkyl R30 is substituted with an -NH2.

The compound according to claim 12, further characterized in that R 10 is selected from the group consisting of nitro, alkyl, halogen, haloalkyl, haloalkoxy, alkoxy, cyano, -S (O) 2 -alkyl, -NH2, -NH (alkyl), -N (alkyl) 2, cycloalkyl, aryl, heteroaryl, heterocyclyl, -alkyl-heterocyclyl, -cycloalkyl-NH2, -S (O) 2-NH2, -S (O) 2alkyl, -C (O) NH 2, hydroxy, -C (O) N (H) (cycloalkyl), -C (0) N (H) (alkyl), -N (H) (cycloalkyl), -C (O) O -alkyl, -C (O) OH, -S (O) 2N (H) (alkyl), -S (0) 2OH, -S-haloalkyl, -S (O) 2-haloalkyl, hydroxyalkyl, alkoxyalkyl, -O -alkyl-cycloalkyl, -alkyl-O-alkyl-cycloalkyl, -C (O) alkyl, aminoalkyl, -alkyl-NH (alkyl), -alkyl-N (alkyl) 2, -CH = NO-alkyl, -C ( O) NH-alkyl-N (alkyl) 2, -C (O) -heterocyclyl, and -NH-C (O) -alkyl, wherein each of said aryl and heteroaryl R10 is optionally substituted with 1-2 selected residues of the a group consisting of alkyl, -NH2, -NH (alkyl), and -N (alkyl) 2; or where two R10 moieties attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a heterocyclyl ring.

The compound according to claim 13, further characterized in that R 10 is selected from the group consisting of hydrogen, nitro, methyl, fluorine, bromine, trifluoromethyl, chloro, difluoromethoxy, trifluoromethoxy, methoxy, hydroxyl, cyano, -S (O ) 2CH3, -NH2, isopropyl, cyclopropyl, -cyclopropyl-NH2, -NH (cyclopropyl), -NH (CH3), -S (O) 2-NH2, -C (O) NH2, -C (O) OCH3, -C (O) OH, S (O) 2N (H) CH 3, -C (O) NH (CH 3), -C (O) NH (cyclopropyl), -S (O) 2 OH, -S-CF 3, S (O) 2-CF 3, ethoxy, hydroxymethyl, methoxymethyl, isopropoxy, -OCH2-cyclopropyl, CH2O-CH2-cyclopropyl, -C (O) CH3, -C (O) CH3, -CH (CH3) OH, -CH2NH2, CH (CH3) NH2, -CH2NH-CH3, -CH (CH3) OH, -CH2NHCH3 , -CH = N-OCH3, C (CH3) = N-OCH3, -C (O) OCH2CH3, -C (O) NHCH2CH2N (CH3) 2, -NH-C (O) CH3, or where two R10 moieties attached to the same carbon atom are taken together with the carbon atom to which they are attached to form

15. The compound according to claim 1, further characterized in that Y is selected from the group consisting of a covalent bond and -O-.

16. The compound according to claim 15, further characterized in that Y is a covalent bond.

17. The compound according to claim 15, further characterized in that Y is -O-.

18. The compound according to claim 1, further characterized in that Z is selected from the group consisting of a covalent bond and -O-.

19. The compound according to claim 18, further characterized in that Z is -O-.

The compound according to claim 1, further characterized in that R1 is selected from the group consisting of hydrogen, cyano, halogen, alkyl, aryl, heteroaryl, haloalkyl, and alkynyl; wherein said alkyl R1 is unsubstituted or is substituted with an aryl, heteroaryl, or heterocyclyl, where when said aryl, heteroaryl, or heterocyclyl contains two adjacent carbon atom radicals, said radicals may 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 said aryl, heteroaryl or heterocyclyl substituent of said alkyl R1 optionally with said cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members is unsubstituted or optionally substituted independently with one to four R20 moieties.

The compound according to claim 1, further characterized in that R 2 is selected from the group consisting of hydrogen, cyano, halogen, alkyl, aryl, heteroaryl, haloalkyl, and alkynyl; wherein said alkyl R1 is unsubstituted or is substituted with an aryl, heteroaryl, or heterocyclyl, where when said aryl, heteroaryl, or heterocyclyl contains two adjacent carbon atom radicals, said radicals may 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 said aryl, heteroaryl or heterocyclyl substituent of said alkyl R optionally with said cycloalkyl, aryl, heterocyclyl or heteroaryl ring of five to eight members is unsubstituted or optionally substituted independently with one to four R20 moieties.

22. The compound according to claim 16, further characterized in that R1 is halogen or cyano.

23. The compound according to claim 22, further characterized in that R1 is fluorine, chlorine, or cyano.

24. The compound according to claim 17, further characterized in that R1 is selected from the group consisting of alkyl, haloalkyl, and alkynyl; wherein said alkyl R1 is unsubstituted or is substituted with a heteroaryl, wherein when said 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 of five or six members; wherein said heteroaryl substituent of said alkyl R1, optionally with said five or six membered aryl is substituted with alkyl.

25. The compound according to claim 24, further characterized in that R1 is selected from the group consisting of CH3, -CH2-C = C-CH3, difluoromethyl,

26. The compound according to claim 1, further characterized in that the compound of Formula (I) is represented by the compound of formula (III): wherein in formula (III), X is - (CH2) 1-2-, and T, V, Y, R1, and R3 are as indicated in Formula (I).

27. The compound according to claim 26, further characterized in that X is -CH2-.

28. The compound according to claim 1, further characterized in that the compound of Formula (I) is represented by the compound of formula (IV): wherein in formula (IV), X is - (CH2)? 2-, T, V, Y, R1, and R3 are as indicated in Formula (I).

29. The compound according to claim 28, further characterized in that X is -CH2-.

30. A compound selected from the group consisting of twenty or a pharmaceutically acceptable salt, solvate or ester thereof.

31. The compound according to claim 30, further characterized in that it is selected from the group consisting of: twenty or a pharmaceutically acceptable salt, solvate or ester thereof.

32. The compound according to claim 31, further characterized in that it is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or ester thereof.

33. A compound of claim 1 in purified form.

34. 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.

35. 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, ADAMs or any combination of these.

36. The use of the pharmaceutical composition of the claim 34, in the development of a medicament useful for treating disorders associated with TACE, TNF-α, aggrecanase, MMPs, ADAMs or any combination of these.

37. 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 the treatment of a disorder or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastasis, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in a subject.

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

39. 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 the treatment of a disorder or disease selected from the group consisting of septic shock, hemodynamic shock, septicemic syndrome, post ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, rejection of the grafts, cancers such as cutaneous T-cell lymphoma, diseases that involve angiogenesis, autoimmune diseases, diseases of inflammations of the skin, diseases of intestinal inflammation such as Crohn's disease and colitis, osteo and rheumatoid arthritis, ankylosing spondylitis, soreatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Behcehe's disease, syndrome of Sjogren, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar lesions, periodontal disease, HIV, non-insulin-dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, pulmonary fibrosis id iopathic, broncho-pulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral vascular accident, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing alveolitis, psoriasis, rejection of transplants, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible obstruction of respiratory tract, adult acute respiratory syndrome, asthma, chronic obstructive pulmonary diseases (COPD) and bronchitis in a subject.

40. 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 disorder or disease associated with COPD.

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

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

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

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

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

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

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

48. 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®, Betaseron, Copaxone or another compound indicated for the treatment of multiple sclerosis, for the preparation of a drug useful for the treatment of a disorder or disease associated with multiple sclerosis.

49. The use as claimed in claim 36, wherein the medicament is further adapted to be administrable with at least one medicament selected from the group consisting of disease modifying antirheumatic drugs (DMARDS), non-spheroidal anti-inflammatory drugs (NSAIDs). , selective inhibitors of cycloxygenase-2 (COX-2), COX-1 inhibitors, immunosuppressants, biological response modifiers (BRMs), anti-inflammatory agents and H1 antagonists.

50. The use as claimed in claim 37, wherein the medicament is further adapted to be administrable with at least one medicament selected from the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressants, BRMs, anti-inflammatory agents and H1 antagonists.

51. The use as claimed in claim 38, wherein the medicament is further adapted to be administrable with at least one medicament selected from the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressants, BRMs, anti-inflammatory agents and H1 antagonists.