MX2008007092A - Compounds for the treatment of inflammatory disorders and microbial diseases - 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, aggrecanase, ADMP, LpxC, ADAMs, TACE, TNF-αor combinations thereof.

Description

COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY DISORDERS AND MICROBIAL DISEASES BACKGROUND OF THE INVENTION FIELD OF THE INVENTION; This invention relates generally to functional compounds of tartaric acid can inhibit matrix metalloproteinases (MMPs according acronym), a disintegrin and metalloproteases (ADAMs), aggrecanase, or metalloprotease degradation of aggrecan (ADMP) and / or converting enzyme - alpha tumor necrosis factor (TACE according acronym) and thereby release the alpha tumor necrosis factor prevents (TNF-a, according acronym), pharmaceutical compositions comprising such compounds , and methods for the treatment using said compounds. The invention also relates to tartaric acid functional compounds that can inhibit UDP-3-0- (R-3-hydroxymyristoyl) -N-acetylglucosamine deacetylase (LpxC), and as a result have antimicrobial activity. BRIEF DESCRIPTION OF THE INVENTION Osteoarthritis and rheumatoid arthritis (OA and RA, respectively) are destructive diseases of the articular cartilage characterized by localized erosion of the cartilage surface. The findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of sulfate radio-labeling with respect to controls, suggesting 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 belief that metalloproteases are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA and LA cartilage; activity corresponds to the severity of the injury (Mankin et al., Arthritis Rheum, 21, 1978, 761-766, Woessner et al., Arthritis Rheum, 26, 1983, 63-68 and Ibid., 27, 1984, 305-312). Additionally, it identified aggrecanase] (a metalloprotease recently identified) that provides the specific cleavage product of proteoglycan, found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-1222). Metalloproteases (MPs) have been implicated as the key enzymes in the destruction of cartilage and bone in mammals. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors (see Wahl et al Ann. Rep. Med. Chem. 25, 175-184, AP, Sari 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 proteoglycan and collagen, leading to the resorption of the extracellular matrix. This is a characteristic of many pathological conditions, such as RA and OA, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally, these catabolic enzymes are tightly regulated at the level of! its synthesis as well as its 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 MMP's. Tumor necrosis factor-alpha (TNF-a) is a cell-associated cytokine that is processed from a 26 kDa precursor form to an active 17 kd form. See Black R.A. "Tumor necrosis factor-alpha converting enzyme" Int J Biochem Cell Biol. January 2002; 34 (1): 1-5 and Moss ML, White JM, Lambert MH, Andrews RC.'TACE and other ADAM proteases as targets for drug discovery "Drug Discov Today April 1, 2001; 6 (8): 417-426 , each of which is incorporated by reference to this document, TNF-a has been shown to play a pivotal role in immune and inflammatory responses, inappropriate expression or overexpression of TNF-a is a hallmark of a series of diseases, including RA, Crohn's disease, multiple sclerosis, psoriasis and sepsis.

The inhibition of TNF-α production has been shown to be beneficial in many preclinical models of inflammatory disease, making the inhibition of production or signaling of TNF-a an attractive target for the development of new anti-inflammatory drugs. TNF-a is a primary mediator in humans and animals of inflammation, fever and acute phase responses, similar to those observed during acute infection and shock. The excess TNF-a has been shown to be lethal. Blocking the effects of TNF-a with specific antibodies can be beneficial in a variety of conditions, including autoimmune diseases such as RA (Feldman et al, Lancet, (1994) 344, 1110), non-insulin dependent diabetes mellitus ( Lohmander LS et al., Arthritis Rheum 36 (1993) 1214-22) and Crohn's disease (Macdonald T. et al., Clin. Exp. Immunol., 81 (1990) 301). Compounds that inhibit the production of TNF-a are, therefore, of therapeutic importance for the treatment of inflammatory disorders. Recently, it has been shown that metalloproteases, such as TACE, are capable of converting TNF-a from its inactive form to its active form (Gearing et al. Nature, 1994, 370, 555). Since excessive production of TNF-α has been noted in various disease conditions also characterized by tissue degradation mediated by MMP, compounds that inhibit the production of both M Ps and TNF-α may also have a particular advantage in diseases where both mechanisms are involved.

One method to inhibit the damaging effects of TNF-a is to inhibit the enzyme, TACE, before it can! process TNF-a to its soluble form. TACE is a member of the family ???? of type I membrane proteins and mediated the release of ectodomain loss of various signaling and adhesion proteins with membrane anchoring. TACE has become increasingly important in the study of various diseases, including inflammatory disease, due to its role in the unfolding of TNF-a from its "stalk" sequence and thus releasing the soluble form of the TNF-a protein (Black RA Int J Biochem Cell Biol. 2002 34, 1-5). Aggrecan is the main proteoglycan of cartilage and provides this tissue with its mechanical properties < ie compressibility and elasticity. Under arthritic conditions, one of the earliest changes observed in cartilage morphology is the decrease in aggrecan [Mankin et al. (1970) J. Bone Joint Surg. 52A, 424-434], which seems to be due to a higher rate of degradation. The aggrecan molecule is composed of two globular N, G1 and G2 terminal domains, which are sebated by an approximately 150-residue heterologous domain (IGD), followed by a long central glycosaminoglycan (GAG) binding region. a globular domain of terminal C, G3 [Hardingham et al. (1992) in Articular Cartilage and Osteoarthritis: Aggrecan, The Chondroitin Sulfate / Keratan! Sulfate Proteoglycan from Cartilage (Kuettner et al.) Pp. 5- 20, Raven Press, New York and Paulson et al. (1987) Biochem. J. 245, 763-7721. These aggrecan molecules They interact through the Gl domain with hyaluronic acid and a binding protein to form aggregates of high molecular weight which are trapped within the cartilage matrix [Hardingham et al. (1972) Biochim. Biophys. Acta 279, 401-405, Heinegard et al. (1974) J. Bíol. Chem. 249, 4250-4256, and Hardingham, T.E. (1979) Biochem. J. 177, 237-247]. The loss of aggrecan from cartilage under arthritic conditions involves the proteolytic cleavage of the aggrecan core protein within the IGD, producing an N-terminal G-1 fragment that remains bound to hyaluronic acid and the binding protein within the matrix, releasing a A large fragment of aggrecan containing C-terminal GAG that diffuses out of the cartilage matrix. The loss of the C-terminal fragment results in a cartilage deficient in its mechanical properties. This deficiency arises because the GAGs that are present in the C-terminal portion of the aggrecan core protein are the aggrecan components that impart the mechanical properties to the molecule through its high negative charge and water binding capacity.; Therefore, compounds exhibiting inhibition against aggrecanase or metalloprotease of aggrecan degradation (ADMP) could serve as potential therapeutic agents to treat aggrecanase-related disorders cited above, and are therefore desired. Lipid A is the hydrophobic anchor of lipopolysaccharide (LPS) and forms the major lipid component of the outer monolayer of the outer membrane of gram-negative bacteria. Lipid A is required for Bacterial growth and inhibition of its biosynthesis is lethal to bacteria. Additionally, blocking the biosynthesis of Lipido A increases the sensitivity of the bacteria to other antibiotics. One of the key enzymes of bacterial lipid A biosynthesis is LpxC. LpxC catalyzes the removal of the N-acetyl group of UDP-3-O- (R-3-hydroxymyristoyl) -N-acetylglucosamine. The LpxC enzyme is essential in gram negative bacteria for the biosynthesis of Lipido A, and is notably absent from mammalian genomes. Since LpxC is essential for the biosynthesis of Lipido A and the inhibition of lipid A biosynthesis is lethal to bacteria, LpxC inhibitors have utility as antibiotics. In addition, the absence of LpxC from mammalian genomes reduces the potential toxicity of LpxC inhibitors in mammals. Therefore, LpxC is an attractive target for the discovery of antibacterial drugs. There are several patents that describe inhibitors of MMP based on hydroxamate, carboxylate and / or lactam. US Patent No. 6,677,355 and US Patent No. 6,534,491 (B2), describe compounds that are hydroxamic acid derivatives and MMP inhibitors. US Pat. No. 6,495,565 describes lactam derivatives which are potential inhibitors of matri-i and / or TNF-α metalloproteases. US Patent Application Serial No. 1 1/142601 (filed June 1, 2005) discloses tartrate compounds which are useful inhibitors of TACE. I US Patent No. 5,925,659 discloses that certain heterocyclic hydroxamate compounds, in particular oxazoline compounds, have the ability to inhibit LpxC. WO2004 / 00744 refers to N-Hydroxyamide derivatives that have LpxC inhibitory activity, and therefore possess antibacterial activity. j WO2004 / 062601 also refers to small molecule inhibitors of LpxC. There is a need in the art for inhibitors of MMPs, ADAMs, aggrecanase, ADMP, TACE, and TNF-a, which may be useful as anti-inflammatory compounds and protective cartilage therapeutic agents. The inhibition of TNF-α, ADMP, TACE and or of other MMPs can prevent cartilage degradation by these enzymes, thereby alleviating the pathological conditions of OA and RA as well as many other autoimmune diseases. There is also a need in the art for small molecule inhibitors of LpxC as potential antibacterial agents.

BRIEF DESCRIPTION OF THE INVENTION; In its many embodiments, the present invention provides a novel class of compounds as inhibitors of LpxC, TACE, ADMP, aggrecanase, the production of TNF-α, MMPs, ADAMs or any combination aggrecanase, the production of TNF-α, MMPs, ADAMs or any combination thereof, methods of preparing said compounds, pharmaceutical compositions comprising one! or more of said compounds, methods for preparing formulations; Pharmaceuticals comprising one or more of said compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with LpxC, TACE, ADMP, aggrecanase, TNF-a, MMPs,: ADAMs or any combination thereof using said compounds or pharmaceutical compositions. In one embodiment, the present application describes a compound, or pharmaceutically acceptable salts or solvates of said compound, said compound having the general structure shown in formula (I): Formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: A is selected from the group consisting of: and -C02R1; d is 0 to 4;; J is selected from the group consisting of: O, S, and NR5; E is selected from the group consisting of: O, S, and NR5; T is O u S; R1 and R2 are the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl, and heteroaryl; or alternatively R1 and R2, taken together with the N to which 'R1 and R2 are shown attached, represent a 4-8 membered heterocyclic ring having 1 -3 heteroatoms including said N, said heterocyclic ring being optionally fused with aryl , heteroaryl, cycloalkyl, or heterocyclyl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl, heteroaryl and 4-8 membered heterocyclic ring may be unsubstituted or optionally substituted independently with one or more portions which can be the same or different, each down; R 0 is selected from the group consisting of H, alkyl, and fluoroalkyl; R20 is selected from the group consisting of H, alkyl, and fluoroalkyl; R30 is H or alkyl, or alternatively R "? 0 and R40 taken in conjunction with the N to which R40 is shown attached in Formula I, join to form a 4-7 membered heterocyclic ring, where said heterocyclic ring is unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group of portions R70 below, R40 is H or alkyl, R50 is H or alkyl, W is - ( CR132) n-, where n is 0 to 5 or a covalent bond, or alternatively two R13 groups can be fused to form a 3-8 membered cycloalkyl, wherein said 3-8 membered cycloalkyl can be unsubstituted or optionally substituted on independently with one or more portions which may be the same or different, each portion is independently selected from the group of portions R6 shown below, X is absent or present, and if X is present it is selected from Among the group consisting of a covalent bond, alkylp, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be replaced or optionally substituted independently with one or more portions which may be the same or different,! being each portion selected independently of the group of R70 portions that appears below; ! And it is absent or present, and if Y is present, it is selected from between the group consisting of a covalent bond, - [C (R6) 2] n- where n is 1 a 2, -O-, -S-, -NR-, -SOv- where v is 1 to 2, -SOn (CR62) p- where n is 1 or 2 and p is 1 to 4, -0 (CR62) q- or - (CR62) qO- where q is 1 a- 4, -N (R7) S (O) n- or - S (0) nN (R7) - where n is 1 or 2, and -N (R7) C (0) - or -C (0) N (R7) -; Z is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, said Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally fused with aryl, heterocyclyl, heteroaryl or cycloalkyl; where each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl can be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion selected independently from the group of R70 portions that appears below;; I R5 is selected from the group consisting of hydrogen, alkyl, and alkylaryl; j each R6 is the same or different and is independently selected from the group consisting of hydrogen, halogen, -SR 1 5, -S (O) qRl 5 where q is 1 to 2, alkyl, cycloalkyl, heterocyclyl, alkoxy, hydroxy, nitro, cyano, amino, alkenyl, alkynyl, arylalkyl , aminocarbonyl, alkylcarbonyl, and alkoxycarbonyl; each R7 is the same or different and is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, alkenyl, alkynyl, arylalkyl, alkylcarbonyl, and alkoxycarbonyl, wherein each of the aryl, heteroaryl and heterocyclyl can be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group of portions R70 shown below; R 3 is the same or different and is independently selected from the group consisting of hydrogen, halogen, -OH, -OR14, alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylaryl, alkylamino, and alkylcarbonyl; R is alkyl; each R70 is a substituent for H where indicated and is the same or different and is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, - CN, -CF3, -OCF3, -OR1 5, -C (0) R 1 5, -C (0) OR 1 5, -C (0) N (R 1 5) (R 16) I _SR 1 5 ( -S (Q) QN (R 15) (Rl 6) where q is 1 to 2, -C (= NOR 5) R 1 6, -N (R 5) (R 16) I -alkyl-N (R 1 5) (R 1 6), - N (R15) C (0) R16, -CH2-N (R5) C (0) R16, -N (R5) S (O) R1 ^, -N (R15) S (0) 2R16, -CH2-N (R5) S (0) 2R16, -N (R17) S (0) 2N (R16) (R15) IN (R17) S (O) N (R6) (R1 5), -N (R 7) C (0) N (R 16) (R 15) 1 _CH 2 - N (R 1 7) C (O) N (R 6) (R 15), -N (R 1 5) C (0) OR 16, -CH 2 -N (R 5) C (O) OR 16, and - S (0) qR '' ^ where q is from 1 to 2; and where each of the alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl are independently unsubstituted or substituted: with 1 to 5 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo; -CF3, -CN, -OR1 ^, - N (R1 5) (R16), -C (0) OR1 5, -C (0) N (R5) (R16) I and -N (R15) S ( 0) R16; 15 16 17 '< each R, R and R are independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or alternatively R15 and Re taken together with the N to which they are shown attached, join to form a heterocyclic ring of 4-8 members, where said 4-8 membered cycloalkyl may be unsubstituted or optionally replaced independently with one or more portions which can be equal or different, each portion is selected independently from the group consisting of R75 portions that appear below; each R75 is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl, and wherein one of alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl is independently unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, -CF 3, -CN, -OR ^, i -N (R19) 2, -C (0) OR19, -C (0) N (R19) 2, and -N (R19) S (0) R19; Y ! each R19 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. The compounds of Formula I may be useful as inhibitors and may be useful in the treatment and prevention of associated diseases with LpxC, TACE, aggrecanase, ADMP, TNF-a, MMPs, | ADAMs or any combination of them. t DETAILED DESCRIPTION OF THE INVENTION In its various embodiments, the present invention provides a novel class of LpxC inhibitors, TACE, aggrecanase, ADMP, production of TNF-a, MMPs, ADAMs or any combination thereof, pharmaceutical compositions containing one or more of the compounds, and methods for preparing pharmaceutical formulations comprising one or more of said compounds, and treatment methods; prevention or improvement of one or more of the symptoms of inflammation. I In one embodiment, the present intention provides compounds that are represented by the structural formula (I) that appears above or a pharmaceutically acceptable salt, solvate or isomer ? acceptable of them, where the various portions are as described above. In one embodiment, R1 and R2 are the same or different, each being independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl, and heteroaryl; or alternatively R1 and R2, taken together! with the N to which R and R2 are shown attached, they represent a 4-8 membered heterocyclic ring having 1-3 heteroatoms including said N, said heterocyclic ring i being optionally fused to arylp, heteroaryl, cycloalkyl, or heterocyclyl, wherein each one of said alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl, heteroaryl and 4-8 membered heterocyclic ring may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion is selected independently from the consistent group t of R70.; In one embodiment, R1 and R2 are the same or different, each being independently selected from the group consisting of H, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroaryl; or alternatively R1 and R2, taken together with the N to which R and R2 are shown attached, represent a heterocyclic ring; of 4-8 members having 1 -3 heteroatoms including said N, said heterocyclic ring being optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl, heteroaryl and 4-8 membered heterocyclic ring may be unsubstituted or optionally substituted independently with one or more portions which may be equal or different, each portion being independently selected from the group consisting of R70 . In a modality, A is selected from among the group consisting of: where R1 and R2, taken together with the N to which R and R are shown attached, represent a 4-8 membered heterocyclic ring having 1 -3 heteroatoms including said N, said heterocyclic ring being optionally substituted with R70, optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said 4-8 membered heterocyclic ring may be unsubstituted or optionally substituted independently with one or more portions which may be equal or different, each portion being independently selected of the group of portions R70. : In another modality, A is; where R1 and R2 are the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl; and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl and heteroaryl may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group of portions R70.; In another modality, A is' where R1 and R2 are the same or different, each being independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl, and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl and heteroaryl may be unsubstituted or optionally: substituted independently with one or more portions which may be the same or different, each portion being selected independently of the group of portions R70. In another modality, A is; where R1 and R2 are the same or different, each being independently selected from the group consisting of H, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl, and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl and heteroaryl may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group of portions R70. i In another modality, A is! OR In another modality, A is where a is 0 to 4 and x is 0 to 4. In another mode, A is where each x independently is 0 to 4. i In another modality, A is selected from the group consisting of: Y R2 are shown attached, represent a 3-8 membered heterocyclic ring having 1 to 3 heteroatoms including said N, wherein said heterocyclic ring optionally substituted with R70, or optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said ring 3-8 membered heterocyclic may be unsubstituted or optionally substituted in the independent with one or more portions which may be the same or different, each portion being independently selected from the group of portions R70;; where a ring is formed from -NR1R2 and said ring is where ! Each R is a substituent for H where indicated and may be the same or different, each independently selected from the group consisting of -OH, -OR 4, -C (O) OR 1 5, -C (O) N ( R15) (R16), alkyl, aryl, heteroaryl, alkenyl, alkynyl, cycloalkyl and heterocyclyl, wherein said alkyl, aryl, heteroaryl, alkenyl, alkynyl, cycloalkyl and heterocyclyl can be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being selected independently from the group of portions R70; R and R12 taken together with the carbon to which each R 11 and R 2 are shown attached are fused heteroaryl or fused cycloalkyl, wherein said fused heteroaryl and fused cycloalkyl may be unsubstituted or optionally substituted independently with one or more portions. which may be the same or different, each portion being selected independently from the group of portions R70; Y x is 0 to 4, and when x is greater than 1, each portion R9 may be the same or different, each portion is independently selected from the group consisting of portions R9. ! In another modality, A is selected from among the group consisting of: where R and R2, taken together with the N to which R and R2 are shown attached, represent a 3-8 membered heterocyclic ring having 1 -3 heteroatoms including said N, said heterocyclic ring being optionally substituted with R70, or optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said 3-8 membered heterocyclic ring may be unsubstituted or optionally substituted independently with one or more portions which may be equal or different, each portion being selected independently of the group of portions R70; where a ring is formed from -NR1R2 and said ring is where each R9 is a substituent for H where s1e indicates and may be the same or different, each independently selected from the group consisting of -OH, -OR14, -C (O) OR 1 5, -C (O ) N (R 1 5) (R 16) alkyl, aryl, heteroaryl, alkenyl, alkynyl, cycloalkyl and heterocyclyl, wherein said alkyl, aryl, heteroaryl, alkenyl, alkynyl, cycloalkyl and heterocyclyl can be unsubstituted or optionally substituted independently with one or more portions which may be equal or different, each portion being selected independently from the group of portions R70; x is from 0 to 4, and when x is greater than 1, each portion R9 may be the same or different, each portion is independently selected from the group consisting of portions R9; and G is selected from the group consisting of CH2, N R7, O, S, or SO2. In another embodiment, A is selected from the group consisting of: R where R1 and R2, taken together with the N to which R1 and R2 are shown attached, represent a 3-8 membered heterocyclic ring having 1 to 3 heteroatoms including said N, said heterocyclic ring being optionally substituted with R70, or optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said 3-8 membered heterocyclic ring may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group of portions R70; [A ring is formed from -NR1R2 and said ring is selected from the group consisting of: where: x is from 0 to 4, and when x is greater than 1, each portion R 70 it may be the same or different, each portion being independently selected from the group of portions R70i and each R8 is the same or different and is independently H or alkyl. In another modality, A is selected from the consistent group where R1 and R2, taken together: with the N to which R1 and R2 are shown attached, represent a 3-8 membered heterocyclic ring having 1-3 heteroatoms including said N, said heterocyclic ring being optionally substituted with R70 , or optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said 3-8 membered heterocyclic ring may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being selected independently of the group of portions R70; A ring is formed from -NR} ^ 2 and said ring is selected from the group consisting of where x is from 0 to 4, and when x is greater than 1, each portion R70 may be the same or different, each portion being independently selected from the group of portions R70. In another modality, A is selected from the consistent group where R1 and R2, taken together with the N to which R and R2 are shown together, represent a 3-8 membered heterocyclic ring having from 1-3 heteroatoms including said N, said heterocyclic ring being optionally substituted with R70, or optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said heterocyclic ring is -8 members may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being selected independently from the group of portions R70; a ring is formed from -NR R2 and said ring is where ! each R9 is a substitunt for H where indicated and may be the same or different, each independently selected from the group consisting of -OH, -OR14, -C (O) OR 5 -C (O) N (R "| 5) (R1 6)) alkyl, aryl, heteroaryl, alkenyl, alkynyl, cycloalkyl and heterocyclyl, wherein said alkyl, aryl, heteroaryl, alkenyl, alkynyl, cycloalkyl and heterocyclyl can be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each I i portion selected independently of the group of portions R70¡ and x is from 0 to 4, and when x is greater than 1, each portion R9 can be equal or different, each portion is selected independently of between the group consisting of portions R9. i In another modality, J is O.

In another modality, E is O.

In another embodiment, R10 is H or alkyl.

In another embodiment, R20, R30, R40, and R50 are all the same and are H.

In another embodiment, R6 is H or alkyl.

In another embodiment, R6 is H.

In another embodiment, R 13 is H or alkyl.

In another embodiment, R13 is H or -CH3.

In another modality, A is selected from the group consisting of: where R1 and R2, taken together! with the N to which R1 and R2 are shown together, represent a heterocyclic ring of 4-6 members with 1-3 heteroatoms including said N, said ring being heterocyclic optionally substituted with R70, where R70 is aryl.

In another modality, Y is a covalerite bond or - [C (R6) 2] n- where n is from 1 to 2, -CH2-.

In another embodiment, Y is selected from the group consisting of a covalent bond, -CH2-, -C (H) (OH) -, -C (O) - and -O-.; In another modality, Y is a covalent bond or -CH2-. In another modality, Y is a covalent bond. In another mode, W is - (CR132) n-, where n is 0-5. In another modality, W is - (CR 32) n-, where n is 1-5 and each R13 is H or alkyl. In another embodiment, W is selected from the group consisting of -CH2-, -C (H) (CH3) -, -C (CH3) 2- and -CH2CH2-i In another embodiment, W is -CH2-. | In another embodiment, W is -C (H) (CH3) -.; In another embodiment, X is selected from the group consisting of alkyl, aryl, heterocyclyl and heteroaryl. In another embodiment, X is aryl. ! In another embodiment, X is heteroaryl. In another embodiment, X is selected from the group consisting of phenyl, acetidinyl, pyrrolidinyl, piperidinyl, pyridinyl, thienyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl. In another embodiment, X is selected from the group consisting of phenyl, pyridinyl and piperidinyl. j In another modality, X is selected from input the group consisting of ' where: x is 0 to 4, and where x is greater than 1, each portion R70 may be the same or different, each portion being selected independently of the group of portions R70 In the portions shown above for X, X is the portion enclosed by - \ and W and Y are shown only to indicate the extreme from the X that is attached to W and the end to Y. Similar cases occur as length of this request with similar connotations. \ In another modality, X is selected from the group consisting from: where x is from 0 to 4, and when x is greater than 1, each portion R70 can be the same or different, with each portion selected independently of the group of portions R70.; In another embodiment, Z is selected from the group consisting of H, aryl and heteroaryl. 1 i In another mode, Z is selected from the group consisting of of H, phenyl, indolyl, benzimidazolyl, pyrazolyl, thienyl, pyridinyl, thiazolyl, thiadiazolyl, imidazolyl, pyrrolidinyl, pyrazinyl, triazolyl, tetrazolyl and tetracinyl, wherein said phenyl, indolyl, benzimidazolyl, pyrazolyl, thienyl, pyridinyl, thiazolyl, thiadiazolyl, imidazolyl, pyrrolidinyl, pyrazinyl, triazolyl, tetrazolyl and tetracinyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of portions R70.; In another embodiment, Z is selected from the group consisting of: wherein x is from 0 to 4, and when x is greater than 1, each portion R70 may be the same or different, each portion being independently selected from the group of portions R70. In another embodiment, Z is phenyl. In another embodiment, Z is a phenyl substituted with at least one substituent selected from the group consisting of cyano, alkoxy, halogen, alkyl, haloalkyl, hydroxy, aryl, heteroaryl, aryloxy, amino and tetrazole. : In another modality, Z is thienyl. In another embodiment, Z is a thienyl substituted with at least one substituent selected from the group consisting of cyano, alkoxy, halogen, alkyl, haloalkyl, hydroxy, aryl, heteroaryl, aryloxy, amino and tetrazole. ! In another embodiment, Z is pyrazolyl. In another embodiment, Z is a pyrazolyl substituted with at least one substituent selected from the group consisting of cyano, alkoxy, halogen, alkyl, haloalkyl, hydroxy, aryl, heteroaryl, aryloxy, amino and tetrazole ! In another embodiment, Z is pyridinyl.

In another embodiment, Z is a pyridinyl substituted with at least one substituent selected from the group consisting of cyano, alkoxy, halogen, alkyl, haloalkyl, hydroxy, aryl, heteroaryl, aryloxy, amino and tetrazole In another embodiment, Z is imidazolyl.

In another embodiment, Z is an imidazolyl substituted with at least a substituent selected from the group consisting of cyano, alkoxy, halogen, alkyl, haloalkyl, hydroxy, aryl, heteroaryl, aryloxy, amino and tetrazole j In another modality, A is selected from the consistent group from: 1 and R2 are shown attached, represent a heterocyclic ring of 4-8 members having 1 -3 heteroatoms including said N, said ring being heterocyclic optionally substituted with one or more R70, or optionally i fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said ring 4-8 membered heterocyclic may be unsubstituted or optionally replaced independently with one or more portions which can t be the same or different, with each portion selected independently of the group of portions R; E, J and T are equal and are O; ) 20 D30 D40 > R is H or alkyl; Rzu, RJU, R u, and Rou are equal and are H; W is - (CR 1, J32) n-, where n is 0 to 5; X is selected from the group consisting of aryl, heteroaryl and heterocyclyl; And it is selected from the group consisting of a covalent bond, - [C (R) 2] n- where n is from 1 to 2, -O- -NR-; and Z is select from the group consisting of: where: -NR1R2 from R1 R2 is: wherein: each R9 is a substituent for H where indicated and may be the same or different, each independently selected from the group consisting of -OH, -OR4, -C (O) OR1 5, -C (O) N (R 5) (R 6), alkyl, aryl, heteroaryl, alkenyl, alkynyl, cycloalkyl and heterocyclyl, wherein said alkyl, aryl, heteroaryl, alkenyl, alkynyl, cycloalkyl and heterocyclyl can be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being selected independently of the group of portions R70; and x is from 0 to 4, and when x is greater than 1, each portion R9 can be equal or different, each portion is selected independently from the group consisting of portions R9; E, J and T are the same and are O; R 0 is H or alkyl; R20, R30, R40, and R50 are the same and are H; W is - (CR132) n-, where n is 0 to 5; X is selected from the group consisting of aryl, heteroaryl and heterocyclyl; And it is selected from the group consisting of a covalent bond, -tC (R6) 2] n- where n is (R70. * In another modality, A is:; O [ ^ \, R2 wherein R1 and R2, taken together with the N to which R1 and R2 are shown attached, represent a 4-8 membered heterocyclic ring having 1 -3 heteroatoms including said N, said heterocyclic ring being optionally substituted with one or plus R70, or optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said 4-8 membered heterocyclic ring may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion selected independently of the group of portions R70; E, J and T are equal and are O; R10 is H or alkyl; R20, R30, R40, and R50 are the same and are H; W is - (CR132) n-, where n is 0 to 5; X is selected from the group consisting of aryl, heteroaryl and heterocyclyl; Y is selected from the group consisting of a covalent bond, - [C (R6) 2] n- where n is from 1 to 2, -O-, -S-, and -NR1-; and Z is selected from the group consisting of: t In another modality, A is selected from among the consistent group wherein R1 and R2, taken together with the N to which R1 and R2 are shown attached, represent a 3-8 membered heterocyclic ring having from 1-3 heteroatoms including said N, said heterocyclic ring being optionally substituted with one or more R70, or optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said 3-8 membered heterocyclic ring may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion selected independently from the group of portions R70; where E, J and T are equal and are O; R10 is: H or alkyl; R20, R30, R40, and R50 are the same and are H; W is - (CR62) n-, where n is 0 to 5; X is selected from the group consisting of phenyl, piperidinyl, pyridinyl, thienyl, thiazolyl, oxazolyl and pyrazolyl; Y is - [C (R6) 2] n- where n is from 1 to 2; and Z is selected from the group consisting of: In another modality, A is: O where R and R2, taken together with the N to which R1 and R2 are shown attached, represent a 3-8 membered heterocyclic ring having from 1 to 3 heteroatoms including said N, said heterocyclic ring being optionally substituted with one or more R70, or optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclic, wherein said 3-8 member heterocyclic ring may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group of R70 portions; | where E, J and T are equal and are O; R 0 is H or alkyl; R20, R30, R40, and R50 are the same and are H; W is - (CR62) n-, where n is 0 to 5; X is selected from the group consisting of phenyl, piperidinyl, pyridinyl, thienyl, thiazolyl, oxazolyl and pyrazolyl; Y is - [C (R6) 2] n- where n is from 1 to 2; and Z is selected from the group consisting of: In another embodiment, A is selected from the group consisting of: wherein R1 and R2, taken together with the N to which R and R2 are shown attached, represent a 3-8 membered heterocyclic ring having from 1 to 3 heteroatoms including said N,; said heterocyclic ring being optionally substituted with one or more: R70, or optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said ring 3-8 membered heterocyclic can be unsubstituted or optionally replaced independently with one or more portions which can be be the same or different, with each portion selected independently of the group of portions R70; E, J and T are equal and are O; R10 is H or alkyl; R20, R30, R40, and R50 are the same and are H; W is - (CR62) n-, where n is 0 to Í5; X is selected from between the group consisting of phenyl, piperidinyl, pyridinyl, thienyl, thiazolyl, oxazolyl and pyrazolyl; And it is selected from the group consisting of O-, -S-, and -NR1-; and Z is selected from the group consisting of: In another modality, A is OR N 'and \, R2 where R1 and R2, taken together with the N to which R and R2 are shown attached, represent a 3-8 membered heterocyclic ring which has 1 -3 heteroatoms including said N, | being said ring heterocyclic optionally substituted with one or more R70, or optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, where said ring 3-8 membered heterocyclic may be unsubstituted or optionally replaced independently with one or more portions which can be be the same or different, with each portion selected independently of the group of portions R70; where E, J and T are equal and are O; R10 is H or alkyl; R > 2u0, R D30 R40, and R50 are the same and are H; W is - (CR62) n-, where! n is from 0 to 5; X is selected from the group consisting of phenyl, piperidinyl, pyridinyl, thienyl, thiazolyl, oxazolyl and pyrazolyl; And it is selected from the group consisting of O-, -S-, and -NR-; and Z is selected from the group consisting of: another modality, A is selected from among the group consisting from: where R1 and R2, taken together with the N to which R1 and R2 are shown attached, represent a ring: heterocyclic 3-8 members having 1 -3 heteroatoms including said N, said heterocyclic ring optionally substituted with tino or more R70, or i optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said 3-8 membered heterocyclic ring can be unsubstituted or optionally substituted independently with one or more portions the which can be the same or different, each being selected independently of the group of portions R70! where E, J and T are equal and are O; R 0 is H or alkyl; R20, R 30 R40, and R50 are the same and are H; W is - (CR 32) n- where n is 1 or 2; X is selected from the group consisting of phenyl, piperidinyl, pyridinyl, thienyl, thiazolyl, oxazolyl and pyrazolyl; And it's a covalent bond and Z is select from the group consisting of: In another modality, A is OR II INT R \ where R1 and R2, taken together! with the N to which R and they show united, they represent a heterocyclic ring of 3-8 members wherein said heterocyclic ring is optionally substituted with one or more R70, or optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said 3-8 membered heterocyclic ring may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each option being independently selected from the group of portions R70; where E, J and T are equal and are O; R10 is H or alkyl; R20, R30, R40, and R50 are the same and are H; W is - (CR 32) n- where n is 1 or 2; X is selected from the group consisting of phenyl, piperidinyl, pyridinyl, thienyl, thiazolyl, oxazolyl and pyrazolium; And it is a covalent bond and Z is selected from the group consisting of: In another embodiment, X is selected from the group consisting of phenyl, piperidinyl, pyridinyl, thienyl, thiazolyl, oxazolyl, and pyrazolyl. In another embodiment, X is selected from the group consisting of phenyl, piperidinyl, thienyl, and pyridinyl and Y is selected from the group consisting of a covalent bond, - [C (R6) 2] n- where n is 1 to 2 and -O-. In another embodiment, X is phenyl and Y is selected from the group consisting of a covalent bond, -CH2- and -O-. In another embodiment, X is piperidinyl, Y is a covalent bond, and Z is aryl or heteroaryl with two substituents which may be the same or different, each portion being independently selected from the group consisting of cyano, alkoxy, halogen, alkyl, haloalkyl, hydroxy, aryl, heteroaryl, aryloxy and amino. In another embodiment, W is selected from the group consisting of -CH2-, -C (H) CH3-, -C (CH3) 2- and Y is a covalent bond. In another embodiment, W is -CH2- and Y is -CH2-j. In another modality, Z is selected from among the group consisting of: 1 Another embodiment of the invention describes the compounds shown in Table 1 below. As used above, and throughout this description, the following terms, unless otherwise indicated, will be understood as follows: "Patient" includes both humans and animals. "Mammals" means human beings; 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 from about 1 to about 12 carbon atoms in the chain. The most preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. The term "substituted alkyl" means that the alkyl group may be substituted with one or more substituents which may be the same or different, each substituent is independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH (alkyl), -NH (cycloalkyl), -N (alkyl) 2, carboxy and -C (0) 0 -alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. The term "fluoroalkyl" means an alkyl group in which the alkyl is as previously described where one or more hydrogens are replaced with fluorine atoms. "Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 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 p more lower alkyl groups such as methyl, ethyl or propyl, are attached to; a linear alkenyl chain. "Lower alkenyl" means approximately 2 to approximately 6 carbon atoms in the chain which can be straight or branched. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octehyl and decenyl. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. The alkynyl groups; Preferred have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means that the alkynyl group may be substituted with one or more substituents which may be the same or different, each substituent is independently selected from the group consisting of: alkyl, aryl and cycloalkyl. "Aryl" means a monocyclic or aromatic multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group may be optionally substituted with one or more "substituents in the ring system" which may be the same or different and are as defined in this invention. Non-limiting examples of suitable aryl groups include phenyl and paphthyl. "Heteroaryl" means a monocyclic or aromatic multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, wherein one or more of the ring atoms is a non-carbon element , for example, 'nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" may be optionally substituted with one or more "substituents on the ring system" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least one nitrogen atom, oxygen or sulfur respectively, is present as a ring atom. A nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1, 2, 4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo [1,2-a) pyridinyl, imidazo [2,1-bthiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, Midazopyridyl, soquinolinyl, benzoazaindolyl, 1,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl-alkyl group in which aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The link to the mother portion is through the alkyl. "Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkynes comprise a lower alkyl group. A non-limiting example of a suitable alkylaryl group is tolyl. The link to the mother portion is through the aril. "Cycloalkyl" means a ring system: mono- or non-aromatic multicyclic 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 "substituents on the ring system" which may be the same or different, and are as defined above. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and Similar. Non-limiting examples of suitable mülticyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for example, indanyl, tetrahydronaphthyl and the like. "Halogen" means fluorine, chlorine, bromine or yqdo. Fluorine, chlorine and bromine are preferred. j "Substituent in the ring system" means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces a hydrogen available in the ring system. The substituents in the ring system can be the same or different, each 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), Y1Y2N-, Y1Y2N-alkyl-, Y1Y2NC (0) -, YiY2NS02- and -SO ^ Y ^, where? ? and Y2 may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Substituent in the ring system" can also mean a single portion which simultaneously replaces two available hydrogens in two adjacent carbon atoms (one H in each carbon) in one system ring. Examples of such portions are methylenedioxy, ethylenedioxy, -C (CH3) 2- and similar ones which form portions such as, for example: "Heterocyclyl" means a monocyclic ring system or saturated non-aromatic multicyclic comprising approximately 3 a about 10 atoms in the ring, preferably about 5 to about 10 atoms in the ring, where one or more of the I atoms in the ring system is an element that! It's not carbon, example, nitrogen, oxygen or sulfur, alone or in combination. There are not any oxygen atom and / or adjacent sulfur present in the ring system. The Preferred heterocyclyls contain about 5 to about 6 atoms in the ring. The prefix aza, oxa or aunt before the root name heterocyclyl means that at least one nitrogen, oxygen or sulfur atom respectively, it is present as an atom in the ring. Any -NH in a heterocyclyl ring may exist protected such as, for example, as a group -N (Boc), -N (CBz), -N (Cough) and the like; said protections are also considered part of this invention. The, heterocyclyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined in this invention. The nitrogen or sulfur atom of the heterocyclyl may be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. The Non-limiting examples of suitable monocyclic heterocyclic rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorinolinyl, thiazolidinyl, 4-dioxanyl, tetrahydrofuranyl, tetrahi rotophenyl, lactam, lactone, and the like. It should be noted that in ring systems containing heteroatoms of this invention, there are no hydroxyl groups on carbon atoms adjacent to an N, O or S, nor are there any N or S groups on the carbon adjacent to another heteroatom. Therefore, for example, in the ring: there is no -OH attached directly to the carbons marked 2 and 5. It should also be noted that tautprominic forms such as, for example, the portions:! consider equivalents in certain embodiments of this invention. "Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl group and a lower alkyl group. He link to the mother portion is through alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. "Heteroaralkyl" means a heteroaryl-alkyl- group in which the 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 to the mother portion is through the alkyl. "Hydroxyalkyl" means an HO-alkyl group wherein 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 to the mother portion is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.; "Aroyl" means an aryl-C (O) - group in which the aryl group is as previously described. The link to the mother portion is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The link to the mother portion is through the oxygen of the ether. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The link to the mother portion is through the oxygen of the ether. "Aralkyloxy" means an aralkyl-O-1 group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1-, 2-naphthalenemethoxy. The link to the mother portion is through the oxygen of the ether. "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The link to the mother portion is through sulfur. "Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The link to the mother portion is through sulfur. "Aralkylthio" means an aralkyl-S- group; wherein the aralkyl group is as previously described. A non-limiting example of a suitable aralkylthio group is benzylthio. The link to the mother portion is through sulfur. "Alkoxycarbonyl" means an alkyl-p-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The link to the mother portion is through the carbonyl.

"Aryloxycarbonyl" means an aryl-O-C (O) - group. The examples do not Limits of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The link to the mother portion is through the carbonyl.

"Aralkoxycarbonyl" means an aralkyl-O-C (O) - group. Example non-limiting of a suitable aralkoxycarbonyl group is! benzyloxycarbonyl. He link to the mother portion is through the carbonyl.

"Alkylsulfonyl" means an alkyl-S (02) - group. The groups Preferred are those in which the alkyl group is lower alkyl. He link to the mother portion is through the sulfonyl.; "Arylsulfonyl" means an aryl-S (02) - group. The link to the portion mother is through sulfonyl.

The term "substituted" means that one or more hydrogens on the designated atom are replaced with a selection of the indicated group, with the condition that the normal valence of the atom designated under existing circumstances does not exceed, and that substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in compounds stable By "stable compound" or "stable structure" is meant an compound that is strong enough to survive isolation up to a useful degree of purity of a reaction mixture; and formulation in a effective therapeutic agent. ! The term "optionally substituted". means substitution optional with groups, radicals or specified portions.

The term "isolated" or "in isolation" for a compound, is refers to the physical state of said compound after being isolated from a synthetic process or natural source or the combination thereof. The term "purified" or "in purified form" for a compound refers to the state physical condition of said compound after being obtained from a procedure or purification procedures described in this invention or well known by those skilled in the art, with sufficient purity to be characterizable by conventional analytical techniques described in this invention or known by the experts. I It should also be noted that any carbon as well also heteroatom with valences not satisfied in. the text, schemes, Examples and Tables of this invention are assumed to have the amount enough of hydrogen atom (s) to satisfy the valences.

When a functional group in a compound is called "protected", this means that the group is in modified form to avoid side reactions at the protected site when the compound is submitted to a reaction. The appropriate protective groups will be recognized by those skilled in the art as well as by reference to conventional textbooks such as, for example; T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.

When any variable (eg, aryl, heterocycle, R2, etc.) appears more than once in any constituent or; in Formula I, its definition in each occurrence is independent of its definition in each of the other appearances.

As used herein, the term "composition" has the purpose 1 of encompassing a product comprising the ingredients specified in specified quantities, as well as any product that is the result, direct or indirect, of the combination: of the ingredients specified in the specified quantities.

The prodrugs and solvates of the compounds of the invention they are also contemplated here. The term "prodrug", as used in this document denotes a compound that is a drug precursor which, after administration to a subject, undergoes chemical conversion by metabolic or chemical processes to produce a compound of Formula I or a salt and / or solvate thereof. A description of prodrugs is provides in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both documents are incorporated here as reference.; "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 bonding, including bonding hydrogen. In certain cases, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crosslinked crystalline crystalline solid. "Solvato" covers both | solvates in solution phase as isolators. Non-limiting examples of suitable solvates include ethanolates, methanolates and the like. "Hydrate" is a solvate where the solvent molecule is H20. "Effective amount" or "therapeutically effective amount", describe an amount of compound or composition of the present invention effective to inhibit CDK (s) and thus produce! The desired therapeutic, relieving, inhibiting or preventive effect. The compounds of Formula I can form salts that are also within the scope of this invention. The reference to a compound of Formula I in this invention is understood to include reference to its salts, unless otherwise indicated. The term "salts (s)", as used in this invention, denotes acid salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. Additionally, when a compound of Formula I contains both a basic portion, such as, but not limited to, a pyridine or imidazole, and an acid portion, such as, but not limited to, a carboxylic acid, zwitterions may be formed ("salts"). internal ") and are included within the term" sale (s) "as used in this document. 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 reacting a compound of Formula I with a amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Examples of acid addition salts include acetates, Ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphor sulfonates, fumarates, hydrochlorides, Hydrobromides, iodides, lactates, maleates,! methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. Additionally, the acids that are generally considered adequate for the formation of salts pharmaceutically useful starting from basic pharmaceutical compounds are described, for example, by P. Stahl et al, Camille GJ (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences] (1977) 66 (1) 1 -19; P.

Gould, International J. of Pharmaceutics (1986) 33 201; -217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; Y in The Orange Book (Food &Drug Administration, Washington, D.C. in his website). These descriptions are incorporated in this document by reference to them.

Exemplary basic salts include ammonium salts, salts of alkali metals such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as dicyclohexylamines, t-butylamines and salts with amino acids such as arginine, lysine and the like. The basic groups that contain nitrogen can be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl and butyl chlorides, bromides and iodides), dialkylsulfates (by example, dimethyl, diethyl and dibutyl sulphates), long chain halides (by eg, chlorides, bromides and iodides of decyl, lauryl and festearyl), halides of aralkyl (eg, benzyl and phenethyl bromides) and others.; All those acid salts and basic salts have the purpose of be pharmaceutically acceptable salts within the scope of the invention and all the acidic and basic salts are considered equivalent to the free forms I of the corresponding compounds for the purposes of the invention.

The compounds of Formula I, and their salts, solvates and prodrugs, can exist in their tautomeric form (for example, as a amide or mino ether). All these tautomeric forms are contemplated in this invention as part of it. '· All stereoisomers (for example, 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 also 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 absence of asymmetric carbons), rotameric forms, atropisomers, and Diastereomeric forms are contemplated within the scope of this invention, as are 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 they may be mixed, for example, as racemates or with all other stereoisomers, or other selected ones. The chiral centers of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "prodrug" and the like is intended to apply equally to the salt, the solvate and the 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 intended to be included in the present invention. ! The compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can be inhibitors of the activity of LpxC, TACE, aggrecanase, ADMP, TNF-a, ADAM and / or MMP. In one aspect, the invention provides a pharmaceutical composition comprising as active ingredient the pentanes a compound of formula 1. In another aspect, the invention provides a composition Pharmaceutical of formula 1 further comprising at least one pharmaceutically acceptable carrier. In another aspect, the invention provides a method for treating disorders associated with LpxC, TACE, aggrecanase, ADMP, TNF-α, MMPs, ADAMs or any combination thereof, said method comprising administering to a patient in need of such treatment a A pharmaceutical composition comprising therapeutically effective amounts of at least one compound of formula 1. In another aspect, the invention provides a use of a compound of formula 1 for the manufacture of a medicament for treating disorders associated with LpxC, TACE, ADMP, aggrecanase, TNF-a, 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, sepsis syndrome, post-ischemic reperfusion injury, malaria , mycobacterial infection, meningitis ^ psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, inflammatory skin diseases, inflammatory bowel diseases such as Crohn's disease and colitis, OA and RA, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Behcehe's disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, regional pain syndrome complex, radiation damage, hyperoxic alveolar injury, disease periodontal disease, HIV, non-insulin-dependent diabetes mellitus, lupus erythematosus systemic, glaucoma, sarcoidosis, pulmonary fibrosis; idiopathic dysplasia bronchopulmonary disease, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral apoplexy, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing alveolitis, psoriasis, I transplant rejection, atopic dermatitis, vasculitis, allergy, allergic rhinitis seasonal, reversible obstruction of the respiratory tract, adult respiratory failure, asthma, obstructive pulmonary disease chronic (COPD) and / or bronchitis. It is contemplated that a compound of this invention can be useful in the treatment of one or more diseases mentioned.

The compounds of Formula I may also have activity antibacterial and can be useful in the treatment of an infection microbial, including gram-negative and gram-positive infections.

In another aspect, the invention provides a method for preparing a pharmaceutical composition for treating; Associated disorders with LpxC, TACE, aggrecanase, ADMP, TNF-a, MMPs; ADAMs or any combination thereof, said method comprising contacting intimate at least one compound of formula 1 and at least one carrier pharmaceutically acceptable.

In another aspect, the invention provides a compound of formula (I) that exhibits inhibitory activity of LpxC, TACE, aggrecanase, ADMP, TNF-α, MMPs, ADAMs or any combination thereof, including the enantiomers, stereoisomers and tautomers of said compound, and pharmaceutically salts or solvates; acceptable of said compound, said compound selected from among the compounds of structures listed below: twenty I twenty twenty twenty twenty twenty ? i or a salt, pharmaceutically acceptable solvate or ester thereof. In another aspect, the invention provides a pharmaceutical composition for treating disorders associated with LpxC, TACE, aggrecanase, ADMP, TNF-α, MMP, ADAM or any combination thereof in a subject, which comprises administering to the subject in need of said treatment a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof. In another aspect, the invention provides a compound of formula 1 in purified form.; In another aspect, the invention provides a method for the treatment of a condition or disease mediated by LpxC, TACE, aggrecanase, ADMP, MMPs, TNF-α, aggrecanase (such as aggrecanase 1, aggrecanase 2, aggrecanase 3, aggrecanase 4, or aggrecanase 5), 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 1 or a pharmaceutically acceptable salt, solvate or isomer thereof. In another aspect, the invention provides a method for treating a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion due to secondary metastasis, neovascular glaucoma, inflammatory disease of | intestine, sclerosis multiple and psoriasis in a subject, comprising: admjnistrar the subject that such a treatment requires a therapeutically effective amount of at least one compound of formula 1 or a salt, solvate or isomer pharmaceutically acceptable thereof.

In another aspect, the invention provides a method for treating a condition or disease selected from the group consisting of fever, cardiovascular conditions, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoinjune disease and infection by HIV in a subject, which comprises administering to the subject in need of said treatment a therapeutically effective amount: of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer acceptable from it.; In another aspect, the invention provides a method for treating a condition or disease selected from among the consistent septic shock, hemodynamic shock, sepsis syndrome, injury post-ischemic reperfusion, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, inflammatory skin diseases, inflammatory bowel diseases such as Crohn's disease and colitis, psteoarthritis and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, | Adult Still's disease, urethritis, Wegener's granulomatosis, Behcehe's disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, diabetes noninsulin-dependent mellitus, sistémic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral infarction, cerebral ischaemia, nephritis, hepatitis, glomerulonephritis, alveolitis cryptogenic fibrosing, psoriasis, rejection of t ansplante, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible obstruction of the respiratory tract, syndrome of adult respiratory insufficiency, asthma, chronic obstructive pulmonary disease (COPD) and bronchitis in a subject, which it comprises administering to the subject that needs a of said treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof. In another aspect, the invention provides a method for treating a condition 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 1 or a salt, solvate or isomer pharmaceutically acceptable thereof.

In another aspect, the invention provides a method for treating a condition or disease associated with rheumatoid arthritis, comprising: administer to the subject who needs such treatment an amount Therapeutically effective of at least one compound of formula 1 or a salt, pharmaceutically acceptable solvate or isomer thereof.

In another aspect, the invention provides a method for treating a condition or disease associated with Crohn's disease, which comprises: administering to the subject in need of said treatment a Therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.

In another aspect, the invention provides a method for treating a condition or disease associated with psoriasis, which includes: administering to the subject in need of such treatment a therapeutically effective amount I of at least one compound of formula 1 or a salt, pharmaceutically acceptable solvate or isomer of the same.

In another aspect, the invention provides a method for treating a condition or disease associated with ankylosing spondylitis, which comprises: administering to the subject in need of said treatment a Therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof.

In another aspect, the invention provides a method for treating a condition or disease associated with sciatica, which involves: administering I the subject who needs such treatment a quantity therapeutically effective of at least one compound of formula 1 or a salt, solvate or isomer pharmaceutically acceptable thereof. In another aspect, the invention provides a method for treating | a condition or disease associated with regional pain syndrome complex, which comprises: administering to the subject what needs of said treatment a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer acceptable from it. In another aspect, the invention provides a method for treating a condition or disease associated with psoriatic arthritis, comprising: administering to the subject in need of such treatment a therapeutically effective amount I of at least one compound of formula 1 or a salt, pharmaceutically acceptable solvate or isomer thereof.

In another aspect, the invention provides a method for treating a condition or disease associated with multiple sclerosis, which comprises: administering to the subject in need of said treatment a Therapeutically effective amount of at least one compound of formula 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 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; such as methotrexate, azathioprine, leflunomide, penicillinamine, gold salts,; mycophenolate mofetil, cyclophosphamide and other similar drugs. They may also be administered or used in conjunction with NSAID's such as piroxicam, naproxen, indomethacin, ibuprofen and the like; selective COX-2 inhibitors such as Vioxx® and Celebrex®; immunosuppressants such as spheroids, cyclosporin, Tacrolimus, rapamycin and the like; biological response modifiers (BRM's) such as Enbrel®, Remicade®, IL-1 antagonists, anti-CD40, anti-CD28, IL-10, anti-adhesion molecules and the like; and other antiinflammatory agents such as p38 kinase inhibitors, PDE4 inhibitors, other chemically different TACE inhibitors, chemokine receptor antagonists, Thalidomide and other small molecule inhibitors of proinflammatory cytokine production. | Likewise, a compound of the present! The invention can be administered or used in conjunction with an H1 antagonist for the treatment of seasonal allergic rhinitis and / or asthma. Suitable H1 antagonists can be, for example, Claritin®, Clárinex®, Allegra®, or Zyrtec®. In another aspect, the invention provides a method for treating a condition or disease mediated by TACE, aggrecanase, ADMP, MMPs, TNF-a, aggrecanase, or any combination thereof in a subject, comprising: administering to the subject in need of said treatment a Therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt, solvate or isomer thereof in combination with a therapeutically effective amount of at least one medicament selected from the group consisting of disease modifying anti-rheumatic drugs ( DMARDS), NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressants, biological response modifiers (BRM's), anti-inflammatory agents and H1 antagonists. In another aspect, the invention provides a method for treating a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, disease 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 according to claim 1 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 DMARDS ', NSAID's, COX-2 inhibitors, COX-1 inhibitors, immunosuppressants,: BRM's, anti-inflammatory agents and antagonists. H 1 In another aspect, the invention provides a method for treating a condition or disease selected from the group consisting of septic shock, hemodynamic shock, sepsis syndrome, post-ischemic reperfusion, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, inflammatory skin diseases, inflammatory bowel diseases such as Crohn's disease and colitis, osteoarthritis and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis. Still adult disease, urethritis, Wegener's granulomatosis, Behcehe's disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome; radiation damage, hyperoxic alveolar injury, periodontal disease, HIV; non-insulin-dependent diabetes mellitus, systemic lupus erythematosus, glucucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral infarction, cerebral ischemia, 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, 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 according to claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof in combination with an amount Therapeutically effective of at least one drug selected from the group consisting of DMARDS, NSAID's, COX-2 Inhibitors, COX-1 inhibitors, immunosuppressants, BRM's, anti-inflammatory agents and H1 antagonists. ! In another aspect, the invention provides a method for treating RA comprising administering a compound of Formula I in combination with a compound selected from the class consisting of a COX-2 inhibitor, e.g. Ceex® or Vioxx®; a COX-1 inhibitor, eg. Feldene®; an immunosuppressant, e.g. methotrexate or cyclosporin; a steroid, for ex. β-metasone; and an anti-TNF-a compound, e.g. Enbrel® or Remicade®; an inhibitor of PDE IV, or other classes of compounds indicated for the treatment of RA. In another aspect, the invention provides a method for treating multiple sclerosis, which comprises administering a compound of Formula I, in combination with a compound selected from the group consisting of Avonex®, Betaseron, Copaxone or other bulking indicated for treatment of multiple sclerosis. j In another aspect, the invention provides a method for the treatment of a microbial infection in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or ester thereof. In one embodiment, the microbe that causes the infection is a bacterium, in another modality it is a fungus. In one modality, the Microbial infection is a gram negative infection; in another modality, it is a gram negative infection. ! In another aspect, the invention provides a method for the treatment of a microbial infection in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I in combination with urgency or more antibacterial or antifungal agents. In one embodiment, said additional antibacterial agent is active against gram negative bacteria. In another embodiment, said additional antibacterial agent is active against gram positive bacteria. In another embodiment, the bacterial infection is caused by at least one organism selected from the group consisting of: I Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Acinetobacter hydrophila, Actinobacillus actinomycetemcomitans, Aeromonas hydrophila, Alcaligenes xylosoxidans, Bacteroides distasonis, Bacteroides fragilis , Bacteroides melaninogenicus, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bartonella henselae, Bordetella pertussis, Branhamella, catarrhalis, Brucella melitensis, Brucella abortus, Brucella canis, Burkholderia cepacia, Burkholderia mallei, Burkholderia pseudomallei, Campylobacter coli, Campylobacter fetus, Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Citrobacter koseri, Coxiella burnetli, Edwarsiella tarda, Ehrlichia chafeenis, Eikenella corrondens, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Escherichia coli, Flavobacterium I meningosepticum, Francisella tularensis, Fusobacteriun spp., Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainflqenzae, Helicobacter pylori, Kingella kingae, Klebsiella oxytoca, Klebsiella j ozaenae, Klebsiella j pneumoniae, Klebsiella rhinoscleromatis, Legionella pneumophila, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae , Neisseria meningitides, Pasteurella multocida, Plesiomonas shigelloides, Porphyromonas asaccharolytica, Porphyromonas gingivalis, Prevotella bivia, Prevotella buccae, Prevotella corporis, Prevotella endodontalis, Prevotella intermedia, Prevotella melaninogenica, Prevotella oralis, Proteus mirabilis, Proteus myxofaciens, Proteus penner, Proteus \ Zulgaris, Providencia j alcalifaciens, Providencia rettgeri, Providencia stüaríii, Pseudomonas aeruginosa, Pseudomonas fluorescens, Ricketsia prdwozekii, Enteric Salmonella, Serratia marcescens, Shigella boydii, Shigella \ dysenteriae, Shigella flexneri, Shigella sonnei, Stenotrophomonas maltophilia, Streptobacillus moniliformis, Vibrio alginolyticus, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vuluificus, Yersinia enterocolitica, Yersinia pestis, and Yersinia pseudotuberculosis. In another embodiment, the bacterial infection is caused by at least one organism selected from the group consisting of: Acinetobacter baumannii, Acinetobacter spp., Aeromonas hydrophila, Bacteroides fragilis, Bacteroides spp., Bordetella pertissis, Campylobacter I jejuni, Campylobacter spp., Citrobacter freundii, Citrobacfer spp., Enterobacter cloacae, Enterobacter spp., Escherichia coli, Fusobacterium spp., I Haemophilus influenzae, Haemophilus parainfluenza, Helicobacter pylori, Klebsiella pneumoniae, Klebsiella spp., Legionella pn ^ umophila, Moraxella catarrhalis, Morganella morganii, Neisseria goriprrhoeae, Neisseria meningitides, Pasteurella multocida, Prevotella spp., Pro'teus mirabilis, Proteus spp., Providencia stuartii, Pseudomonas aeruginosa, Pseudomonas spp., Salmonella enterica, Salmonella typhi, Serratia marcéscens, Shigella spp., Stenotrophomonas maltophilia, Vibrio cholerae, Vibrio spp., And Yersinia spp. I TACE activity is determined by a kinetic test that measures the rate of increase in fluorescent intensity generated by the TACE catalyzed cleavage of a peptide substrate internally tempered (SPDL-3). In this assay, the purified catalytic domain I of recombinant human TACE (rhTACEc, Residue 215 to? 477 with two mutations (S266A and N452Q) and one tail | 6xHis) is used. It is purified starting from the expression system of baculovirus / H5 cells using affinity chromatography. The SPDL-3 substrate is an internally \ peptide tempered (MCA-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Dpa-Arg-NH2), with its sequence derived from the unfolding site pr -TNFa. MCA is (7- Methoxycoumarin-4-yl) acetyl. Dpa is N-3 - (: 2,4-Dinitrophenyl) -L-2,3-diaminopropionyl. j A 50 μm assay mixture contains 20 mM HEPES, pH 7.3, CaCl2 5 mM, 100 μ.? of ZnCl2, 2% DMSO, 0.04% mptilcellulose, 30 μ? from SPDL-3, 70 pM rhTACEc and a test compound. RhTACEc is preincubated with the test compound for 90 min., at 25 ° C. The reaction is initiated by the addition of the substrate. The intensity fluorescent (excitation at 320 nm, emission at 405 nrri) was measured every 45 seconds for 30 min. , using a fluorospectrometer (GEMINI XS, Molecular Devices). The enzyme reaction rate is shown as Units per second. The effect of a test compound is shown as% of TACE activity in the absence of the compound.

The procedures of the Patent Publication were followed International WO00 / 05256 (published on February 3, 2000) for the detection of ADMP activity and to measure the IC50 of the compounds of the present invention. This was indicative of the attitud disintegrin and metalloproteinase thrombus spondinine 4 and 5 (ADAMTS-4-5).

The enzyme was commercially acquired from Calbiochem (Cat # PF1 1 3) and the peptide substrate described in the patent was ordered to I AnaSpec. i The standard LpxC assay consists of 0.2 nM LpxC enzyme, 1 .0 μ? of UDP-3-0- (R-3-hydroxymyristoyl) - / V-acetylglucosamine, and composed of trial, in assay regulator and 2% DMSO. The test controller is composed of 25 mM HEPES, pH 7.3, 150 mM NaCl, 2.0 mM DTT, and 0.01% of BSA. The enzymatic reaction is carried out in a test plate of 96 wells, in a final volume of 102 μ ?. The solutions of compounds of assays are prepared in 100% DMSO. Additions of the reaction, in order, are: (1) 2.0 iL of compound solution, (2) 80 μ? of test controller, (3) 10 μ? of 10 μ? of UDP-3-0- (R-3-hydroxymyristoyl) -A / -acetylglucosamine (in test regulator) and, (4) 10 μ? of enzyme LpxC (20nM in regulated test) to start the reaction. In reactions of positive contrpl, the addition (1) has 2.0 μ? _ Of 100% DMSO (without compound); these reactions are used I as the total signal value (TSB). The reactions are incubated at temperature environment for 60 minutes when 10 μL of HCl 1 N are added to stop the reaction. The plate is stirred by hand for 10 seconds to ensure complete tempering. The test plates are sealed with tape aluminum foil, and stored at -80 ° C for 24 - 48 hr prior to analysis.

The substrate and product concentrations in the mixtures of reaction are determined with mass spectrometry; high perfomance RapidFire ™ owned by BioTrove (HTMS). The test mixtures are partially purified with reverse phase chromatography, where they are washed with water containing 5 mM ammonium format and eluted on the mass spectrometer in 80% acetonitrile, 20% water, and format ammonium 5 mM. The peak areas of mass spectrometry of the substrate and product are measured to determine the concentration of these analytes.

Test signal is the percentage of substrate that becomes a product. He percent inhibition,% I, in the test samples; is determined from of the following equation: I The inhibitory activities of compounds! representative of the present invention are shown in the Table below. In this Table that appears below, an inhibition of more than 30% is assigned an "A" rating, 10-30% of inhibition is assigned the "B" rating, and less than 10% of inhibition is assigned the "C" rating.

The inhibitory activities of ADMP for representative compounds are shown in the Table below. Compounds that have IC5o values greater than 5 μ? (> 5 μ?) are designated as "D" class. Compounds that have IC5 values greater than 1 μ ,? but up to 5 μ? (> 0.1 μ? - 5 μ?) are designated as class "C". The IC50 values between 0.25 μ? and 1.0 μ? (0.25 μ? - 1 μ?) Are I designated as class "B". IC50 values less than 0.25 μ? (< 0.25 μ?) are designated as class "A".

? Representative examples of the compounds of the invention specific IC50 lores (inhibition of ADMP) are listed in Table jo: ? The pharmaceutical compositions containing the active ingredient i may be in a form suitable for oral use, for example,? like tablets, pills, water suspensions! or oily, powders dispersible or granules, emulsions, hard capsules or; soft, or syrups or elixirs. Compositions designed for oral use can be prepared from according to any method known in the art for the manufacture of pharmaceutical compositions and said compositions may contain one or more agents selected from the group consisting of agents sweeteners, flavoring agents, coloring agents and agents preservatives in order to provide pharmaceutically preparations elegant and palatable. The tablets contain the active ingredient in mixture with non-toxic excipients, pharmaceutically; acceptable, which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents, such as carbonate! calcium, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They can also be coated by the technique described in US Patent Nos. 4,256, 108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release. Formulations for oral use may also be presented as hard gelatin capsules where the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules where the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil. The aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. These excipients are suspending agents, for example, sodium carboxymethyl cellulose, methyl cellulose, hyd oxypropylmethyl cellulose, I sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; The dispersing agents or wetting agents may be a phosphatide of natural occurrence, for example, lecithin, or condensation products of a alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with aliphatic alcohols of long chain, for example, heptadecaethylene-oxicetanol, or products of Condensation of ethylene oxide with acid-based partial esters fatty acids and a hexitol such as polyoxyethylene monooleate (> sorbitol, or products) of condensation of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene monooleate sorbitan. 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 can be formulated by suspending the active ingredient in a vegetable oil, for example, peanut oil, oil olive, sesame oil or coconut oil, or in mineral oil such as paraffin liquid Oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or ethyl alcohol. Sweetening agents such as those discussed above, i and may be added flavoring agents to provide a palatable oral preparation.

These compositions can be preserved by the addition of a antioxidant such as ascorbic acid. ' Dispersible powders and granules suitable for Preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing agent or humectant, suspending agent and one or more preservatives. The agents suitable dispersants or humectants and suspension agents are exemplified by those already mentioned above. As well additional excipients may be present, for example, agents sweeteners, flavorings and colorants. i The pharmaceutical compositions of the invention also they can be in the form of an oil-in-water emulsion. The oil phase it can be a vegetable oil, eg, olive oil or! peanut oil, or a mineral oil, eg, liquid paraffin or mixtures thereof. The agents Suitable emulsifiers can be naturally occurring phosphatides, eg, soybeans, lecithin, and esters or partial esters derived from acids fatty acids and hexitol anhydrides, for example, sorbitol monooleate condensation products of the partial esters with ethylene oxide, eg, polyoxyethylene sorbitan monoleate. Emulsifiers can also contain sweetening and flavoring agents. ' Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Said formulations can also contain a demulcent, a conservative and flavoring and coloring agents.

The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectible solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example, as a solution in 3-butanediol. Vehicles and acceptable solvents that can be used are water, Ringer's solution and! isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally employed as a solvent or suspension medium. For this purpose any soft fixed oil including synthetic mono- or diglycerides can be used. further, fatty acids such as oleic acid can be used in the preparation of injectables. The compounds of the invention can also be administered in the form of suppositories for rectal administration of the drug. The compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at normal temperatures and liquid at the rectal temperature and, therefore, will melt in the rectum to release the drug. That kind of materials are cocoa butter and polyethylene glycols. For topical use, creams are used! ointments, jellies, solutions or suspensions, etc., which contain the compound of the invention.

(For the purposes of this application, the topical application includes rinses i i buccal and gargle.) ' The compounds of the present invention can be administered in the intranasal form by means of topical use of intranasal vehicles appropriate, or by transdermal routes, using those forms of patches transdermal skin cells well known to those skilled in the art. For your administration in the form of a transdermal delivery system, the dose administration, of course, will be continuous instead of intermittent throughout the dosing regimen. The compounds of the present invention can also be delivered as a suppository using bases such as cocoa butter, gelatin glycerin Jda, vegetable oils hydrogenated, mixtures of polyethylene glycols of various molecular weights and polyethylene glycol fatty acid esters.

The dosage regimen that uses the compounds of the present invention is selected according to a variety of factors which include type, species, weight, sex and medical condition of the patient; the severity of the condition to be treated; the administration route; the function kidney and liver of the patient; and the particular compound | of the same employee.

A doctor or veterinarwith ordinary experience can determine and prescribe easily the effective amount of the drug required to avoid, stop or reverse the progress of the condition. The optimal precision to achieve drug concentration within the scale that provides efficacy without toxicity requires a regimen based on the kinetics of drug availability for the target sites. This involves a consideration of the distribution, the I I balance and elimination of a drug. Preferably, the doses of compound of Formula I useful in the method of the present invention range from between 0.01 and 1000 mg per day. More preferably, the dosages range between 0.1 and 1000 mg / day. Most preferable, dosages range from 0.1 and 500 mg / day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01. to 1000 milligrams of the 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 ingredient Active for the symptomatic adjustment of the dosage to the patient to be treated.

An effective amount of the drug is usually supplied at a level of dosage between about 0.0002 mg / kg and about 50 I i mg / kg of body weight per day. The scale is more particularly between approximately 0.001 mg / kg and 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 may be administered in divided doses of two, three or four times per day.

The amount of active ingredient that can be combined with the Carrier materials to produce a single dosage form will vary depending on the treated host and the particular mode of administration.

However, it will be understood that the level of: specific dose for any particular patient will depend on a variety of factors including age, body weight, general health, sex, diet, time of administration, route or administration, rate of excretion, combination pharmacological and the severity of the particular disease that is being trying. ( The compounds of the invention can be produced I by methods known to those skilled in the art and as shows in the following reaction schemes and in the preparations and examples described below.

EXAMPLES The following abbreviations are used in the procedures and schemes:; ACN Acetonitrile i AcOH Acetic acid ADDP 1, 11- (Azodicarbonyl) dipiperidine Anh Anhydrous! Watery Aq; BOC tert-butoxycarbonyl ° C degrees Celsius CBZCI benzyl chloroformate \ CDI Carbodiimide DBU 1, 8-Diazabicyclo [5.4.0] undec-7; DCC Dicyclohexylcarbodiimide DCM dichloromethane DEAD diethyl azodicarboxylate (DHQ) 2PHAL 1, 4-phthalacinodiyl diether d; and hydroquinone DIAD Diisopropilazodicarboxylate I DIEA Diisopropylethylamine DMA N, N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DME Dimethoxyethane DMF Dimethylformamide and DMFDMA?,? - Dimethylformamide dimethylacetal DMPU 1, 3-Dimethyl-3,4,5,6-tetrahydro-2. { 1 h) -pyrimidinone DMSO Dimethylsulfoxide i EDC 1 - (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride The lonization of Electrons Eq Equivalents EtOAc Ethyl acetate EtOH Ethanol 9 grams h. hours 1H proton HATU N, N, N ', N'-tetramethyl-0- (7- azabenzotriazol-1-yl) uronium hexafluorophosphate Hex hexanes HOBt 1 -Hydroxybenzotriazole: i HPLC High pressure liquid chromatography LAH Lithium aluminum hydride; LDA Lithium Diisopropylamide M Molar mCPBA Mere-Chloroperoxybenzoic Metric MeCN Acetonitrile! MeOH Methanol i min minutes! mg Milligrams MHz Megahertz ml Milliliter MS Mass spectroscopy NMM N-Methylmorpholine j NMP 1 -methyl-2-pyrrolidone; ON Overnight j Pd ('Bu3P) 2 Bis- (tri-ref-butylphosphine) palladium | Pd (TPP) 4 Tetrakis- (triphenylphosphine) palladiumPd (Oac) 2 Palladium acetate (ll) PdCl2 (TPP) 2 Bis- (triphenylphosphine) palladium chloride (ll) PdCI2 (ddppf) Dichloroyl dichloride, 1 ' -bis (diphenylphosphino) - ferrocene] palladium (II) Pd2 (dba) 3 Tris (dibenzylideneacetone) dipallate (0) PyBrOP bromo-tris-pyrrolidino-phosphonium hexafluorophosphate Pyr Pyridine! TA Ambient temperature? S02 Silica gel chromatography] 60 sgc Silica gel chromatography 60 tBOC tert-butoxycarbonyl TACE TNFralpha TEA conversion enzyme Triethylamine TFA trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TPP Trifenilphosphine tR Retention time i Spectra of MNR were acquired on a Mercury Spectrometer 400 MHz MNR (Varian), using CDCI3 or DMSO-d6 as solvents. The LC-MS data were obtained using an Agilent 1 100 Series LC / MSD (quadrupole, API-ES) with a capillary voltage configured for 3500 V and operating in positive mode. Analytical HPLC retention times reported (LC / MS) were obtained using a reversed phase! C18 column (150 x 4.6 mm) leaching with a gradient of 5 or 10 | minutes of 0.1% trifluoroacetic acid in water for acetonitrile: water 95: 5 with a flow rate of 3 ml / min. The purification by reverse phase chromatography was achieved using a C18 reverse phase column with a gradient of 0.1% acid trifluoroacetic acid in water for 95: 5 acetonitrile: water with a flow rate of 20 ml / min. Samples were collected using a UV signal (Gilson, 254 nm) or mass spectrum signal (Agilent 1 00 Series LC / SD model SL).

Chromatography was achieved on silica gel! of normal phase in a Biotage instrument using a Quad UV system (P / N 07052) using KP-SIL 32-63 um, 60A columns with 12+ or 25 + M flash cartridges.

The compounds of formula (I) can be produced by procedures known to those skilled in the art and as shown in the following reaction schemes and in the preparations and examples described below. It should not be considered that these preparations and examples limit the competence of the description. Routes of mechanisms alternatives and analogous structures may be evident to experts in The technique. Some of the compounds prepared by these procedures are listed in Table 1. All! the types of forms isomeric compounds are considered within the scope of this invention.

EXAMPLE 1 I General synthesis of ta st inhibitors There are two general routes for the synthesis of diamides from tartrate from amines. The first one (Example 1) uses a monomeric I intermediate / monoester protected by acetonide prepared from dimethyl commercially available acetonide ester using a process of the literature (J. Am. Chem. Soc. 1978, 100, 4865-4872). In general, anyone of General Example 1 or General Example 2 could be used indistinctly, although it was found that Example 2i is more preferred for compounds containing functional groups that! were unstable with with respect to the acidic conditions of deprotection (such as 113).

A variety of amide bond coupling reagents were acceptable, including HATU, CDI, EDC, DCC / HOBt, PyBrOP, CDI supported on polymer with HOBt, carbodiimide supported on polymer, and EDC supported in polymer (PS-EDC) with HOBt. These coupling reagents they could be used with a variety of bases, including triethylamine (TEA), diisopropylethylamine (DIEA), N-methyl morpholine, pyridine, dimethylaminopyridine t (DMAP) and imidazole. In some cases, excess amines in steps of peptide coupling were removed using liquid / liquid extraction or polymeric filter resins such as polymer supported isocyanate (PS-NCO) and / or polymer-supported thickened acid (MPLTsOH). The acids without reacting could be removed using MP carbonate resin or resins from ? polymers containing basic functional groups such as trisamine (ie, PS-trisamine), amberlite or morpholine. Peptide couplings were carried out in a variety of solvents, including DMF, THF, dioxane, acetonitrile, NMP and DCM. These solvents can also be combined in several proportions to optimize the reaction conditions. A route less preferred but viable using ester intermediates Pentafluorophenyl (PFP) can also be used to prepare mono- diamides; Preferred solvents for this approach should include THF. HE can find general peptide coupling strategies, i including PFP-based approaches, in Bodanszky & Bodanszky, The i Practice of Peptide Synthesis, second edition, Springer-Verlag, 1994.

The cleavage (saponification) of the methyl ester of the intermediary could be achieved in a variety of well-known conditions, including: a slight excess (1.1-3 equivalents) of a base, KOH in methanol, LiOH in THF / water, LiOH in; methanol / water, and NaOH / THF / MeOH / water. The removal of the acetonide protecting group is could produce using a variety of acidic conditions, including combinations of TFA: water (such as 80:20). : I Part A: To the monomethyl ester of 2,2-dimethyl- [1, 3] dioxolane-4R, 5R-dicarboxylic acid (1) (Musich, JA; Rapoport, H .; J. Am. Chem. Soc. 1978, 100, i 4865 -4872) (500 mg, 2.45 mmol) in DMF (5 mL) was added 2-thiophene-ethylamine. (316 μ ?, 2.70 mmol), DIEA (0.94 ml, 5.4 mmol) and HATU! (989 mg, 2.60 mmol).

The reaction mixture was stirred overnight and the DMF was removed in vacuo.

The residue was dissolved in EtOAc, washed with water, bicarbonate solution saturated, 0.1 N HCl, and brine. The organic layer was dried over sodium sulfate sodium and concentrated. Purification by column chromatography (S02, 10% EtOAc / DCM) gave 2 as an oil (491 mg, 64%). H NMR (400 MHz, CDCI3) d 7.17 (dd, 1 H, J = 1.2, 5.2 Hz), 6.95 (dd, 1 H, J = 2.1, 5.2 Hz), 6.84 (d, 1 H, J = 2.4 Hz), 6.66 (bs, 1 H, NH), 4.72 (ABq, 2H, J = 13.2 Hz), 3. 84 (s, 3H), 3.65 (m, 1 H), 3.57 (m, 1 H), 3.09 (t, 2H, J = ¡6.4 Hz), 1 .47 (s, 3H), 1 .40 (s, 3H); HPLC-MS t R = 1.63 min (UV254"m); Mass calculated for formula C14H19N05S 313.1, LCMS observed m / z 314.2 (M + H). i Part B:! To 2 (869 mg, 2.77 mmol) in THF (10 mL) was added LiOH 1.0 (3 mL, 3 mmol) and the reaction was stirred overnight at room temperature ambient. The reaction mixture was diluted with water (10 ml) and the THF eliminated the vacuum. The basic aqueous layer was extracted with diethyl ether and the ether rinse was discarded. The aqueous layer was acidified with 1.0 N HCl and extracted with diethyl ether. The combined organic layers were dried over sodium sulfate and concentrated to give 3 as a yellow solid (443). mg, 53%). H NMR (400 MHz, CDCl 3) d 7.21 (dd, 1 H, ll = 1.2, 5.2 Hz), 6.97 I (dd, 1 H, J = 3.6, 5.2 Hz), 6.90 (bs, 1 H, NH), 6.86 (d, TI H, J = 3.2 Hz), 4.48 (ABq, 2H, J = 9.2 Hz), 3.76 (m, 1 H), 3.60 (m, 1 H), 3.15 (m, 2H), 1.53 (s, 3H), 1 .41 (s, 3H); HPLC-MS t R = 1.34 min (UV254 nm); Mass calculated for formula C13Hi7N05S 299.1, LCMS observed m / z 300.1 (M + H).

Part C:! To 3 (150 mg, 0.5 mmol) in DMF (2 mL) was added racemic 2- (4-fluoro-phenyl) -pyrrolidine (99 mg, 0.6 mmol), DIEA (261 μ ?, 1.5 mmol), and HATU (228 mg, 0.6 mmol) and the reaction mixture was stirred overnight at room temperature. The DMF was removed in vacuo and the residue dissolved in ethyl acetate. The organic layer was washed with 0.1 N NaOH, 0.1 N HCl, water, and brine, dried over sodium sulfate and concentrated. The purification by column chromatography (SiO2, 10% to 50% EtOAc / DCM) gave a oil (220 mg, 99%). The diastereomers were resolved (as described in Example 18) by reverse phase HPLC | to give the isomer desired 4 (78 mg, 35%) after lyophilization. HPLC-MS tR = 1.93 min (UV254 nm); Mass calculated for the formula C23H27FN2O4S 446.2, LCMS observed m / z 447.3 (M + H). | I Part D: i Compound 4 (78 mg, 0.17 mmpl) was dissolved in TFA: water 90:10 (5 ml) and stirred for 4 hours at room temperature. The mixture of The reaction was quenched with 1: 1 ACN: water (10 mL) and concentrated. The residue was redissolved in 1: 1 ACN: water (10 mL) and concentrated. Lyophilization gave 5 I as a white solid (62 mg, 87%). 1 H NMR (400 MHz, CDCl 3) mixture rotamers d 7.16-6.8 (m, 8H), 5.23-5.1 1 (m, 1 H), 4.85 (m, 1 H), 4.40-4.15 (m, I 1 H), 3.90-3.48 (m, 6H), 3.00 (m, 2H), 2.33 (m, 1 H), 2.05-1.83 (m, 3H) HPLC-MS tR = 1.50 min (UV254 nm); Mass calculated for the formula C2oH23FN2O4S 406. 1, LCMS observed m / z 407.2 (M + H).

The following Table contains the synthesized compounds using the above procedures.

EXAMPLE 2 Route of anhydride for tartrate diamide inhibitors A second general route for diamide compounds starting from an anhydrous intermediate is outlined below in Example 2. The (+) - diacetyl-L-tartaric anhydride (48) is a commercial item and reacts easily with a variety of amines to generate the monoacid / monoamide intermediate. The preferred solvent for ring opening is DCM; although DMF, THF or dioxane can also be compatible. He Next step of peptide coupling proceeds under a variety of standard conditions given for Example 1. The acetate groups are can eliminate using a variety of conditions, including hydrazine / methanol, NaOMe in methanol, ammonia / methanol, hydroxide lithium / THF / water (saponification), potassium carbonate in methanol, or carbonate of MP. On some occasions, the set of preferred conditions for the Parallel synthesis is to use MP carbonate. It has also been observed that one or both acetate protecting groups can be split during synthetic transformations that involve nucleophiles, basic reagents, heating in protic solvents or exposure to organometallic reagents.

EXAMPLE 2A: Part A: To 48 (26 mg, 0.1 mmol) in DMF (1 mL) was added 2,4-difluorophenylpiperazine (20 mg, 0.1 mmol). The reaction mixture was stirred for 1.5 hours. To the crude mixture was added 2-thiophene-ethylamine (14 μ ?, 0.12). mmol), DIEA (38 μ ?, 0.22 mmol) and HATU (42 mg, 0.1 1 mmol). The reaction stirred overnight at room temperature. The reaction mixture is poured into water and extracted with EtOAc. The combined organic layers are washed with 0.1 N NaOH, 0.1 N HCl, and brine; were dried over sulfate sodium and concentrated in vacuo to give 49 as an oil (49 mg, 94%).

HPLC-MS t R = 2.10 min (UV254 nm); mass calculated for the formula i C24H27F2N306S 523.2, LCMS observed m / z 524.4 (M + H); purity > 95% (ELSD).

Part B:! To 49 (49 mg, 0.09 mmol) in MeOH (2 mL) was added hydrazine anhydrous (5 μ ?, 0.16 mmol). The reaction mixture was stirred overnight room temperature. The reaction mixture was concentrated in vacuo and lyophilized to give 50 as a white powder (40 mg, 100%). 1 H NMR (400 MHz, CDCI3) d 7.17 (d, 1 H, J = 5.2 Hz), 6.96 (m, 2H), 6.85 jm, 4H), 4.87 (s, 1 H), 4. 24 (s, 1 H), 3.90 (m, 2H), 3.72 (m, 2H), 3.60 (m, 4H), 3.Q8 (m, 4H); HPLC-MS tR = 1.85 min (UV254 nm); mass calculated for the formula C20H23F2N3O4S I 439.1, LCMS observed m / z 440.2 (M + H).; EXAMPLE 2B j i Part A: i A 48 (26 mg, 0.1 mmol) in DMF (1 mL) was added N-methyl- (1-phenyl-ethyl) -amine (15 μ ?, 0.1 mmol). The reaction mixture was stirred for 1 hour. To the crude mixture was added 2-thiophene-ethylamine (47 μ ?, 0.4 mmol), HOBt I (27 mg, 0.2 mmol), carbodiimide resin of PS (312: mg, 0.4 mmol). To reaction mixture was added PS-TsOH resin (0.6 mmol) and resin MP carbonate (0.4 mmol). The reaction settled overnight, leaked and concentrated. Compound 51 was used without further purification. HPLC-MS ÍR = 1.82 min (UV254 nm); mass calculated for the formula C23H28N2O6S 460.2, LCMS observed m / z 461.1 (M + H). ! Part B:? To 51 in MeOH (2 ml) was added anhydrous hydrazine (5 pl, 0.16 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, purified by Reverse phase preparatory HPLC and lyophilized to give 52 as a powder white (6.7 mg, 18% total). 1H NMR (400 MHz, CDCI3) main rotamer d 7. 40- 7.25 (m, 6H), 7.16 (d, 1 H, J = 4.8 Hz), 6.95 (app.t, 1 H, J = 4.8 Hz), 6.87 i (bs, 1 H, NH), 5.96 ( q, 1 H, J = 7.2 Hz), 4.91 (d, 1 H, J = 1.2 Hz), 4.22 (d, 1 H, J = 1 .2 Hz), 3.60 (m, 2H), 3.08 (m, 2H), 2.79 (s, 3H), 1 .56 (d, 3H, J = 5.7Hz); I HPLC-MS t R = 3.80 min (UV254 nm, 0 min); mass calculated for the formula C 19H24N2C S 376.2, LCMS observed m / z 377.2 (M + H).

EXAMPLE 2C: Compound 53 was prepared accordingly; with the procedure described by D. Miller et al (J. Med. Chem. 1999, 42, 2287).

Parts A and B: Compound 55 was prepared using procedures similar to those described in Example 14, Parts D and E. Data for 54: H NMR (400 MHz, CDCl 3) d 7.51 -7.25 (m, 6H), 6.22 (s, 1 H), 5.75-5.67 (m, 2H), 5.36 (s, 2H), 5.28-4.61 (m, 4H), 3.69-3.40 (m, 2H), 2.74 (s, 1 H), 2.24 (s, 3H), 2.18 (s, 3H). Data for ¿5: H NMR (400 MHz, CDCI3) d 7.54-7.26 (m, 6H), 6.24 (s, 1 H), 5.22-5.02 (m, 2H), 4.94-4.82 (m, 3H) 4.42 ( s, 1 H), 3.72-3.50 (m, 2H), 2.92-2.76 (m, 2H) MS (El) m / z M + H Obs. 377. 1 ! I I I 2D EXAMPLE Method A Method A, Step 1 Compound 106 (R1 = R2 = CH2Ph) was prepared from 48 i following the procedure described in Example 4A, Parte C.

Method A, Step 2? To a THF / MeCN solution (1: 1, 0.5 ml)! of EDI resin of I I polystyrene (57 mg, 3 eq) in a fritted cartridge of: 6 ml was added a THF / MeCN solution (1: 1) of 106 (0.028 mmol), a THF solution of HOBT (0.3 ml, 1.5 eq) and a 1 M THF / MeCN solution (1: 1) of 2-furanetylamine (0.056 ml, 2 eq). The cartridge was capped and allowed to stir at 25 ° C for 20 h. Polystyrene isocyanate resin (57 mg, 3 eq) was added and polystyrene trisamine (39 mg, 6 eq) followed by 0.5 ml of THF and the mixture was stirred for 6 h. The suspension was filtered and the filtrate was concentrated to give 107 (R1 = R2 = CH2Ph, R3 = CH2CH2 (C4H4O).

Method A, Step 3 I Compound 107 was treated with a 2N solution of NH3 in MeOH (3 mL) for 1.5 h. The solvent was then removed under vacuum to give 108 (R1 = R2 = CH2Ph, R3 = CH2CH2 (C4H4O). ' EXAMPLE 2D TABLE A I B5 B6 Method B, Step 1: | Compound B2 was prepared (R1 = CH2Ph, | R2 = CH3) from 48 following the procedure described in Example 4A Part C.

Method B, Step 2: To a solution of DMF (40 ml) of B2 (2.0 g, 5.93 mmol), HOBT (880 mg, 6.52 mmol), and N-Boc-1,3-propylene diamine (1 '.14 g, 6.52 mmol) were added EDCI (1.48 g, 7.61 mmol) at 25 ° C under N2. After shaking during h, 1 N HCl was added, the products were extracted with ethyl acetate (3X), they were combined, then washed with sat. NaHCO3, water (3x), and dried over MgSO4. The products were then filtered and concentrated in vacuo give B3 (R1 = CH2Ph, R2 = CH3, n = 3).

Method B, Step 3: To a solution of MeCN (30 mL) of B3 (1.118 g, 2.4 mmol) a ° C was added 20 ml of a 4N solution of HCI eri dioxane. The solution it was capped and stirred at 25 ° C for 2.5 h. The solvent was then removed under vacuum. The product was then dissolved in 45 ml of THFr / MeCN / DMF (4: 4: 1) and polystyrene resin NEt2 (4.5 g, 14.4 mmol) was added. After shaking for 1.5 h, the solution was filtered and the resin was washed with | THF: MeCN (1: 1). The The filtrates were then diluted to 120 ml with additional THF / MeCN (1: 1) and used B4 (R1 = CH2Ph, R2 = CH3, n = 3) in the preparation of the next library: I Method B, Step 4: | i Polystyrene EDC resin (30mg, 0.045 mmol) was added to 96 wells of a deep well microtiter plate, followed by the stock solution of MeCN / THF / DMF (6: 6: 1) (1 ml) of B4 (0.015 mmol) and HOBT I (0.0225 mmol). Then, 1 M stock solutions of each of the individual acids (R1-96COOH) (0.023 ml, 0.021 mmol) to the wells, which then they were sealed and shaken at 25 ° C for 20 h. The solutions leaked through a polypropylene frit in a 2a microtiter shaft plate that I contains polystyrene isocyanate resin (3 equivalents, 0.045 mmol) and polystyrene resin trisamine (6 equivalents, 0.09 mmol). Once washed the top plate with MeCN (0.5 ml), the plate was removed, 1 the plate was sealed lower microtiter and stirred at 25 ° C for 16 h. Then, the solutions they were filtered through a polypropylene frit in a collection plate of 96 wells. The wells on the top plate were washed! then with MeCN (0.5 ml), and the plate was removed. Then, the resulting solutions in the collection plate I were transferred to flasks and the solvents were removed under vacuum by SpeedVac, to give the B5 amides. ' Method B, Step 5: Compounds B6 were prepared from B5 following the procedure described in Method A, Step 3 (see above). 2D EXAMPLE Method C '"O OH u Step 3 1 H 155 156 157 Method C, Step 1: Compound 153 (R1R N = 4-phenylpiperazine) was prepared starting from I following the procedure described in Method B, Step 1 (see above).

Method C, Step 2: I Compound 154 was prepared (R R N = 4-phenylpiperazine, n = 3) from 153 following the procedure described in f \ | method B, Step 2 (see j above). i Method C, Step 3: jt Compound 155 (RRN = 4-phenylpiperazine, n = 3) was prepared from 154 following the procedure described in Method B, Step 3 (see above) and used in the preparation of the next library: Method C, Step 4: I DIEA polystyrene resin (30rng, 0.045 mmol) was added to 72 wells of a deep well polypropylene microtiter plate followed by a stock solution of MeCN / THF / DMF (6: 6: 1) (1 ml) of 155 (0.05 mmol). Then, stock solutions 1v1 of each of the individual sulfonyl chlorides (R-72S02CI) (0.023?, 0.021 mmol) at the wells, which were then sealed and shaken at 25 C for 20 h. The solutions were filtered through a polypropylene frit in a second microtitre plate containing polystyrene isocyanate resin (3 equivalents, 0.045 mmol) and polystyrene trisamine resin (6 equivalents, i | 0.09 mmol). Once the upper plate was washed with MeCN (0.5 ml), the plate, the lower microtiter plate was sealed and stirred at 25 ° C for 4pm Then, the solutions were filtered through a polypropylene frit in a 96 well collection plate. The wells of the upper plate are They were then washed with MeCN (0.5 ml), and the plate was removed. Then, the solutions resulting in the collection plate were transferred to containers and the solvents were removed under vacuum by a Spe dVac to give the sulfonamides 156. | i i l Method C, Step 5: ¡¡ Compounds 157 were prepared from 156 following the procedure described in Method A, Step 3j (see above). I í EXAMPLE 2D j These compounds were prepared using Method A: EXAMPLE 2D TABLE D I These compounds were prepared using Method A: EXAMPLE 2D TABLE E j EXAMPLE 3! Heteroaryl biaryl compounds A precursor of the compound can be prepared so as to facilitate the synthesis of direct analogues. Examples of schemes for the synthesis of biaryls are listed below. It is known that aryl halides and "pseudo halides" (ie, triflates) react with boronic acids under a variety of established conditions (Top., Curr. Chem. 2002, 219, 12-49). A variety of bases are known for this reaction in the literature, including sodium carbonate, potassium carbonate, cesium carbonate, potassium t-butoxide, sodium t-butoxide, TEA, DIEA, potassium fluoride, and phosphate. of potassium For most applications, potassium phosphate was preferred and gave acceptable productions and chemoselectivity. Numerous solvents have also been used in the literature for Suzuki reactions, including THF, dioxane, NMP, DMF, DME, DMA, toluene and water. In general, we discovered that the preferred solvents are THF or dioxane. Solvents can also be mixed in various proportions to improve reactivity and / or chemoselectivity. The sources of palladium for this reaction are also numerous, including Pd (TPP) 4, Pd (OAc) 2, PdCI2 (TPP) 2, PdCI2 (dppf), Pd2 (dba) 3. In general, it was discovered that PdCI2 (dppf) is a preferred source of palladium.

I Part A: j To an ice-cold solution in methanol (100 ml) of 4-bromo-thiophene-2-carbaldehyde (183) (90%, 1.1 g, 58.1 mmol, 1.000 equiv) was added sodium borohydride in portions ( 2.20 g, 58.1 mmol, 1 .00 equiv) during approximately 10 minutes. The cooling bath was removed and the solution of reaction was allowed to stand 30 min. The reaction was deactivated at rt by the addition of acetone (until the gas evolution ceased), concentrated, and partitioned between ethyl acetate and 0.1 N HCl. The organic phase was washed with water, brine, dried (sodium sulfate), filtered and then concentrated to give 184 as an orange oil (10.5 g, 95%) that is; used without purification additional. 1 H NMR (400 MHz, CDCl 3) d 7.1 8 (s, 1 H), 6.93 (s, 1 H), 4.81 (s, 2 H). i I Part B: ¡¡ A 184 (4.38 g, 22.7 mmol) in toluene i (25 ml) was added phosphorus tribromide (2.36 ml, 25 mmol). The reaction mixture was heated in I to a 90 ° C oil bath for 15 minutes. After cooling to At room temperature the reaction mixture was poured onto ice and extracted with ethyl acetate. The combined organic layer was washed with water (2x), saturated solution of sodium bicarbonate (1 x) and saturated chloride solution of sodium, dried over magnesium sulfate and concentrated to give as a light brown oil (5.51 g, 95%). The material was used without further purification. J i 1 H NMR (400 MHz, CDCl 3) d 7.21 (s, 1 H), 7.03 (s, 1 H), 4.66 (s, 2H). I Part C: j To 185 (5.51 g, 21.5 mmol) in DMF (20 mL) was added phthalimide (3.80 g, 25.8 mmol) and cesium carbonate (7.72 g, 23.7 mmol). The mixture of The reaction was stirred overnight at room temperature. The mixture of The reaction was filtered and the filtrate was concentrated. The residue was dissolved in acetate ethyl and water. The organic layer was separated, washed with a saturated solution of Sodium chloride, dried over sodium sulfate and concentrated to give a brown solid I. Recrystallization from ~ 30% acetate ethyl / hexanes gave 186 as a peach-colored solid (6.38 g, 2 drops, 92%). 1 H NMR (400 MHz, CDCI3) d 7.86 (m, 2H), 7.72 (m, 2H), 7.1 1 (s, 1 H), 7.07 (s, 1 H), 4.97 (s, 2H). HPLC-MS t R = 2.02 min (UV254 nm); mass calculated for formula C i 3H8BrNO2S 321 .0, LCMS observed m / z 322.0 (M + H).

Part D: A suspension of 1686 (5.76 g, 17.8 mmol) and hydrate of Hydrazine (3.5 ml, 72 mmol) in ethanol (50 ml) was added at reflux. The suspension was clarified by heating it before a precipitate formed thick white The reaction mixture was heated for 1 hour and cooled.

The white precipitate was broken by the addition of ethanol (50 ml) and the sonication of the mixture. The precipitate was removed by filtration and the The solids were carefully washed with ethanol and ethyl acetate. The filtrate is concentrated to vacuum. The residue was dissolved in ethyl acetate and water. The layers They separated. The organic layer was washed with saturated sodium chloride solution. sodium, dried over sodium sulfate and concentrated to give 1 87 as a Brown orange oil (2.66 g, 78%). 1 H NMR (400 MHz, CDCl 3) d 7.10 (s, 1 H), 6.84 (s, 1 H), 4.04 (s, 2H). HPLC-MS t R = 0.58 min (UV254 nm); Dough calculated for the formula C5H6BrNS 190.9, LCMS observed m / z 192.0 (M + H). j Part E: Following the procedure described in Example 1 part A: a 88 (prepared as described in Example 4 Pait C of anhydride (+) - diacetyl-L-tartaric (48) and 2-chlorophenylpiperazine) (916 2.22 mmol) in DMF (5 ml) was added 187 (502 mg, 2.61 mmol), DIEA (850 μ;?, 4.88 mmol) and HATU (928 mg, 2.44 mmol). Purification by column chromatography (SiO2, 20% to 50% EtOAc / DCM) gave 189 as a whitish foam (652 mg, 50%). 1 H NMR (400 MHz, CDCl 3) d 7.37 (dd, 1 H, ii = 1.2, 7.6 Hz), 7.25 j (dt, 1 H, J = 1.2, 7.6 Hz), 7.14 (d, 1 H , J = 1 .2 Hz), 7.03 (m, 2H), 6.92 (d, 1 H, J = I 1 .2 Hz), 6.74 (m, 1 H, NH), 5.92 (d, 1 H, J = 3.6 Hz), 5.7.0 (d, 1 H, J = 4.0 Hz), 4.73 (dd, 1 H, J = 6.4, 15.2 Hz), 4.50 (dd, 1 H, J = 5.6, 15.6 Hz), 3.83 (m, 3H), 3.65 (m, 1 H), 3.20 - 3.00 (m, 4H), 2.21 (s, 3H), 2.1 1 3H); Mass calculated for the formula C ^ H ^ BrCINaES 585.0, LCMS observed m / z 586.1 (M + H). t Part F: i To 189 (59 mg, 0.1 mmol), phenyl boronic acid (13 mg, 0.1 1 mmol), potassium phosphate (42 mg, 0.2 mmol), and PdCi2 (dppf) (4 mg, 0.005 mmol), was added dioxane (2 ml). The reaction mixture was saturated with argon and heated at 80 ° C overnight. The reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, 20% EtOAc / DCM) gave 190 as a whitish foam (36 mg, 58%, 94% purity). HPLC-MS t R = 5.61 min (UV254 nm, 10 min); mass calculated for the formula C29H30CIN3O6S 583.2, LCMS observed m / z 584.2 (M + H).

Part G: To 190 (36 mg, 0.062 mmol) in methanol was added methoxide of 0.5 M sodium in methanol (6 μ ?, 0.003 mmol). Mix ! reaction was stirred for 1.5 hours at room temperature, it was deactivated with 0.1 N HCl and concentrated. Purification by reverse phase preparative LC gave 191 i as a white solid (3.2 mg, 10%). 1 H NMR (400 MHz, CDCl 3) d 7.55 (dd, i 2 H, J = 1.2, 8.4 Hz), 7.40 to 7.20 (m, 9H), 7.09 (m, 1 H,, NH), 4.91 (d, 1 H, J = 2. 4 Hz), 4.70 (m, 2H), 4.33 (d, 1 H, J = 2.0 Hz), 4.00 (m, 2H), 3.85 (m, 2H), 3. 20 (m, 4H); HPLC-MS t R = 1.94 min (UV254 J; Mass calculated for the formula C25H26CIN304S 499.1, LCMS observed m / z 50?! .2 (M + H).

EXAMPLE 3B 3-Pyridyl-Biaryl i i i Part A: | i To 193 (prepared as described in Example 1) (1.5 g, 4.24 mmol) in DMF (10 mL) was added 194 (0.725 g, 5.09 mmol) and HATU (1.94 g, 5.09 mmol). The reaction mixture was stirred during; night at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2> 80% ethyl acetate / hexanes) gave 195 as a colorless oil (1.73 g, 86%). HPLC-MS tR = 1.92 and 1.97 min (UV254 nm); Mass calculated for the formula C 23 H 25 Cl 2 N 3 O 4 477.1, LCMS observed m / z 478.1 (M + H). I I I Part B, Step 1: I ii Phenylboronic acid (10 mg, 0.084 mmol), potassium phosphate (36 mg, 0.168 mmol) and PdCI2 (dppf) (3.1 mg, 10 mol%) under argon in a flask. 4-ml was added 195 (20 mg, 0.042 mmol) in dioxane (0.5 ml). The reaction mixture was heated at 100 ° C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated. HPLC-MS t R 2.01 min (UV254 nm); Mass calculated for the formula C29H3oCIN3O 519.2, LCMS observed m / z 520.2 (M + H). | I i i i i I Step 2: \ i The raw material from Step 1 was dissolved in TFA: water 80:20 (1 ml) at 0 ° C and stirred at room temperature for 2 hours. The mixture of The reaction was quenched with water: acetonitrile 1: 1 (2 mL) and concentrated. The purification by preparatory LC reverse phase dip 196 as a solid after lyophilization. HPLC-MS t R = 3.54 min (UV254 nm, 10 min); Dough calculated for the formula C26H26CIN3O4 479.2, LCMS Observed m / z 480.2 (M + H). | EXAMPLE 3C Part A: j A 5-bromo-pyridine-2-carbonitrile (209) (1.0 g, 5.46 mmol) in tetrahydrofuran (10 mL) at -78 ° C was added hydride; lithium aluminum (1.0 M,? 13.66 mL, 13.66 mmol). The reaction was stirred for 2 hours at -78 ° C. The mixture was deactivated at -78 ° C with THF: water 10: 1. The mixture heated up Room temperature was diluted with ethyl acetate and stirred with hydroxide sodium 1.0 N for 10 minutes. The reaction mixture was filtered through Celite and the layers separated. The organic layer was washed with 1.0 N sodium hydroxide and brine, dried over sodium sulfate and concentrated to a give 210 as an oil (600 mg). The material was used without further purification. i Part B: 'I A 193 (1 .13 g, 3.2 mmol) in DMF (10 ml) ke added 210 (0.600 g) g, 3.2 mmol) and HATU (1.34 g, 3.52 mmol). The reaction mixture was stirred for 5 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated to give 211 as an oil (380 mg). HPLC-MS tR = 2.00 and 2.05 min (?? 254 nm); Mass calculated for the formula C23H25BrCIN3O4 521.1, LCMS observed m / z 522.1 (M + Hl). i j Part C, Step 1: '.

To 2-chlorophenylboronic acid (24 mg, 0.1 ^ 2 mmol), phosphate potassium (65 mg, 0.306 mmol) and PdCl2 (dppf) (3.1 mg, 5 mol%) under argon in a 4 ml vial was added 21 1 (40 mg, 0.076 mmol) in dioxane (0.5 ml). The The reaction mixture was heated at 100 ° C for 16 hours. The mixture of The reaction was cooled to room temperature, diluted with ethyl acetate and it was filtered through Celite. The filtrate was concentrated.

Step 2: I The raw material from Step 1 was dissolved in 80:20 TFA: water (1 ml) at 0 ° C and stirred at room temperature for 2 hours. The mixture of The reaction was quenched with water: acetonitrile 1: 1 (2 mL) and concentrated. The purification by reverse phase preparatory LC gave 212 as a solid i after lyophilization. HPLC-MS R = 4.10 and 4.13 min (UV254 nm, 10 min); Mass calculated for the formula C26H25CI2 3O4 513.2, lICMS observed m / z 514. 2 (M + H). ? The following compounds were prepared using the above procedures! EXAMPLE 4: I Thiophene-benzyl compounds Couplings of the Negishi type mediated by Pd were an efficient way to generate a set of relevant compounds for this series where Ar was a phenyl ring. Although a range of palladium sources i is known, we discovered that Pd (P'Bu3) 2 was preferred. The reaction can be run in a variety of solvent systems, including, dioxane, THF, or DMA. A preferred method used the zinc reagent solvent, which it was typically available as a stock solution of THF. The elimination of the t-BOC group can be completed using a variety of acidic conditions including TFA / water, HCl in methanol, and HCl in dioxane; all of which proceeded equally well with most of the Substrates of the reaction. The reactions were typically concentrated and dried frozen to give HCl or TFA salts. The reactions of Negishi proceeded in a comparable way, and in many cases better, when the amine was protected by a phthalimide. The phthalimide protecting group is could eliminate by heating in ethanol contain hydrate hydrazine.

EXAMPLE 4A: I Part A: j To 186 (3.47 g, 10.8 mmol) and bis- (tri-tert-butyl-phosphine) palladium (0.28) g, 0.54 mmol) in a flask under argon, zinc chloride 2- chlorobenzyl (0.5 M in THF, 54 mL, 27 mmol) was added. The reaction stirred to room temperature for 3 hours. The reaction mixture was diluted with EtOAc (200 mL) and washed with saturated solution of ammonium chloride (100 mL), bicarbonate solution (100 mL) and brine (100 mL). The organic layer dried over sodium sulfate and concentrated. The purification by Column chromatography (S1O2, 20% EtOAc / Hex) said 228 as a solid white (3.59 g, 91%). 1 H NMR (400 MHz, CDCl 3) d 7.8¼ (dd, 2H, J = 3.2, 5.6 Hz), 7.71 (dd, 2H, J = 3.2, 5.6 Hz), 7.36 (m, 1 H), 7.17 (??, 3H), 6.99 (d, 1 H, J = i 1 .0 Hz), 6.78 (d, 1 H, J = 1 .0 Hz), 4.95 (s, 2H), 4.00 (s, 2Jjl).

Part B:; I A 228 (3.55 g, 9.72 mmol) suspended in ethanol (35 ml) was added hydrazine monohydrate (1.9 ml, 38.9 mmol). The reaction mixture it was heated to reflux for 2 hours. After cooling, the solids removed by filtration and washed with ethanol (100 ml) and ethyl acetate ethyl (50 ml). The filtrate was concentrated and the residue was dissolved in ethyl acetate (150 mi) and water (100 mi). The organic layer was separated, washed with brine (100 ml), dried over sodium sulfate and concentrated | to give 229 as a yellow oil (2.54 g, 99%).

Part C: | To 48 (2.16 mg, 10.0 mmol) in DCM (10 ml) 'isoindoline was added (1.13 ml, 10.0 mmol). The reaction was stirred at room temperature for 2 hours. hours. The solvent was removed in vacuo and the residue was partitioned between ethyl and HCl 1 .0 N. The organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated to give 230 as a solid dark (3.35 g, 100%). 1 H NMR (400 MHz, DMSO-d6) d jl 3.63 (bs, 1 H), 7.38 - 7. 28 (m, 4H), 5.01 (d, 1 H, J = 13.2 Hz), 4.93 (d, 1 H, J = 14.0 Hz), 4.71 (d, 1 H, i J = 16.4 Hz), 4.56 ( d, 1 H, J = 15.6 Hz), 2.12 (s, 3 H), 2.07 (s, 3 H); HPLC-MS tR = 1 .10 min (UV254 nm); mass calculated for the formula C 6H17N07 335.1, LCMS observed m / z 336.1 (M + H). ! i Part D: < I A 230 (18 mg, 0.053 mmol) in NMP (2 mL) was added 229 (19 mg, 0.08 mmol), DIEA (26 μ ?, 0.148 mmol) and HATU (3f) mg, 0.08 mmol). The The reaction mixture was stirred overnight. The reaction mixture was poured in water and extracted with ethyl acetate. The combined organic layer was washed with 0.1 N NaOH, 0.1 N HCl and brine, dried over sodium sulfate and concentrated to give 231.

: Part E: A 231 (1 18 mg, 0.21 6 mmol) in methanol (3 mL) and DCM (3 mL) were added MP carbonate resin (2.54 mmol / g, 85 mg). The reaction was stirred i! j I ? ? for 3 hours, it was filtered and concentrated to give 232 how a white solid (94 mg, 92%). 1H NMR (400 MHz, DMSO-d6) d 8.34 (t, ¡1 H, J = 2.0 Hz) 7.79 (dd 1 H, J = 0.8, 8.0 Hz), 7.64 (dt, 1 H, J = 1 .6, 8.0 Hz), 7.47 (d, 1 H, J = 7.6 Hz), 7. 40 (dt, 1 H, J = 0.8, 7.6 Hz), 7.35 - 7.27 (m, 4H), 6.97 (d, 1 H, J = 1 .6 Hz), 6. 81 (d, 1 H, J = 1 .2 Hz), 5.67 (d, 1 H, J = 6.4 Hz), 5.05 (d, 1 H, J = 12.8 Hz), 4. 97 (d, 1 H, J = 8.0 Hz), 4.90 (d, 1 H, J = 13.2 Hz), 4.75 (d, 1 H, J = 13.2 Hz), 4. 60 (m, 2H), 4.36 (m, 2H, J = 6.4, 15.2 Hz) 4.24 (dd, 1 H, J = 3.2, 6.8 Hz); HPLC-MS t R = 1.85 (UV254 nm); mass calculated for the formula C24H23CIN204S 470. 1, LCMS observed m / z 471 .1.

Part A: A 233 (4.00 g, 13.7 mmol) and bis- (tri-tert-buty-phosphine) palladium (0.28) g, 0.54 mmol) in a flask under argon was added 2-chlorobenzyl zinc chloride (0.5 M in THF, 69 mL, 34.5 mmol). The | The reaction was stirred at room temperature overnight. The reaction mixture was diluted with I EtOAc (200 mL) and washed with saturated ammonium chloride solution (100 mL). mi), bicarbonate solution (100 ml) and brine (100 ml). The organic layer dried over sodium sulfate and concentrated. The purification by Column chromatography (SiO2, 15% EtOAc / Hex) gave 234 as a solid white (4.5 g, 95%). 1 H NMR (400 MHz, CDCl 3) d 7.36 (< jl, 1 HJ = 3.6 Hz), 7.25 i - 7.18 (m, 4H), 6.74 (s, H), 6.64 (d, 1 H, J = 3.6 Hz ), 4. 0 (d, 2H, J = 5.2 Hz), 4. 22 (s, 2H). Part I: Part I 234 (450 mg, 1.34 mmol) was added 4M HCl in dioxane (1.5 ml) and the reaction was stirred for 30 minutes. The dioxanp was removed in vacuo. i The residue was dissolved in THF (10 ml) and DIEA (500 μl, 2.68 mmol) was added. and 48 (275 mg, 1.27 mmol). The reaction was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (60 ml) and washed with 1 .0 N HCl. The organic layer was dried over sodium sulfate. sodium and concentrated to give 235 as a yellow foam (505 mg, 90%). i i Part C: j To 235 (40 mg, 0.09 mmol) in DMF (2 mL) were added DI EA (50 μ ?, 0.29 mmol), isoindoline (14 mg, 0.12 mmol), and HATLÍ (45 mg, 0.12 mmol).

The reaction mixture was stirred for 6 hours. The reaction mixture is Dilute with ethyl acetate (30 mL) and wash with 0.1 N NaOH, 0.1 N HCl and brine. The organic layer was dried over sodium sulfate. The gross product was dissolved in methanol (3 ml) and potassium carbonate (100 mg) was added in water (1 ml) After stirring for 30 minutes, the reaction mixture was dilute with ethyl acetate (20 ml) and wash with brine. The organic layer dried over sodium sulfate and concentrated. The purification by LC Reverse phase preparatory gave 236 as a white solid. 1H NMR (400 MHz, DMSO-d6) d 8.29 (t, 1 H, J = 6.4 Hz) 7.42 (dd, 1 H, J i = 1 .6, 7.8 Hz), 7.37 - 7. 23 (m, 7H), 6.74 (d, 1 H, J = 3.6 Hz), 6.65 (d, 1 H, J = 3.? Hz), 5.66 (d, 1 H, J = i 5.6 Hz), 5.04 (d, 1 H, J = 14.8 Hz), 4.97 (bs, 1 H), 4.89 j (d, 1 H, J = 15.2 Hz), 4. 75 (d, 1 H, J = 16.4 Hz), 4.60 (m, 2H), 4.38 (dd, 1 H, j j = 6.4, 15.2 Hz), 4.23 (bs, 1 H), 4.15 (s, 2H); HPLC-MS t R = 4.92 min (UV2.4 nm, 10 min); mass j calculated for the formula C24H23CIN2O4S 470.1, LCMS observed m / z 471 .1.

EXAMPLE 4C Thiophene-benzyl Compound 237 was prepared according to procedure I described by A. J. Hutchison et al (European Patent 0323 $ 07 A2, Dec. 7, 1989).

Parts A: j Compound 238 was prepared by procedures similar to those described in Example 5 Part A.

Parts B-E: I Compound 242 was prepared by similar procedures to those described in Example 4B Parts A, a C. HPLC-MS tR = 2.05 min (UV254 nm); mass calculated for the formula C27H28CIFN2O4S 530.1, LCMS observed I m / z 531.1 (M + H). I The following compounds were prepared by procedures described in Example 4A-4C. i I j I I I EXAMPLE 5 Part A: To a solution of 187 (2.68 g, 14.0 mmol); and pyridine (2.26 mL, 28 mmol) in dichloromethane (25 mL) was added di-tert-butyl dicarbonate (3.21 g, 14.7 mmol). The mixture was stirred overnight at room temperature.

The reaction mixture was poured into water (25 ml) and the layers separated. The organic layer was washed with 1.0 N HCl (20 mL), water (20 mL), and solution saturated sodium chloride (20 ml), dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, DCM) i gave 305 as a light orange solid (3.64 g, 89%). 1 H NMR (400 MHz, CDCI3) d 7. 1 (s, 1 H), 6.87 (s, 1 H), 4.01 (bs, 1 H), 4.44 (d, 2H, J = 6.0 Hz), i 1 .48 (s, 9H) . I! Part B: 1 A n-butyl lithium (2.5 M, 0.31 mL, 0.78 mmol) in THF (2 mL) at -78 ° C under argon, 305 (100 mg, 0.34 mmol) in THF (1.5 ml) was added dropwise. The reaction mixture was stirred for 30 minutes at -78 ° C. Then, it was added 2-thiophene carbaldehyde (60 μ ?, 0.68 mmol). The reaction mixture was stirred for 30 minutes at -78 ° C. The reaction mixture was deactivated with Saturated ammonium chloride solution and heated to room temperature ambient. The mixture was diluted with ethyl acetate (10 ml) and the layers were they separated. The organic layer was washed with water and brine. It dried on Sodium sulfate and concentrated. Purification by chromatography in column (SiO2, 20% EtOAc / hexane) gave 306 (47 mg, 42%). 1H NMR (400 MHz, CDCl 3) d 7.28 (m, 1 H), 7.16 (s, 1 H) 6.95 (m, 2H) 6.93 (s, 1 H), 6.05 (s, 1 H), 4.88 (bs, 1 H), 4.43 (d, 2H, J = 5.6 Hz), 2.43 (bs, 1 H), 1.48 (s, 9H).

Part C: A 306 (47 mg, 0.14 mmol) in DCM (2 mL) was added triethylsilane (0.2 mi). The mixture was cooled in an ice bath and TFA (0.2 ml) was added. The mixture was warmed to room temperature and stirred overnight. The solvents were removed in vacuo and 307 was used without further purification. 1 H NMR (400 MHz, CD 3 OD) d 7.20 (m, 2 H), 7.09 (s, 1 H) 6.90 (m, 1 H), 6.86 (m, 1 H), 4.26 (s, 2 H), 4.15 ( s, 2H).

Part D: A 230 (19 mg, 0.06 mmol) in DMF (2 mL) was added 307 (18 mg, 0. 06 mmol), DIEA (29 μ ?, 0.17 mmol) and HATU (28 mg, 0 | 07 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (20 ml) and water (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. Compound 308 was used without further purification. HPLC-MS t R 1.91 min (UV254 nm); mass calculated for the formula C26H26 206S2 526.1, iLCMS observed m / z 269.9 (M + H). ! i Part E: | Compound 308 and carbonate be potassium (20 mg) in methanol (2.5 ml) and water (0.5 ml) were mixed and stirred for 30 minutes. Mix of reaction was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The purification by LC Reverse phase preparatory gave 309 as a white solid. 1 H NMR (400 MHz, DMSO-de) d 8.33 (t, 1 H, J = 5.6 Hz), 7.30 (m, 5H) ,: 7.03 (s, 1 H), 6.92 (s, 1 H), 6.67 (s, 1 H), 6.82 (s, 1 H), 5.04 (d, 1 H, J = 14.0 Hz), 4.90 (d, 1 H, J = 14.0 Hz), 4.75 (d, 1 H, J = 16.0 Hz), 4.60 (m, 2H), 4.41 (dd, 1 H, J = 6.8, 14.8 Hz), 4. 33 (dd, 1 H, J = 5.6, 14.4 Hz), 4.25 (s, 1 H), 4.04 (s, 2H) Í; HPLC-MS tR = 4.45 min (UV254 10 min); mass calculated for the formula C22H22N2O4S2 442.1, LCMS observed m / z 443.0 (M + H).

The following compounds were prepared using the procedures described above. Part C did not produce dehydration for compounds such as 314 and 317. I i EXAMPLE 6 EXAMPLE 6A: Part A: 1 A mixture of 2- (aminomethyl) thiophene (319) (1.57 g, 3.8 mmol), monomethyl phthalate (2.75 g, 15.3 mmol), EDC (3.26 g, 6.6 mmol), HOBt was stirred. (2.79 g, 20.7 mmol) and triethylamine (5 mL, 27.6 mfriol) in DCM (40 mL) for 12 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The layers The combined organics were washed with 1 .0 N HCl, bicarbonate solution and brine, dried over sodium sulfate and concentrated. The recrystallization of the mixture from ethyl acetate / hexanes gave 320 as one solid (2.20 g, 67%). 1 H NMR (400 MHz, CDCl 3) d 7.85 (m, 2 H), 7.71 (m, 2H), 7.21 (m, 1 H), 7.15 (m, 1 H), 6.94 (m, 1 H), 5.03 (s, 2H).

Part B: | (Feigel, M., Lugert, G., Heichert, C; Liebigs Ann. Chem. 1987, 367). To paraformaldehyde (250 mg) in HCl (conc, 5 ml) chloride was added 0.5 M zinc in THF (1.7 ml, 0.85 mmol). To this mixture was added 320 (235 mg, 0. 85 mmol) in portions and then dioxane (3 ml). The reaction mixture is stirred at 60 ° C for 45 minutes. The reaction mixture was cooled and diluted with water (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated. The recrystallization from ethyl acetate / hexane gave 321 as a solid (190 mg, 78%). 1 H NMR (400 MHz, CDCl 3) d 7.86 (dd, 2 H, J = 3.2, 5.6 Hz), 7. 72 (dd, 2H, J = 3.2, 5.6 Hz), 6.98 (d, 1 H, J = 3.6 Hzj, 6.90 (d, 1 H, J = 3.6 Hz), 4.98 (s, 2H), 4.72 (s, 2H). j: Part C: A mixture 321 (190 mg, 0.65 mmol), 2-methylbenzimidazole (12 mg, 0.85 mmol), sodium iodide (catalytic) and cesium carbonate (275 mg, 0.85 mmol) in DMF (6 ml) overnight, at room temperature. The reaction mixture was divided! between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. ethyl (2 x 50 ml). The combined organic layers were laid with a solution of sodium bicarbonate and brine were dried over sodium sulfate and they concentrated. Recrystallization from ethyl acetate / hexane gave 322 (65 mg) and 322 contaminated with 2-methylbenzimidazole (120 mg). 1H NMR (400 MHz, CDCI3) d 7.83 (dd, 2H, J = 3.2, 5.6 Hz), 7.70 (ddj 2H, J = 3.2, 5.6 Hz), i 7.68 (m, 1 H), 7.29 (m, 1 H), 7.23 (m, 2H), 6.95 (d, 1 H, J? 3.6 Hz), 6.70 (d, 1 H, i J = 3.6 Hz), 5.36 (s, 2H), 4.91 (s, 2H), 2.64 (s) , 3H); Hfkc-MS tR = 1 .14 min (UV254 nm); mass calculated for the formula C22H17 302S 387.1, LCMS observed m / z 388.1 (M + H). ! Part D:! Compound 322 (90 mg, 0.23 mmol) was refluxed. hydrazine hydrate (50 μ ?, 0.93 mmol) in ethanol (10 ml) j and DCM (5 ml) during hours. The reaction mixture was cooled and filtered. The filtrate was concentrated and the crude product was used without further purification. | I Part E: I I A 230 (83 mg, 0.24 mmol) in DMF (5 ml) 323 (82 mg, 0. 32 mmol), DIEA (300 μl, 1.6 mmol) and HATU (135 mg, 0.36 mmol). The reaction mixture was stirred overnight at room temperature. The mixture of The reaction was diluted with ethyl acetate (50 ml) and water (50 ml). The layers are separated and the aqueous layer was extracted with ethyl acetate. The layers combined organic washes with sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The compound 324 was used without further purification. HPLC-MS R = 1.13 min (UV nm); dough calculated for the formula C30H30N4O6S 574.2, LCMS observed m / z 575.1 (M + H).

Part F: Compound 324 (-120 mg, 0.21 mmol) and potassium carbonate (100 mg) in methanol (5 mL) and water (1 mL) were mixed. After 5 minutes, a solid precipitated and the reaction was stirred for 30 minutes. The solid i was collected by filtration. The purification by LC Reverse phase preparatory gave 325 as a white solid. 1H NMR (400 MHz, DMSO-d6) d 8.35 (t, 1 H, J = 6.0 Hz), 7.93 (d, 1 H, j J = 8.0 Hz), 7.73 (d, 1 H, J = 6.8 Hz), 7.48 (m, 2H), 7.33 (m, 1 H), 7.27 (m, 3H), 7.08 (d, 1 H, J = 3.6 Hz), 6.82 (d, 1 H, J = 3.6 Hz), 5.80 (s, 2H), 5.02 (d, 1 H, J = 14.4 Hz), 4.86 (d, 1 H, J = 15.2 Hz), 4.74 (d, 1 H, J = 16.8 Hz), 4.58 (d, 1 H, jJ = 16.4 Hz), 4.57 (s, 1 H), 4.33 (m, 2 H), 4.22 (s, 1 H), 2.84 (s, 3 H); HPLC-MS; tR = 2.74 min (UV254? I nm, 10 min); mass calculated for the formula C26H26N4O4S 490.2, LCMS I observed m / z 491.2 (M + H). i EXAMPLE 6B: Part A: To p-butyl lithium (2.5 M, 0.91 mL, 2.28 mmol) in THF (5 mL) at -78 ° C under argon was added 305 (300 mg, 1.03 mmol) in THF (5 mL) per drop. The The reaction mixture was stirred for 30 minutes at -78PC. Then i dimethyl formamide (151 mg, 2.06 mmol) was added. The reaction mixture was stirred for 30 minutes at -78 ° C. The reaction mixture was deactivated with Saturated ammonium chloride solution and heated to room temperature ambient. The mixture was diluted with ethyl acetate (1 p ml) and the layers were they separated. The organic layer was washed with water and brine. It dried on Sodium sulfate and concentrated. The residue was dissolved in methanol and sodium borohydride (156 mg, 4.12 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 0.1 N HCl, water and brine. The layer organic was dried over sodium sulfate and concentrated. The purification by column chromatography (SiO2, 25% EtOAc / i h 'exan) gave 326 (147 mg, 58%). 1 H NMR (400 MHz, CDCl 3) d 7.10 (s, 1 H), 6.94 (s, 1 H), 4.63 (s, 2H), 4. 45 (d, 2H, J = 4.7 Hz), 1.48 (s, 9H). I i Part B: j A 326 (30 mg, 0.1 2 mmol) in THF (2 mL) was added Benzimidazole (19 mg, 0.16 mmol), triphenylphosphine (42 mg, 0.16 mmol) and DIAD (32 mg, 0.16 mmol). The reaction mixture was stirred overnight room temperature. The reaction mixture was concentrated. The residue is dissolved in dichloromethane (2 ml) and TFA (0.5 ml) was added. The mixture of The reaction was stirred for 30 minutes and concentrated. The residue dissolved in diethyl ether and washed twice with water. The combined aqueous layer was made DIEA basic and extracted with ethyl acetate. The combined organic layer is washed with brine, dried and concentrated to give 327 as a film i (41 mg). The material was used without further purification.

Part C: [ To 230 (20 mg, 0.06 mmol) in DMF (2 mL) was added 327 (19 mg, 0. 08 mmol), DIEA (31 μ ?, 0.18 mmol), DMAP (1 mg) and HATU (30 mg, 0.08) mmol). The reaction mixture was stirred overnight. The mixture was poured in water and extracted with ethyl acetate. The combined organic layers are washed with 0.1 N NaOH, water and brine, dried over sodium sulfate and they concentrated. Compound 328 was used without further purification.

Mass calculated for the formula C29H28N4O6S 560.2, LCMS observed m / z 561.2 (M + H).

Part D: Compound 328 and potassium carbonate (20 mg) were mixed in methanol (2.5 ml) and water (0.5 ml) and stirred for 30 minutes. Mix of reaction was diluted with ethyl acetate, washed with! water and brine, it dried over sodium sulfate and concentrated. The purification by LC Reverse phase high school gave 329 as a solid blarjco (8 mg). HPLC-MS i i t R = 2.77 min (UV254 nm, 0 min); mass calculated for the formula C25H24N4O4S 476. 2, LCMS observed m / z 477.1 (M + H). i EXAMPLE 6C Part A: N- (Hydroxymethyl) phthalimide (1.0 g, 5.6 mmol) was dissolved in acid triflic 1% in trifluoroacetic acid (10 ml) at 0 ° C. To this mixture 330 was added (0.52 mL, 5.6 mmol). The reaction mixture was warmed to room temperature I slowly and stirred overnight. The reaction mixture is poured into ice water (100 ml) and extracted with DCM. Organic layers combined were washed with sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. Purification by I column chromatography (SiO2l 30% EtOAc / Hex) gave 331 (619 mg, 41%). 1 HOUR NMR (400 MHz, CDCl 3) d 9.85 (d, 1 H, J = 1.6 Hz), 7.86 (m, 2 H), 7.81 (d, 1 H, J = 1.6 Hz), 7.76 (s, 1 H), 7.73 (m, 2 H), 4.87 (s, 2 H). | Part B: Compound 331 (315 mg, 1.16 mmol) was dissolved in methylene: methanol 1: 1 (10 ml) and cooled in an ice bath. To this solution Sodium borohydride (1.1 mg, 0.29 mmol) was added and the reaction stirred for 30 minutes. Additional sodium borohydride (3 mg, 0.08 mmol) and the reaction was stirred for 30 minutes. The reaction mixture is diluted with methylene chloride and washed with saturated sodium chloride solution. ammonium, water and brine. The reaction mixture was dried over sodium sulfate and concentrated to give 332 as a soft solid (310 mg, 98%). 1 HOUR NMR (400 MHz, CD3OD) d 7.83 (m, 2H), 7.79 (m, 2H), | 7.24 (s, 1 H), 6.97 (s, i 1 H), 4.76 (s, 2H), 4.65 (s, 2H).

Part C: A mixture of 332 (97 mg, 0.36 nmol) and tribromide was stirred phosphorus (34 μ ?, 0.39 mmol) in DCM (5 ml) for 30 minutes at room temperature ambient. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with a solution of sodium bicarbonate and brine were dried over sodium sulfate and concentrated to give 333 as a white solid (104 mg, 87%). 1 H NMR (400 MHz, CDCI3) d 7.85 (dd, 2H, J = 2.8, 5.2 Hz), 7.72 (dd, 2H, J = 2.8, 5.2 Hz), 7.32 (s, 1 H), 7.15 (s, 1 H) ), 4.77 (s, 2H), 4.66 (s, 2H).

Part D:; A mixture of 333 (450 mg, 1 1 .34 mmol), 2-methyl-benzimidazole (355 mg, 2.69 mmol) and cesip carbonate (875 mg, 2.69 mmol) was stirred. in DMF (5 ml) overnight at room temperature. The mixture of The reaction was diluted with ethyl acetate and washed with needle and brine, dried on sodium sulfate and concentrated. The recrystallization from acetate of ethyl / hexanes gave 334 as a white solid (252 mg, 49%). 1H NMR (400 MHz, CDCl 3) d 7.84 (dd, 2H, J = 2.8, 5.2 Hz), 7.72 (dd, 2H, J = 2.8, 5.2 Hz), 7. 68 (m, 1 H), 7.23 (m, 3H), 7.19 (s, 1 H), 7.05 (s, 1 H), j 5.38 (s, 2H), 4.75 (s, 2H), 2.66 (s, 3H). | i Part E: A mixture of 334 (225 mg, 0.58 mmol) e was refluxed. hydrazine hydrate (1 13 μ ?, 2.32 mmol) n ethanol (4 ml) for 4 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to give 335 as a solid yellow (148 mg, 99%).

Part F: To 230 (12 mg, 0.036 mmol) in DMF (2 mL) was added 335 (12 mg, 0.045 mmol), DIEA (18 μ ?, 0.1 1 mmol) and HATU (17 mg, 0.045 mmol). The reaction mixture was stirred overnight at room temperature. The The reaction mixture was diluted with ethyl acetate (20 ml) and water (20 ml). The I layers were separated and the aqueous layer was extracted with ethyl acetate. The The combined organic layers were washed with sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated.

Compound 336 was used without further purification. HPUC-MS tR = 1 .22 min (UV254 nm); mass calculated for the formula C30H30 4O6S 574.2, LCMS observed m / z 575.0 (M + H).; Part G:; Compound 336 and potassium carbonate (20 mg) were mixed in methanol (1.5 ml) and stirred for 30 minutes. The reaction mixture is diluted with ethyl acetate, washed with water and brine; dried over sulfate of sodium and concentrated. Purification by means of LC preparatory phase reverse gave 337 as a white solid. 1H NMR (400 Mljlz, DMSO-d6) d 8.23 (t, 1 H, J = 6.4 Hz), 7.89 (m, 1 H), 7.70 (m, 1 H), 7.44 (m, 2H), 7.33 (m, 1 H), 7.27 (m, 3H), 7.20 (s, 1 H), 7.14 (s, 1 H), 5.80 (s, 2H), 5.04 (d, 1¡H, J = 13.2 Hz), 4.88 I (d, 1 H) , J = 15.2 Hz), 4.73 (m, 2H), 4.60 (m, 2H), 4.25? T ?, 2H), 2.83 (s, 3H); I HPLC-MS IR = 2.04 min (UV25 nm, 10 min); mass calculated for the formula C26H26N4O4S 490.2, LCMS observed m / z 491.1 (M + H). j The following compounds were prepared using the procedures described in Example 6A to 6C.

EXAMPLE 7: Part A: To 232 (26 mg, 0.056 mmol) in toluene (5 mL) was added dibutyltin (20 mg, 0.08 mmol). The mixture was heated for 3 hours at reflux with a Dean Stark trap. The mixture was reconciled. The residue is dissolved in NMP (3 mL) and treated with cesium fluoride (8.5 mg, 0.056 mmol) and iodomethane (14 μ ?, 0.224 mmol). The reaction mixture was heated to 50 ° C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, They were dried over sodium sulfate and concentrated. The purification by Preparatory HPLC gave 350 (3.4 mg, 13%). HPLC-MS t R 5.26 min (UV254 nm, minutes ); mass calculated for the formula C25H25CIIN2O4S 484.1, LCMS observed m / z 485.0 (M + H). Í Part A: A BOC-glycine (353) (25.0 g, 0.143 mol) dissolved in dry THF (100 ml) and cooled to -20 ° C under a nitrogen atmosphere was added Hunig's base j (23.1 g, 31. 1 ml, 0.357 mol) then isobutylchloroormate (21.4 g, 20.4 ml, 0.157 mol). It was stirred at -20 ° C for 60 minutes. Methyl ester of i serine (354) (24.4 g, 0.157 mol) was added, then Hunig's base (23.1 g, 31 .1 ml, 0.357 mol). The reaction mixture was warmed to room temperature, stirred for 18 h and concentrated. The residue was divided between fslaOH 0.5 N (300 ml) CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over magnesium sulfate and concentrated. t It was purified by silica gel chromatography (eluent: 1% MeOH-I CH 2 Cl 2 to 3% MeOH-CH 2 Cl 2) to give 20.5 g (52%) of product 355 as a yellow solid. MS m / e: 277 (M + H). ! I For n = 2: MS m / e: 291 (M + H)! Part B: To compound 355 (4.55g, 16.5 mmol) dissolved in CH2Cl2 (200 mL) and cooled to -50 ° C under a nitrogen atmosphere was added diethylaminosulfur trifluoride j (3.19 g, 2.4 mL, 19.8 mmol) per g. by syringe. It was stirred at -50 ° C for 2 h, carbonate dex potassium (3.88 g, 28.1 mmol) was added, and it was slowly warmed to room temperature for 2 h. 0.2 N NaOH (100 ml) and separate layers were added. The aqueous layer was extracted with CH2Cl2, the combined organic extracts were dried (MgSO4), filtered, and concentrated. It was purified by silica gel chromatography (eluent: 2% MeOH-CH 2 Cl 2 at 4% MeOH-CH 2 Cl 2) to give 3.06 g (72%) of the product 356 as a yellow solid. MS m / e: 259 (M + H). i For n = 2: MS m / e: 273 (M + H) i Part C: i To compound 356 (6.10 g, 23.6 mmol) dissolved in CH2Cl2 (250 mi) and cooled to 0 ° C, DBU (12.59 g, 12.4 mL, 82.7 mmol) was added and bromotrichloromethane (16.40 g, 8.1 ml, 82.7 mmol). slowly warmed i to room temperature for 2 h and stirred for 16 h. 0.1 N NaOH (200 ml) and separate layers were added. It was extracted; the aqueous layer with CH2Cl2, the combined organic extracts were dried (MgSO4), filtered and concentrated. It was purified by silica gel chromatography (eluent: 2% of MeOH-CH 2 Cl 2 to 3% MeOH-CH 2 Cl 2) to give 4.27 g (71%) of the product 357 as an orange oil. MS m / e: 257 (M + H). j For n = 2: MS m / e: 271 (M + H): Part D: To compound 357 (4.25 g, 16.6 mmol) dissolved in Et20 (1 00 ml) lithium borohydride (1.44 g, 66.3 mmol) and MeOH (2.13 g, 2.7 ml, 66. 3 mmol). It was refluxed for 3 h, enriched to room temperature, and concentrated. Water (100 ml) was added, extracted with CH 2 Cl 2, The combined organic extracts were dried (MgSO4), filtered and concentrated. i It was purified by silica gel chromatography (eluent: 5% MeOH-CH 2 Cl 2 to 10% MeOH-CH 2 Cl 2) to give 2.43 g (64%) of the product 358 as a yellow oil MS m / e: 229 (M + H).

For n = 2: MS m / e: 243 (M + H) Part E: To compound 358 (1.41 g, 6.18 mmol) dissolved in CH2Cl2 (35 mL) and cooled to -25 C was added dropwise triethylamine (1.25 g, 1.7 mL, 12.4 mmol) then mesyl chloride ( 0.85 g, 0.57 mL, 7.41 mmol). It was heated to 0 C and slowly for 60 minutes. Water (50 ml) was added, extracted with I CH2CI2, the combined organic extracts were dried | (MgSO4), filtered, and concentrated to give 1.89 g (100%) of product 359 as an oil yellow. MS m / e: 251 (? + 2-tBu).

For n = 2: MS m / e: 265 (? + 2-tBu) Part F: Was copper cyanide (1.66 g, 18.5 mmol) suspended in dry THF? (70 ml) under a nitrogen atmosphere and cooled to -25 ° C. Added Phenyl magnesium bromide (3.0 M in Et20, 12.3 mL, 7.0 mmol) per drip | by syringe so that the internal temperature | outside of < -20 ° C. It was stirred at -20 ° C for 30 minutes then at 0 ° C for 30 minutes. I was heated to 15 ° C, then the internal temperature was re-cooled to -25 ° C. Compound i 359 (1.89 g, 6.1 8 mmol) dissolved in dry THF (20 mL) was added dropwise by syringe. It was stirred at -25 ° C internal temperature for 2 h then 0 ° C for 16 h. Concentrate, add NH4OH 2 ijl (100 ml), extract with CH2Cl2, the combined organic extracts were dried (MgSO4), filtered and concentrated. It was purified by silica gel chromatography (eluent:! 5% EtOAc-hexane to 20% EtOAc-hexane) to give 0.82 jg (46%) of the product i 360A as a yellow oil. MS m / e: 289 (M + H). | The following intermediaries were prepared according to the i procedure eleven CH2Cl2: M). HE stirred at room temperature for 4 h, then concentrated to give 0.78 g (100%) of product 361 A (hydrochloride salt) as a yellow solid. MS m / e: 189 (M + H).

The following intermediaries will be prepared in accordance with the previous procedure: Part H: (JFL 80324-023) | Compound 361 A (0.2 g, 0.677 mmol) was combined, compound 362 (0.30 g, 0.812 mmol), HATU (0.51 g, 1.35 mmol), and triethylamine i (0.21 g, 0.28 mL, 2.03 mmol) in dry DMF (8 mL). S stirred at temperature environment for 16 h. Concentrated, 0.5 N NaOH (15 mL) was added, i Part I: To compound 363 (0.24 g, 0.450 mmol) dissolved in MeOH (10 mL) was added 0.5 M NaOMe in MeOH (0.09 mL, 0.045 mmol). It was stirred at room temperature for 60 minutes. Added HCI 4 N in dioxane EXAMPLE 9 Thiazole-benzyl inhibitors »OC« H'¾ COOEt Part 0 R M Part G. { - ".M Part E BOCMH 'n: - tBOCHH, OH Pane f Part H Part A: Glycinamide 385 HCI (60.0 g, 0.543 mol) suspended in MeOH (1000 ml) and cooled to 0 ° C added triethylamine (109.9 g, 151.4 ml, 1.09 mol) and tBOC anhydride (148.0 g, 0.678 mol) in portions. It warmed up to room temperature and stirred for 24 h. It was concentrated, it was added 1 N NaOH (600 ml), extracted with CH2Cl2, the combined organic extracts were dried (MgSO4), filtered and concentrated to give 53.0 g (56%) of product 396 as a white solid. MS m / e: 175 (M + H). I For n = 2: MS m / e: 189 (M + H) i! Part B: To compound 386 (21.63 g, 0.124 mol) dissolved in THF (400 ml) Lawesson's Reagent (30.13 g, 0.074 mol) was added. It was stirred at room temperature for 16 h then it was concentrated. It was purified by chromatography and silica gel (eluent: 3% MeOH-CH 2 Cl 2) then it was purified by chromatography on silica gel (eluent: 2% MeOH-CH1CI2) to give 23.59 g (100%) of product 387 as a light green solid. MS m / e: 135 (? + 2-tBu).

For n = 2: MS m / e: 149 (? + 2-tBu) Part C: i I To compound 387 (6.00 g, 31.5 mmol) dissolved in CH2Cl2 (150 mi) was added ethyl bromopyruvate (6.76 g, 4.4 ml, 34.7 mmol). He stirred to room temperature for 5 h, then concentrated. I sieves were added 3A (6 g) and EtOH (150 ml) and refluxed for 16 h. It leaked and it concentrated to give a dark foam. The foam was dissolved in CH2Cl2: EtOH 1: 1 (100 mL) and triethylamine (6.40 g, 8.8 mL, 63.1 mmol) was added. and tBOC anhydride (7.60 g, 34.7 mmol). It was stirred at room temperature I for 5 h then it was concentrated. NaOH 0.25 N (100 ml) was added, extracted With CH2Cl2, the combined organic extracts were dried (MgSO4), they filtered and concentrated. It was purified by silica gel chromatography (eluent: 10% EtOAc-CH2CI2 at 30% EtOAc-CH2CI2) to give 6.00 g (67%) of product 388 as a brown oil. MS m / e: 287 (M + H).

For n = 2: MS m / e: 301 (M + H) | Part D:! To compound 388 (4.70 g, 16.4 mmol) disu elite in Et 2 O (140 ml) Lithium borohydride (1.43 g, 65.7 mmol) and M ^ OH (2.10 g, 2.7 ml, 65. 7 mmol). It was refluxed for 16 h, cooled to temperature environment, and concentrated. Water (100 ml) was added, extracted with CH 2 Cl 2, dried the combined organic extracts (MgSO4), filtered and they concentrated. It was purified by silica gel chromatography (eluent: 2% MeOH-CH 2 Cl 2 at 5% MeOH-CH 2 Cl 2) to give 3.70 g (92%) of the product 389 as a yellow solid. MS m / e: 245 (M + H).

For n = 2: MS m / e: 259 (M + H): í Part E: To compound 389 (5.30 g, 21.7 mmol) dissolved in CH2Cl2 (130 mi) and cooled to -25 ° C added triethylamine (4.40 g, 6.0 ml, 43.4 mmol) then mesyl chloride (3.00 g, 2.0 ml, 26.0 mmol) per drop. It was heated up to 0 ° C slowly for 60 minutes. Water (100 ml) was added, extracted with CH2Cl2, the combined organic extracts were dried (MgSO4), filtered and concentrated to give 7.00 g (100%) of the product 390 as an oil yellow. MS m / e: 223 (? + 2-tBOC).

For n = 2: MS m / e: 237 (? + 2-tBOC) j I | I I Part F: To compound 390 (0.60 g, 1.86 mmol) dissolved in dry DMF (25 ml) was added 4-hydroxypyridine (0.22 g, 2.30 mmol) and cesium carbonate (1.20 g). g, 3.72 mmol). It was stirred at room temperature for 16 h then concentrated. Water (25 ml) was added, extracted with CH2Cl2, the Combined organic extracts (MgSO4) were filtered and concentrated. It was purified by silica gel chromatography (eluent: 10% MeOH with NH3-CH2CI2) to give 0.40 g (68%) of the product 391 A as an oil colorless. MS m / e: 322 (M + H).

The following intermediaries were prepared in accordance with the previous procedure: ' Part G: | i Copper cyanide (1.65 g, 18 i4 mmol) was suspended in dry THF I (70 ml) under a nitrogen atmosphere and cooled to -25 ° C. Phenyl magnesium bromide (3.0 M in Et20, 12.3 mL, 37.0 mmol) was added dropwise by syringe so that the internal temperature would be < -20 ° C. It stirred at -20 ° C for 30 minutes then at 0 ° C for 30 minutes. It warmed up ° C internal temperature, then re-cooled to -25 ° C. Compound added 390 (1.98 g, 6.14 mmol) dissolved in dry THF (20 ml) by dripping through syringe. It was stirred at -25 ° C internal temperature for 2 h then at 0 ° C for 16 h. Concentrate, add 2N NH4OH (100 mL), extract with CH2CI2, the combined organic extracts were dried (MgSO4), filtered and they concentrated. It was purified by silica gel chromatography (eluent: 5% EtOAc-hexane to 20% EtOAc-hexane) to give 1.14 g (66%) of the product 392A as a yellow oil. MS m / e: 305 (M + H).

The following intermediaries were prepared according to the previous procedure: Part H: To compound 392A (0.30 g, 0.986 mmol) dissolved in CH 2 Cl 2: MeOH 1: 1 (10 mL) was added 4 N HCl in dioxane (2.4 mL, 9.86 mmol). I was stirred at room temperature for 16 h then concentrated to give 0. 23 g (100%) of the product 393A (hydrochloride salt) as a beige foam.

MS m / e: 205 (M + H). The following intermediaries were prepared according to the above procedure: j i I Part I: . { Compound 393A (10Q mg, 0.416 mmol), compound 362 (181 mg, 0.499 mmol), HATU (316 mg, 0.832 mmol), and triethylamine (126 mg, 0.17 mL, 1.25 mmol) in DMF were combined. | co (6 mi). It was stirred at room temperature for 16 h. Concentrate, add 0.5 N NaOH (15 mL), extract with CH 2 Cl 2, dry the combined organic extracts I (MgSO 4), filter and concentrate. It was purified by silica gel chromatography (eluent: 3% MeOH-CH2Cl2) to give 120 mg (52%) of the product 394A as a colorless oil. MS m / e: 550 (M + H). or t Part J: ' To Compound 394A (0.1 2 g, 0.218 mmol) dissolved in MeOH (6 mL) was added 0.5 M NaOMe in MeOH (0.044 mL, 0.0218 mmol). He stirred to room temperature for 60 minutes. IHCI 4 N in dioxane was added (0.055 mL, 0.218 mmol) and concentrated to give 0.10 gj (100%) of the product 395 like a light yellow foam. MS m / e: 466 (M + H).

The following compounds were prepared according to previous procedure: i EXAMPLE 9B SCHEME 1 Reference for compound 449:! i K. Nicolaou, N. P. King, M. R. V. Finlay, Y. He, F. Roschangar, D. Vourloumis, H. Vallberg, F. Sarabia, S. Ninkovic, D. H¡epworth; Bioorg. Med.

Chem. 1999, 7, 665-697.

Part A: j i To compound 449 (4.86 g, 25.0 mmol) dissolved in CH2Cl2 (200 ml) cooled to -30 ° C triethylamine (5.07 g, 7.0 ml, 50.1 mmol) and then mesyl chloride (3.44 g, 2.3 ml, 30.1 mmol) was added dropwise. syringe. It was heated slowly to 0 ° C for 60 minutes. Added water (200 ml), extracted with CH2Cl2, the organic extracts were dried combined (MgSO4), filtered and concentrated to give 6.80 g (100%) of the product 450 as an orange oil. MS m / e: 272 (M + H).

Part B: To compound 450 (6.80 g, 25.0 mmol) dissolved in DMF (100 ml) sodium azide (3.25 g, 50.0 mmol) was added and heated at 80 ° C for 2 hours. h. It was cooled to room temperature and concentrated. Water was added (200 mi), extracted with CH2Cl2, the combined organic extracts were dried (MgSO4), filtered and concentrated. It was purified by chromatography of silica gel (eluent: 5% EtOAc-hexane to 10% EtOAc-hexane) to give 4.18 g (76%) of the product 451 as an orange oil. MS m / e: 219 (M + H). ! Part C: To compound 451 (4.18 g, 19.1 mmol) dissolved in 10: 1 of I THF: water by volume (150 ml) was added triphenylphosphine (20.0 g, 76.3 mmol) and it was refluxed for 2 h. It was cooled to room temperature and concentrated. It was purified by silica gel chromatography (eluent: 3% MeOH with NH3-CH2CI2) to give 6.18 g of the 452 product (with triphenylphosphine) as a yellow solid. 100% yield of the product 452 It would be 3.68 g. MS m / e: 194 (M + H).

Part D: To compound 452 (3.68 g, 19.1 mmol) dissolved in CH2Cl2 (100 mi) tBOC anhydride (5.21 g, 23.9 mmol) was added. It was stirred at temperature environment for 2 h then concentrated. It was purified by chromatography of silica gel (eluent: 3% MeOH-CH2Cl2) to yield 3.97 g (71%) of the 453 product as a yellow oil. MS m / e: 293 (M + H).

Part E: i To compound 453 (1.07 g, 3.65 mmol) dissolved in dry THF (10 mL) under a nitrogen atmosphere was added 2-chlorobenzyl zinc chloride. (0.5 M in THF, 14.6 mL, 7.30 mmol) and b¡s (tr¡-t-butylphosphine) palladium (0.14 g, 0. 274 mmol). It was heated at 60 ° C for 2 h. It was cooled to room temperature and concentrated. 0.2 N HCl (30 mL) was added, extracted with CH2Cl2, The combined organic extracts were dried (MgSO4), filtered and concentrated. It was purified by silica gel chromatography (eluent: % EtOAc-hexane to 15% EtOAc-hexane) to give 0.61 g (49%) of the 454 product as a yellow oil. MS m / e: 339 (M + H).

SCHEME 2 Part K Part L ??? ? 4S1 V ..

Part F: I i I To compound 389 (2.00 g, 8.18 mmol) dissolved in MeOH (40 mL) I was added 4 N HCl in dioxane (20.5 mL, 81.8 mmol). It was stirred at temperature environment for 3 h. Concentrated to give 1.48 g (100%) of the product 455 as a white solid. MS m / e: 145 (M + H).

Part G: Compound 455 (1.48 g, 8.18 mmol) suspended in CH2Cl2 (50 ml) was added triethylamine (2.48 g, 3.4 ml, 24.5 mmol) and cooled to 0 ° C. CBZCI (1 .54 g, 1 .3 ml, 9.00 mmol) dissolved in CH2Cl2 (10 ml) was added by drip through an addition funnel. Stirred at 0 ° C for 30 minutes then at room temperature for 2 h. 0.2 N fslaOH (100 ml) was added, was extracted with CH2Cl2, the combined organic extracts were dried (MgSO4), filtered and concentrated. It was purified by chromatography of silica gel (eluent: 5% MeOH-CH2CI2 at 10% MeOH-pH2CI2) to give 1.41. g (62%) of the product 456 as a white solid. MS m /?: 279 (M + H).

Part H: | To compound 456 (1.40 g, 5.03 mmol) dissolved in CH2Cl2 (40 ml) and cooled to -30 ° C triethylamine (1.02 g, 1.4 mi, 10.1 mmol) and then, mesyl chloride (0.69 g, 0.47 mL, 6.04 mmol) per drip by syringe. HE heated slowly to 0 ° C for 60 minutes. Water (50 ml) was added, extracted with CH2Cl2, the combined organic extracts were dried (MgSO4), I t I filtered and concentrated to give 1.79 g (100%) of the 457 product as a yellow oil MS m / e: 357 (M + H).

Part I: A 2- (1,3-dioxan-2-yl) phenylmagnesium bromide (0.25 M in THF, 100 mL, 25.0 mmol) under a nitrogen atmosphere and cooled to -25 ° C. internal temperature was added copper cyanide (1.12 g, j 12.5 mmol). It stirred at -25 ° C for 1 h then at 0 ° C for 1 h. It was set to 15 ° C internal temperature then re-cooled to -25 ° C. Compound compound 457 (1.78 g, 4.99 mmol) dissolved in dry THF (15 ml) by drip by syringe. t stirred at -25 ° C internal temperature for 1 h then a | 0 ° C for 16 h. HE concentrated, added NH2OH 2 N (100 ml) and CH2Cl2 | l 00 ml), and filtered at through Celite. The layers of the filtrate were separated, extracted with CH2Cl2, The combined organic extracts were dried (MgSO4), filtered and they concentrated. It was purified by silica gpl chromatography (eluent: % EtOAc-hexane at 40% EtOAc-hexane) to give 1.35 g (64%) of the 458 product as a white solid. MS m / e: 425 (M + H).

Part J: Compound 458 (1.34 g, 3.16 mmol) was dissolved in CH 2 Cl 2 (10 mL)! water (2 ml) and TFA (8 ml) were added. It was stirred at room temperature for i5 h then it was concentrated. 1N NaOH (50 mL) was added, extracted with CH2Cl2, The combined organic extracts were dried (MgS; 04), filtered and they concentrated. It was purified by silica gel chromatography (eluent: % EtOAc-CH2CI2 at 30% EtOAc-CH2CI2) to give 1.05 g (91%) of the 459 product as a yellow oil. MS m / e: 367 (M + H).

Part K: To compound 459 (0.74 g, 2.02 mmol) dissolved in CH2Cl2 (20 ml) dimethylamine (2 M in THF, 2.0 mL, 4.04 mmol) was added, 3A sieves (0.60 g), glacial acetic acid (0.12 g, 0.12 ml, 2.02 mmol), then triacetoxyborohydride of sodium (0.64 g, 3.03 mmol). It was stirred at room temperature for 16 h. 0.5 N NaOH (25 mL) was added, CH 2 Cl 2 was extracted, the combined organic extracts were dried (MgSO 4), filtered and concentrated. It was purified by silica gel chromatography (eluent: 5% MeOH with NH 3 -CH 2 Cl 2 to 15% MeOH with NH 3 -CH 2 Cl 2) to give 0.65 g (81%) of the product 460 i as a yellow oil. MS m / e: 396 (M + H).

Part L: To compound 460 (0.64 g, 1.62 mmol) dissolved in MeOH (5 ml) THF (2 mL) and 6.25 N NaOH (5 mL) were added. It was refluxed for 3 h.

It was cooled to room temperature and concentrated, j It was purified by chromatography on silica gel (eluent: 10% MeQH with NH3-CH2CI2 a % MeOH with NH3-CH2Cl2) to give 0.31 g (74%) of the product 461 as an orange oil MS m / e: 262 (M + H). i I The selected compounds that were prepared using the The procedures of Example 9B were exemplified in the previous Section.

EXAMPLE 10 2-heteroaryl pyrrolidines and derivatives EXAMPLE 10A «7 Part A: To D-1-N-Boc-prolinamide (462) (2.5 g, 1 1.71 mmol) in THF (15 mL) was added Lawesson's reagent (2.36 g, 5.8 mmol), in portions, to room temperature. The reaction mixture was stirred for 3.5 hours under argon atmosphere. The solvents were removed in vacuo. Purification I by column chromatography (SiO2, 5% MeOH / DCM) gave 463 as a light yellow solid (2.5 g, 93%).

Part B: A mixture of 463 (500 mg, 2.15 mmol) and hydrogenated potassium carbonate I (1.74 g, 17.35 mmol) in DME (1 ml) was stirred for 10 minutes. Ethyl bromopyruvate (0.81 ml, 6.45 mmol) was added dropwise. by syringe to the reaction mixture. The reaction mixture was stirred for 30 minutes. The reaction mixture was cooled to 0 ° C and a mixture of trifluoroacetic anhydride (1.21 ml, 8.6 mmol) and 2,6-lutidine (2.12 ml, 18.3 mmol) it was added by dripping by syringe for 10 minutes. The mixture of ? The reaction was stirred for 30 minutes at 0 ° C. The solvents were removed under vacuum. The residue was dissolved in chloroform, washed with 0.1 N HCl, solution of 1-bicarbonate and brine, dried over sodium sulfate and concentrated. The purification by column chromatography (SiO2, 30% EtOAc / hexane) gave 464 as a light yellow solid (520 mg, 74%). HF LC-MS tR = 1.88 min (UV254 nm); Mass calculated for the formula C15H22 2O4S 326.1, LCMS observed m / z 327.1 (M + H). ! Part C: I I A 464 (486 mg, 1.49 mmol) in dioxane (1 mL) was added HCl 4 N I in dioxane (1 mL). The reaction mixture was stirred for 1 hour at Room temperature and concentrated. HPLC-MS t R = 0.60 min (UV254 nm); Mass calculated for the formula CioH14N2O2S 226.1, LCMS observed m / z 227. 1 (M + H). i Part D: i To 48 (216 mg, 1.0 mmol) in THF (2 ml) was added 229 material (238 mg, 1 mmol). The reaction mixture was stirred overnight room temperature. The reaction mixture was concentrated and lyophilized to give a white powder (4.0 mg, 90%). HPLC-MS t R = 1.74 min (UV254 nm); Dough calculated for the formula C20H20CINO7S 453.0, LCMS observed m / z 454.0 (M + H).

Part E: To 465 (26 mg, 0.1 mmol) in DMF (0.5 mL) was added DIEA (35 μ ?, 0.2 mmol), 466 (54 mg, 0.12 mmol) in DMF (1 mL) and then HATU (57 mg, 0.15 mmol). The reaction mixture was stirred overnight at room temperature ambient. The reaction mixture was diluted with ethyl acetate (20 ml) and water i (20 ml) and the layers were separated. The organic layer was washed with 0.1 N NaOH, I HCl 0.1 N and brine, dried over sodium sulfate and concentrated. He Compound 467 was used without further purification. HPILC-MS tR = 2.06 min (UV254 nm); Mass calculated for the formula C3oH32CI 308S2 661 .1, LCMS observed m / z 662.0 (M + H).

Part F: To 467 in methanol (1 ml) was added 7.0 M ammonia in methanol (1 ml). The reaction mixture was stirred for: 1 hour at temperature environment and concentrated. Purification by LC: preparatory reverse phase i gave 468 as a white powder (2 mg). HPLC-MS tR = 5.04 min (UV254 nm, 10 min); Mass calculated for the formula C26H28CI 3O6S2 577.1, LCMS i observed m / z 578.0 (M + H). i EXAMPLE 10B Part A: A solution of LDA was formed by the addition of 1.6 M n-butyl lithium (34 mL, 54.5 mmol) to diisopropylamine (8.47 mL, 60 mmol) in THF (20 mL) at -78 ° C. The reaction mixture was stirred at -78 ° C for 20 minutes and warmed to 0 ° C gradually. The LDA solution was added dropwise to a mixture of N-Boc-D-proline methyl ester (469) (2.5 g, 10.9 mmol) and chloroiodomethane (3.17 mL, 43.6 mmol) in THF (20 mL) at -78 ° C through a cannula for 30 minutes. The reaction mixture was stirred at -78 ° C for 30 minutes. A solution of acetic acid (15 mL) in THF (15 mL) was added slowly over 20 minutes at -78 ° C. The reaction mixture was stirred for 20 minutes and then warmed to room temperature. Mix The reaction mixture was diluted with ethyl acetate and washed with water, baking soda and brine. The organic layer was dried over sodium sulfate sodium and concentrated. Purification by column chromatography (Si02, 20% EtOAc / hexane) gave 470 as a solide »light brown (2.0 g, 74%). HPLC-MS t R = 1.80 min (UV254 nm); Mass calculated for the formula CiiHi eCIN03 247.1, LCMS observed m / z 248.1 (M + H). ! j Part B: A mixture of 470 (250 mg, 1.0 mmol) and thiourea (152 mg, 2 mg). mmol) was stirred for 72 hours. The reaction mixture was diluted with acetate of ethyl and washed with sodium bicarbonate solution and brine. The layer organic was dried over sodium sulfate and concentrated. The purification by column chromatography (SiO, 80% EtOAc / hexane) gave 471 as a white solid (201 mg, 75%). HPLC-MS t R = 0.67 min (UV254 nm); Mass calculated for the formula Ci2H19N302S 269.1, LCMS observed m / z 270. 1 (M + H). ! i Part C: j I A 471 (201 mg, 0.75 mmol) in dioxane (1 mL) was added HCl 4 N i in dioxane (1 mL). The reaction mixture was stirred for 1 hour at Room temperature and concentrated. ! Part D: A mixture of 466 (45 mg, 0.1 mmol), 472 (29 mg, 0.1 2 mmol), DIEA (50 μ ?, 0.28 mmol) and HATU (57 mg, 0.1 mmol) and »DMF (2 mL) was stirred overnight at room temperature. The reaction mixture was diluted i with ethyl acetate (20 mL) and water (20 mL) and the layers separated. The organic layer I was washed with 0.1 N NaOH, 0.1 N HCl and salt, dried over Sodium sulfate and concentrated. The residue was dissolved in methanol (1 ml) and added 7.0 M ammonia in methanol (1 mL). The reaction mixture was stirred for 1 hour at room temperature and concentrated. The purification by reverse phase preparatory LC gave 473 cdmo a white powder.

HPLC-MS t R = 1.42 min (UV254 nm); Mass calculated for the formula C23H25CIN4O4S2 520. 1, LCMS observed m / z 521. 1 (M + ljl). i N. et to the; Tetra gregó 2,2-dimethoxy-ethylamine (61 4 mg, 5.84 mmol), EDCI (1.1 g, 5.84 mmol), HOBT j (658 mg, 4.87 mmol), and NMM (1.08 mL, 9.8 mmol). The reaction mixture is stirred overnight at 25 ° C. Saturated aqueous solution of NaHCO 3 (50 ml). The aqueous layer was extracted with CH2Cl2 (50 ml x3). The layers The combined organics were washed with brine (50 ml), dried over Na 2 SO 4, and concentrated by rotary evaporator to give 1-i-benzyl-pyrrolidine-2-carboxylic acid (2,2-dimethoxy-ethyl) -amide as an oil i yellow To 1-benzyl-pyrrolidine-2-carboxylic acid (2,2-dimethoxy-ethyl) -amide is added acetic acid (10 ml) and ammonium acetate (1 g). The reaction mixture was heated to 140 ° C overnight. One '? ß? that cooled, it poured in 100 ml of ice water with agitation. Solid NaHC03 was added in small portions with stirring to regulate the pH of the solution to 8-9. The aqueous solution was extracted with EtOAc (100 ml x2). The organic layers combined were washed with brine, dried over Na2SO, and concentrated with evaporator by rotation. Compound 475 (10 mg) was isolated by SiO2 chromatography (CH2Cl2 / MeOH / NH3: 40: 1: 0.1 et 20: 1: 0.1). MS: m / z 228. 3 [M + H] +. ! | Part B: 5-Pyrrolidin-2-yl-1 H-imidazole I A 475 (10 mg) in 10 ml of EtOH was added Pd / C (10%, 50 mg). i The reaction mixture was hydrogenated under hydrogen [3J45 x 105 Pa (50 psi)] for 24 hours. The solid was filtered and the solution evaporated by rotary evaporator to give 5-pyrrolidin-2-yl-1 / - / - imidazole (476) (67 mg). MS m / z 138.2 [M + H] +. 1 H-MNR (300 MHz, CDCl 3): d ppm: 6.95 (s, 2H), 4.35 (t, 1 H, I I I j EXAMPLE 11 2-Phenyl pyrrolidines and derivatives EXAMPLE 11 A: - bromophenyl) -pyrrolidine (503) (prepared by the method of Sorgi, K.L .; Maryanoff, C. A .; McComsey, D. F .; Graden, D. W .; Maryanoft, B. E .; J. Am.

Chem. Soc. 1990, 1 12, 3567) (1.12 g, 4.95 mmol), DIEA (1.75 ml, 10.0 mmol) and HATU (1.88 g, 4.95 mmol). The reaction mixture was stirred overnight at room temperature. The DMF was removed under vacuum and the residue was divided between ethyl acetate (20 ml) and water (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate solution, 1.0 N HCl and brine, C18H22BrNO5 41 1 .1, LCMS observed m / z 412.2 (M + H). j i: Part B: i To the piperazine-1-carboxylic acid tert-butylester (279 mg, 1.5 mmol), potassium phosphate (530 mg, 2.5 mmol), Pd2 (dba) 3 (23 mg, 0.025 mmol) and 2- (dicyclohexylphosphino) biphenyl (35 mg, 0.1 mmol) under Argon atmosphere was added the Part A (414 mg, 1.0 mmol). The reaction mixture is evacuated and saturated with argon. The mixture was heated overnight at 90 ° C. The reaction mixture was diluted with ethyl acetate, filtered through i Celite and concentrated to give a mixture of methyl ester 505A and acid 505B like an orange film (679 mg). The material was used without purification additional. 505A: HPLC-MS tR = 2.08 and 2.14 min (ester, UV254 nm); dough calculated for the formula C27H39N3O7 517.3, LCMS observed m / z 51 8.0 (M + H). 505B: HPLC-MS tR = 1.83 and 1.91 min (acid, UV254 nm); dough calculated for the formula C26H37 307 503.3, LCMS observed m / z 504.1 (M + H).

Part I: To the mixture of 505A and 505B (~ 1 mmol) in THF (4 mL) and water (1 mL) was added 1.0 M lithium hydroxide (1.2 mL, 1.2). mmol). The mixture of The reaction was stirred overnight at room temperature. The mixture of The reaction was diluted with water (10 ml) and the THF was removed in vacuo. The layer aqueous was washed with diethyl ether (3 x 10 mL), acidified; with HCI 1 .0 N and it extracted with ethyl acetate (3 x 10 mL). The layers! ethyl acetate The combined extracts were dried over sodium sulfate and concentrated. The purification by reverse phase preparatory LC gave the desired isomer 506 (1 07 mg, 96% purity). HPLC-MS tR = 1.83 min (UV254 nm); mass calculated for the formula C26H37N3O7 503.3, LCMS observed m / z 504 (M + H).

Part D: j To 506 (1 07 mg, 0.21 mmol) in DMF (5 mL) was added 229 (55 mg, 0.23 mmol), DIEA (80 μ ?, 0.46 mmol) and HATU (87 mg, 0.23 mmol). The The reaction mixture was stirred overnight at room temperature. The DMF i was removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers separated. The organic layer was washed with 0.1 N NaOjH, 0.1 N HCl, and brine, dried over sodium sulfate and concentrated. The purification by column chromatography (SiO2, 50% EtOAc ^ hexane) gave 507 (98 mg, 64%). HPLC-MS t R = 2.49 min (?? 254 nm); mass calculated for the formula i C38H47CIN4O6S 722.2, LCMS observed m / z 723.1 (M + H). I Part E: i To 507 (98 mg, 0.1 4 mmol) was added TFA: water 80:20 (4 mL) and the The mixture was stirred for 4 hours at room temperature. The reaction deactivated with 1: 1 acetonitrile: water (10 ml) and concentrated. The residue was dissolved in ethyl acetate and washed with sodium bicarbonate solution. Sodium chloride was added to the aqueous layer and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in acetonitrile (2 mL) and 1.0 N HCl (0.3 mL) and concentrated. The material was lyophilized to give 508 as the HCl salt as a white powder (75 mg, 86%). HPLC-MS t R = 1.27 min (UV254 nm); mass calculated for the formula i C3oH35CIN4O4S 582.2, LCMS observed m / z 583.2 (M + H).

EXAMPLE 1 1 B Part A: To a solution of compound 503 (5.0 g, 22.1 mmol) in dry CH 2 Cl 2 (80 mL) was added di-tert-butyl dicarbonate (5.55 g, 25.4 mmol). The solution was stirred at room temperature for 2 hours. The solvent is eliminated by rotary evaporator. The product was isolated by chromatography of the silica gel (Hexane / EtOAc 5: 1 to 3: 1) to give the Compound 509 (5.7 g, 79%).

Part B: In a double-neck flask, compound 509 (1.0 g, 3. 06 mmol), MeOH (8 mL), triethylamine (6 mL), DMF (6 mL), and Pd (PPh3) 2 Cl2. A condenser with a 3-way valve on the upper part i was attached to the flask. A balloon and a tank of carbon monoxide were attached to the three-way valve. The balloon was filled with CO and the system was stunned times. Then, the balloon was filled with CO and connected to a) flask system. He flask was heated in an 80 ° C oil bath for 36 hours. After After cooling to room temperature, water (50 ml) and EtOAc were added. (100 mi) The organic phase was separated, washed with water (50 ml) twice and brine, dried over Na2SO4, concentrated with rotary ejaporator, The product was isolated by silica gel chromatography (Hexane / EtOAc 10: 1 to 5: 1) to give compound 510 (610 mg, 65%). I Part C: Compound 510 (384 mg, 1.26 mmol) was dissolved in dioxane / water (3: 1, 4 mL) and LiOH (100 mg, 2.38 mmol) was added. The solution it was stirred at room temperature for four hours. Added solution saturated with NH4CI (20 ml). The aqueous phase was extracted EtOAc ion (25 ml) two times. The organic phases were combined, washed with brine, dried over Na2SO4, concentrated by rotary evaporator, and dried in vacuo to give compound 511 (368 mg, 10 (j)%).

Part E: Compound 511 (76 mg, 0.26 mmol) was dissolved in CH 2 Cl 2 dry (1.5 mi). N-methyl piperazine (0.035 ijnl, 0.31 mmol), EDCI were added (75 mg, 0.39 mmol), HOBT (43 mg, 0.31 mmol), and iJlMM (0.086 mL, 0.78 mmol). The solution was stirred at room temperature for 16 hours. Saturated NaHCO3 solution (5 mL) and CH2Cl2 (5 mL) were added and the layers separated. The aqueous phase was extracted with CH 2 Cl 2 (5 mL) twice. The phases organic extracts were combined, dried over Na2SO4, concentrated by rotary evaporator. The product was isolated by chromatography of silica gel to give compound 512 (90 mg, 92%).

Part F:! I Compound 512 (90 mg, 0.24 mmol) was dissolved in MeOH (1 mi) and HCl (4M in dioxane, 0.25 ml, 1 mmol) was added. The solution was stirred to Room temperature during the night. The solvent was removed by Rotary evaporator to give compound 513 (83 mg, 100%).

EXAMPLE 11 C: (60 ml), and lithium borohydride (0.78 g, 36.2 mmol) was added. The solution is heated to reflux for 16 h then cooled to room temperature. MeOH (4 mL) was added, and the solvent was removed by rotary evaporator.

Water (75 ml) was added, and the aqueous solution was extracted with CH2Cl2 (75 ml) I three times. The combined organic extracts were dried (MgSO4), they filtered and concentrated. The product was purified by chromatography of silica gel (eluent: 5% MeOH-CH 2 Cl 2 at 10% MeOH-CH 2 Cl 2) to give 3.28 g (98%) of compound 514, MS (m / e for M + 1) j 278.

Part H:! Oxalyl chloride (1.87 g, 1.3 ml, 14.7 mmol) was dissolved in Dry CH2CI2 (35 mL) and cooled to -78 ° C under a nitrogen atmosphere. HE DMSO (2.30 g, 2.1 ml, 29.5 mmol) dissolved in dry CH2Cl2 was added dropwise. (5 mi) by means of an addition funnel. The solution was stirred at -78 ° C for minutes later, compound 514 (3.27 g, 1i 1.8 mmol) dissolved in CH2Cl2 (15 ml). The reaction mixture was stirred at -78 ° C for 60 minutes, then triethylamine (3.58 g, 4.9 ml, 35.4 mmol) was added. The mixture of The reaction was stirred at -78 ° C for 15 minutes then warmed to 0 ° C. added water (75 ml), and the layers separated. The aqueous phase was extracted with CH2Cl2 (75 ml) twice. The combined organic extracts were dried (MgSO4), filtered and concentrated. The product was purified by chromatography on silica gel (eluent: 5% EtOAc-CH2CI2 at 10% of EtOAc-CH2Cl2) to give 2.94 g (90%) of the product 515: MS (m / e for M + 1): 276. | i i i Part I: i Compound 515 (0.50 g, 1.82 mmol) was dissolved in CH2Cl2 (10 mi), and sieves 3A (0.50 g), dimethylamine in THF (2 M, 1.8 m, 3.64 mmol), glacial acetic acid (0.109 g, 1.82 mmol), and triacetoxyborohydride was added sodium (0.579 g, 2.73 mmol). The reaction mixture was stirred at room temperature environment for 24 h. 1 N NaOH (25 ml) was added, and the aqueous solution was extracted with CH2Cl2 (25 ml) four times. The combined organic extracts were dried (MgSO4), filtered and concentrated. The product was purified by silica gel chromatography (eluent: 5% MeOH-CH 2 Cl 2 a % MeOH-CH2Cl2) to give 0.396 g (72%) of the product 516. MS (m / e for M + 1): 305.

The following intermediaries were also prepared.

Part J: The following compounds were prepared using the procedure described in Example 1 1 B Part F. you des Part A: j To a solution of 543 (1.01 g, 3.17 mmol) and 4-bromobenzylamine I (0.71 g, 3.83 mmol) in CH 2 Cl 2 (10 mL) cooled to 0 ° C ie added DIEA (1. mi, 6.31 mmol) followed by PyBrOP (1.0 g, 3.43 mmol). The reaction The mixture was heated to room temperature and stirred for 16 hours. The liquid is concentrated, and the thick oil was captured in EtOAc. The organic layer was washed with KHSO4 0.5 N (1 x), sat. NaHCO3 (1 x), dried (a2S04), filtered and concentrated. The residue was purified by silica gel chromatography (eluting from 0% to 100% EtOAc / hexanes) to give 544 (1.27 g, 2.61 mmol, 82% yield) as a tan oil. MS m / e: 487.1 (M + H).

Part B: A solution of 544 (0.105 g, 0.21.5 mmol), acid 2- I! cyanophenylboronic acid (0.032 g, 0.215 mmol), and Pd (dppf) Cl2 ¾0.016 g, 0.021 mmol) in CH3CN (1 ml) and K2CO3 1 N (1 ml) was heated in a microwave SmithCreator (container of 2-5 ml, 150 ° C for 10 minutes). The mixture was concentrated and the residue was purified by silica gel chromatography i (eluting from 0% to 100% EtOAc / hexanes) to give 545 (0.062 g, 0.12 mmol, 56% yield) as a tan oil. MS m / e: 510.1 (M + H).

Part C: j A solution of 545 (0.049 g, 0.096 mmol) in a 70% mixture of TFA / 20% CH2Cl2 / 10% H2O was stirred at room temperature I for 2 hours. The mixture was concentrated, and the residue was purified by Reverse phase HPLC (eluting 5:95 to 95: 5 CH3CN / H20 (0.1% HC02H)) to provide 546 (0.023 g, 0.049 mmol, 51% yield) as a solid white. MS m / e: 470.1 (M + H). ! CH2Cl2 / MeOH) to give 549 (0.14 g, 0.55 mmol, 50% yield) as a brown oil. MS m / e: 256.1 (M + H).

I Part B: j To a solution of 549 (0.21 g, 0.82 mmo) and 543 (0.19 g, 0.59 mmol) in CH2Cl2 (5 ml) cooled to 0 ° C DIEA was added followed by PyBrOP. The reaction was stirred for 20 hours by heating: gradually to room temperature. The mixture was concentrated, and the brown oil was captured in EtOAc. The organic phase was washed with KHS04 0.5 N (x), sat. NaHCO3 (1x), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (eluting 0% to 100 ° or EtOAc / hexanes) to give 550 (0.29 g, 0.51 mmol, 87% yield) as a brown oil. S m / e: 557.1 (M + H).

Part C: I i To a solution of 550 (0.26 g, 0.47 mmol) in a mixture of THF (2 mL) / MeOH (2 mL) / H2O (1 mL) was added LiOH.H2O (0.052 g, 1.24 mmol) in a solid portion. The reaction was stirred overnight and then acidified to pH ~ 3 with 1 N HCl. After dilution with EtOAc, the organic layer was removed, and the aqueous phase was extracted with EtOAc (3x). The combined organics were dried (Na2SO4), filtered and concentrated. The residue was purified by reverse phase HPLC (eluting 10:90 to 100: 0 CH 3 CN / H 2 O (0.1% HCO 2 H) to give 551 (0.22 g, 0.38 mmol, 88% yield). : 529.1 (M + H). i Part D:; To a solution of 551 (55 mg, 0.104 mmol) in CH2Cl2 (1 mL) was added HOBt bound to polystyrene (109 mg, 0.095 mmol) j DIC (0.067 mL, 0.427 mmol), and DMAP (7 mg, 0.057 mmol) and stirred overnight. The mixture filtered, then washed with DMF (3 x 3 mL), CH 2 Cl 2 (3 x 3 mL), DMF (3 x 3 mL), and THF (3 x 3 mL). The resin was dried under vacuum overnight. To the acid attached to dry resin (82 mg, 0.034 mmol) was added 3-chlorobenzylamine (8.33 μ ?, 0. 068 mmol) in CH2Cl2 (1 mL) and the mixture was stirred overnight. To Isocyanate resin bound to polystyrene (70 mg, 0.102 i mmol) was added to the mixture and stirred for 5 hours. The desired product was filtered and the filtered i was washed with CH 2 Cl 2 (3 x 3 mL) and THF (3 x 3 mL). The organic i i portions were concentrated in vacuo to give 552 (14.6 mg, 0.022 mmol, 66% yield). i MS m / e: 652.2 (M + H). i Part E: I A 552 (14.6 mg, 0.022 mmol) was added 2 ml of a mixture of TFA / CH2Cl2 / H2O (7/2/1) and stirred at room temperature for 2 h. The The mixture was concentrated in vacuo. The mixture was purified by phase HPLC reverse to give 553 (3.7 mg, 0.006 mmol, 27% yield). MS m / e: 612. 1 (M + H). t! i I I I Compound 554 was prepared by the procedure described in Example 4 Part C. HPLC-MS tR = 1.39 min (UV2 ^ nm); calculated mass! I for the formula C14H16CIN05 397.1, LCMS observed mjz 398.1 (M + H). i I I Part A: i A 554 (355 mg, 0.89 mmol) in DMF (5 mlj hydrochloride was added of 2-fluoro-4-bromobenzylamine (257 mg, 1.07 mmol), DIEA (530 ul, 3.03 mmol) and HATU (407 mg, 1.07 mmol). The reaction was stirred overnight room temperature. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with 0.1 N NaOH, HCl 0. 1 N, and brine; They were dried over sodium sulfate and concentrated. The purification by column chromatography (Si02, 80% acetate ethyl / hexanes) gave 555 as a foam (320 mg, 62%). HPLC-MS tR = 2.03 i min (UV254 nm); mass calculated for the formula C25H25BrCIFN206 582.1, LCMS observed m / z 583.0 (M + H).

Part B: To 555 (320 mg, 0.55 mmol) in MeOH (5 mL) was added hydrazine anhydride (28 μ ?, 0.88 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and lyophilized to give 556 as a white powder (275 mg, 1 Q0%). HPLC-MS tR = 1.81 min (UV254 nm); mass calculated for the formula C2i H2i BrCIFN204 498.0, LCMS observed m / z 499.0 (M + H).

Part C: Compound 556 (46 mg, 0.092 mmol) in dioxane (1 ml) was added to a solution of 2-methoxyphenylboronic acid (22 mej, 0.1 4 mmol), phosphate of potassium (42 mg, 0.2 mmol), and PdCI2 (dppf) (4 mg, 0.005 mmol) under argon atmosphere. The reaction mixture was heated at 80 [deg.] C. during the night. After cooling the mixture was filtered through Celite and the bed was Rinse with ethyl acetate. The filtrate was concentrated. The purification by Reverse phase preparatory LC gave 557 as a white solid (26 mg) after lyophilization. HPLC-MS t R = 1.97 min (UV2 $ 4 nm); calculated mass for the formula C26H2BCIFN205 526.2, LCMS observed m / z 527.0 (M + H).

Part A: A mixture of 4-bromo-benzylamine hydrochloride was stirred (558) (1.0 g, 4.5 mmol), di-tert-butyl dicarbonate (1.48 g, 6.8 mmol) and DIEA (2.4 mL, 13.8 mmol) in chloroform (40 mL) overnight at room temperature ambient. The reaction mixture was washed with 1.0 HCl Ni water and brine, dried over sodium sulfate and concentrated. The purification by column chromatography (SiO2, 20% ethyl acetate / hexane) gave a mixture of 559 (1.17 g, 91%). 1 H NMR (400 MHz, CDCl 3) d 7.44 (d, 2 H, J = 8.8 Hz), 7. 15 (d, 2H, J = 8.8 Hz), 4.85 (bs, 1 H), 4.27 (d, 2H, J = 5.7 Hz), 1.48 (s, 9H). j Part B: j A mixture of 559 (100 mg, 0.35 mmol), 560 (107 mg) was heated. mg, 0.52 mmol), potassium phosphate (223 mg, 1.05 mmol) j and PdCI2 (dppf) (14 mg, 0. 018 mmol) in dioxane (5 ml) under argon atmosphere up to 80 ° C during the night. The reaction mixture was cooled and filtered through Celite. The bed i of Celite was washed with ethyl acetate. The filtrate was washed with saturated sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated. Purification by column chromatography (Si02, 20% of ethyl acetate / hexane) gave 561 slightly impure (466 mg). HPLC-MS tR = 2. 35 min (UV25 nm); mass calculated for the formula C19H20F3NO3 367.1, i LCMS observed m / z 390.1 (M + Na). j I Part C: Compound 561 (129 mg, 0.35 mmol) was stirred in DCM: TFA 3: 1 (4 mi) for 1 hour. The residue was dissolved in DCM (5 mL) and concentrated.

The residue was dissolved in diethyl ether (20 ml) and treated with 1.0 M HCl in diethylether. (2 mi) The resulting white solid was collected by filtration and washed with diethyl ether to give 562 (90 mg, 85% 2 steps). 1H NlJlR (400 MHz, DMSO-d6) d 8.3 (bs, 3H), 7.50 (m, 8H), 4.09 (s, 2H). i Part D: Compound 563 was prepared using procedures similar to those described in Example 1 1 A. Compound 564 was prepared from 562 and 563 using procedures similar to those described in Example 1 Part A. HPLC-MS t R = 2.49 min (UV nm); mass calculated for the formula C31 H3oCIF3N2O5 602.2, LCMS observed m / z 603.2 (M + H).

Water. The layers were separated and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated to give 567 (1.76 g, 67%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3) d 7.46 (dd, 1 H, J = 6. 3, 8.8 Hz), 6.62 (dd, 1 H, J = 2.7, 10.5 Hz), 6.57 (m, 1 = 2.7), 4.08 (q, 2H, J = 6.9 Hz), 1.50 (t, 3H, J = 7.0 Hz).

Part B: Compound 569 (607 mg, 58%) was prepared from 567 yi 568 (prepared by the methods of Maku, | S. et al. (J. Comb. I i Chem. 2003, 5, 379)) using the procedures described in Example 12D Part B. HPLC-MS tR = 2.1 3 min (UV25 nm); mass calculated for the formula C17H15F4NO2 341.1, LCMS observed m / z 342.1 (M + H). Part I: 569 (607 mg, 1.78 mmol) in methanol (6 mL) was added 10% I potassium carbonate in 2: 1 methanol (20 mL). To obtain a clear solution, additional water (5 ml) was added. The reaction mixture was stirred overnight at room temperature. The methanol was removed in vacuo. The residue is divided between water and ethyl acetate. The layers were separated and the aqueous layer it was extracted with ethyl acetate. The combined organic layers were washed brine, dried over sodium sulfate and concentrated. The residue is dissolved in diethyl ether (20 ml) and treated with 1.0 HCl in diethyl ether (5 ml). He The resulting white solid was collected by filtration and washed with diethylether to give 570 (377 mg, 75%). 1 H NMR (400 MHz, DMSO-d6) d 8.27 (bs, 3H), 7. 49 (m, 4H), 7.29 (dd, 1 H, J = 6.9, 8.3 Hz), 7.00 (dd, 1 h J = 2.5, 1 1 .4 Hz), 6. 83 (dt, 1 H, J = 2.8, 8.6, 10.8Hz) 4.05 (m, 4H), 1.27 (t, 3H, J = 6.5 Hz).

Part D: i Compound 571 was prepared using procedures described j in Example 12E Part D. Purification by chromatography on column (SiO2, 20% ethyl acetate / hexane) gave 571 (104 mg, 95%).

HPLC-MS t R = 2.40 min (UV254 nm); mass calculated for the formula C32H34CIFN2O5 580.2, LCMS observed m / z 581.2 (M + HI.

Part E: Compound 572 was prepared using the procedures described i in Example 12D Part E. HPLC-MS tR = 2.06 ?? '?? (UV254 nm); dough calculated for the formula C29H30CIFN2O5 540.2, LCMS observed m / z 541.2 I (M + H). : Part A: ! To a mixture of 2-propylphenol (573) (0.5 ml, 3.63 mmol) and DIEA (0.950 mL, 5.45 mmol) in DCM (20 mL) at 0 ° C was added triflic anhydride (0.734 mL, 4.36 mmol) in DCM (10 mL) was added via an addition funnel. The The reaction mixture was stirred for 45 minutes. The mixture was poured into water.

The layers were separated and the organic layer was washed with! saturated solution sodium bicarbonate and brine, dried over sodium sulfate and concentrated. Purification by column chromatography (Si02, 5% ethyl acetate / hexane) gave 574 (916 mg, 100%). 1 H NMR (400 MHz, CDCl 3) di 7.30 (m, 2H), 7.26 (m, 2H), 2.70 (m, 2H), 1.68 (m, 2H), 1 JoO (t, 3H, J = 7.3 Hz ). i Part B: ' Compound 575 (288 mg, 89%) was prepared using the procedures described in Example 12D Part B and a temperature of reaction of 100 ° C. HPLC-MS t R = 2.30 min (UV254 nm); mass calculated for the formula C18H18F3NO 321 .1, LCMS observed m / z 322Í2 (M + H).

Part C: | Compound 576 (203 ng, 86%) was prepared using the procedure described in Example 12E Part C. 1H NlylR (400 MHz, DMSO- i d6) d 8.27 (bs, 3H), 7.52 (d, 2H, J = 8.0 Hz), 7.32 (d, 2H, J = 8.1 Hz ), 7.31 (m, i 2H), 7.22 (m, 1 H), 7.10 (d, 1 H, J = 7.1 Hz), 4.08 (s, 2H,) 2.54 (m, 2H), 1.44 ( m, 2H), 0.75 (t, 3H, J = 7.7 Hz).

Part D: i 1 Compound 577 (62 mg, 92%) was prepared in accordance with procedure described in Example 12D Part D. HPjLC-MS tR = 2.55 min i (UV254 nm); mass calculated for the formula C33H37 (£ lN2O4 560.2, LCMS observed m / z 561.2 (M + H).

Part E: Compound 578 (53 mg, 93fo) was prepared according to (48 mg, 0.2 mmol) in carbon tetrachloride (50 ml) † until reflux under a Nitrogen atmosphere for 16 hours. The reaction mixture was cooled and filter. The filtrate was washed with water (2x), saturated bicarbonate solution of sodium and brine, dried over sodium sulfate and concentrated to give a mixture of 580 and dibromed product (4.02 g). The material was used without additional purification. 1 H NMR (400 MHz, CDCl 3) d 7.52 (dd, 1 H, J = 6.6, 7.6 Hz), 7.17 (dd, 1 H, J = 2.0, 8.9 Hz), 7.1 1 (dd, 1 H, J = 2.0, 8.2 Hz), 4.42 (s, 2H).

Part B: I A mixture of 580 (4.02 g, 15.0 mmol),! phthalimide (2.65 g, 18 mmol) and cesium carbonate (5.38 g, 16.5 mmol) in DMF (30 ml) was stirred for 72 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The combined organic layers were washed with water (3X) and brine, dried over sodium sulfate and concentrated. The recrystallization from 30% ethyl acetate / hexanes gave 581 slightly impure (3.28 g) as a yellow solid. H NMR (400 MHz, CDCI3) d 7.86 (m, 2H), 7.74 (m, 2H), 7.49 (dd, 1 H, J = 7.3, 8.4 Hz), 7.20 (dd, 1 H, J = 1 .9, 9.3 Hz), 7.06 (dd, 1 H, J = 2.0, 7.9 Hz), 4.80 (s, 2H). i Part C: 'I A mixture of 581 (1 .00 g, 3.0 mmol) and monohydrate was heated of hydrazine (580 ul, 12.0 mmol) in ethanol (25 ml) was refluxed for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered. The precipitate it was washed with ethyl acetate. The filtrate was concentrated and the residue dissolved in? water and ethyl acetate. The layers separated. The organic layer was washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated to give 582 (375 mg) as an oil yellow. 1 H NMR (400 MHz, CDCl 3) d 7.48 (t, 1 H, J = 8.5 Hz), 7.12 (dd, 1 H, J = 2.2, 9.5 Hz), 6.99 (dd, 1 H, J = 1 .6, 8.2 Hz), 3.86 (s, 2H) Part D: Compound 583 was prepared using procedures similar to those described in Example 12C Part A. HPLC-MS tR 4 1.82 min (UV254 J; mass calculated for the formula C23H22BrFN206 520.0, LCMS observed m / z I 521.0 (M + H). | j Part E: i j Compound 584 was prepared using the procedures described in Example 12C Part B. HPLC-MS tR = 1.8lj min (UV254 nm); dough calculated for the formula C 9H18BrFN2O 436.0, LCMS j observed m / z 437.0 (M + H). ! Part F: Compound 585 was prepared using procedures similar to those described in Example 12C Part C, HPLC-MS tR = 4.12 min (UV254 nm, min); mass calculated for the formula C26H22F 3O4 459.2, LCMS observed m / z 460.1 (M + H). The following Table contains compounds prepared using the procedures described in Example 12 A-G.

I I I I I EXAMPLE 13 Compound 631 was prepared by the procedures described in Example 1 1 A. S Part A: To a solution of 631 (0.46 g) and 632 (1 .2! Eq) in 10 ml DMF at I 0 ° C was added HATU (1.5 eq) and HOBt (1.5 eq). The reaction was stirred at t.a. overnight before the removal of the solvent under vacuum and the residue is chromatographed using ethyl acetate in Hexane (0-100%) to give 0.46 grams of the desired product 633.! Part B: i To a solution of 0.46 g of 633 in 10 ml of DCM was added Dess-Martin reagent (1 .1 eq) and the reaction was stirred at t.ai for 30 min before of treating it with saturated aqueous solution of sodium bicarbonate and thiosulfate sodium 7: 1 (w / w). The aqueous layer was extracted with DCM (2X) and the combined organic layers I were dried over anhydrous sodium sulfate. After Removal of the solvent, the crude reaction product was dissolved in 2 ml of pyridine. To the solution was added 1.5 eq of hydroxylamine hydrochloride and the solution was heated to reflux for 30 min before the removal of the vacuum solvent and the residue was subjected to chromatography using ethyl acetate. ethyl in Hexane (0-100%) to give 0.4 grams of the product 634.

Part C: I To a flask containing 634 (0.42 g) in anhydrous DMF at 0 ° C was added NBS (1 eq) and the solution was allowed to warm to t.a. overnight before the addition of another NBS equivalent and the solution He stirred for another night. The final reaction mixture was poured onto ice and it was extracted with DCM. The organic phase was washed with water and brine, dried over sodium sulfate. After the removal of the solvent, the residue chromatographed using ethyl acetate in hexane (0-100%) to give 0.38 grams of the desired product. j To a solution of 0.035 grams of the above compound in 2 ml of DCM was added vinylacetate (2 eq) and DIEA (3.5 eq) and the solution was stirred at t.a. overnight. After the removal of the solvent, the residue chromatographed using ethyl acetate in hexane (0-100%) to give 20 mg of the product which was treated with 50% TFA in DCM for 2h, Before purification using an RPLC HPLC system to give 10 mg of the desired product 635. The following compounds were generated using similar procedures. ' EXAMPLE 14 Part A:; A Schlenck flask was flame dried under N2 flow, covered with a septum, and allowed to cool to rt. Phthalimide (640) added (4.13 g, 28.1 mmol) followed by anhydrous THF (100 ml). Once the phthalimide was dissolved, the flask was placed in a bath of ice water and allowed to cool for 20 min. A solution of 1 M of 3-fluorophenylmagnesium bromide in THF (25 ml) was added causing the formation of a I precipitated. DMPU (5 ml) was added, causing the reaction mixture to it will clear again. More 3-fluorophenylmagnesium bromide was added (35 mi) for 10 min. The reaction mixture was stirred at 0 ° C for 3.5 h, then deactivated with sodium phosphate buffer 1.0 pH 6.5. The resulting mixture I was diluted with EtOAc and the layers were separated. The organic layer is washed with water and brine, then dried with MgSO.sub.2. The evaporation of solvent gave a whitish solid (7.4 g). This material was crushed in CH2Cl2 / hexanes to give 4.0 g of pure 641, MS (El) m / z, Obs. M + H 244.0 i Part B: A Schlenck flask was dried with flame under N2 flow, covered with a septum, and allowed to cool to ta. LiAIH4 (1.26 g, 33.2 mmol) and i ACI3 (1.47 g, 11.1 mmol) were added to the flask, followed by anhydrous THF. The flask was immediately placed in a bath of ice water and allowed to cool under agitation. Compound 641 was added to the flask in portions. The The reaction mixture was stirred for 3 h, during this time it was heated until ° C. The reaction was re-cooled to 0 ° C and water (3 ml) was added. Added aqueous sodium hydroxide 3.0 N (6 ml) followed by aguá (9 ml). The mixture of The reaction was filtered through a pad of Celite which was rinsed with EtOAc. He The resulting filtrate was concentrated to dry and gave a green solid. The crude product was partially purified by instant sgc using a! gradient 40% -50% EtOAc / hexanes, followed by 98% EtOAc / 2% I Et3N. The fractions containing the desired clear product were Compound 642 (0.56 g, 2.6 mmol) was dissolved in CH2Cl2 (8 i mi). Triethylamine (1 mL) was added followed by anhydride (! +) - diacetyl- (L) -tartaric acid (0.65 g, 3.00 mmol). The reaction mixture was allowed to stir at rt overnight. The reaction mixture was concentrated to what was dried and purified by sgc using 2% -5% mobile phase MeoH / CH2CI2 with 1% acetic acid which was added thereto. After the evaporation of the solvent and the azeotropic removal of acetic acid with heptane, | Compound i 643 was obtained as a white solid (0.33 g). MS (El) m / z Obs M-j-H 430.1.

Part D: Compound 643 (92 mg, 0.214 mmol), HOBT (36 mg, 0.26 mmol), DMF (1.5 mi), 2-thiophene ethylamine (44 mg, 0.34 mmol), and N-i methylmorpholine (50 pL) were added to a flask. EDC was added and the reaction mixture was allowed to stir overnight at rt. The reaction mixture was diluted with The OAc and was washed with aqueous NaHCO 3, citric acid, aguá, and brine. The organic layer was dried with MgSO 4 and concentrated to give a brown oil. He crude product was purified by instant sgc by jury a gradient % -80% EtOAc / Hexanes. Two diastereomeric compounds were isolated - 644 Diastereomer A (0.02 g) MS (El) m / z Obs M + H 539.06 and 645 Diastereomer B (0.03 g) MS (El) m / z Obs M + H 539.03. j Part E: Compound 645 was dissolved in 2 M methanolic ammonia and stirred at rt for 30 m. The reaction was purified until dried. The product crude was purified by preparative TLC on silica plates using 1: 1 EtOAc: Hexanes as the mobile phase. 646B: MS (El) m / z Obs M + H 455.1.

I 0 OH H 649B 531 .2 532.1 I I EXAMPLE 15 Part A: | ? Compound 650 (8.36 g, 73.9 mmol) and carbamate were dissolved of tert-butyl (25.96 g, 222 mmol) in acetonitrile (300 ml) and acid was added trifluroacetic. The reaction was stirred overnight ai ta under N2, then concentrated. The resulting mixture was dissolved in EtOAc and washed with water. The The organic layer was dried with Na2SO4 and concentrated until dried. He crude product was purified by instant sgc using 1: 3 EtOAc: Hexanes as the mobile phase to give 30.27 g of the product 651. 1 H I I NMR (400 MHz, CDCl 3) d 7.78 (s, 1 H), 7.40 (s, 1 H), 6.38-6.30 (m, 1 H), 1 .51 (s, 18H) MS (El) m / z Obs M + H 330.1.

Part B: Compound 651 (30.27 g, [.89 mmol) was dissolved in propanol (1500 mL) and sodium borohydride (| 17.0 g, 46 mmol) was added. The reaction mixture was refluxed for 3 h, then concentrated on the rotovap. The resulting material was diluted with EtOAc, washed with water, and dried with Na2SO. The solvents were evaporated and the crude product was purified by instantaneous sgc using 1: 2 EtOAc: Hexanes ccj > the mobile phase to give 1 1 .58 g of 652. Production = 73% in steps one and two. 1 H NMR (400 i MHz, CDCl 3) d 7.78 (s, 1 H), 7.33 (s, 1 H), 5.35 (s, 1 H), 4.69 (s, 2 H), 1.53 (s, 9 H); MS (El) MS (El) m / z Obs M + H 215.0.

Part C: Compound 652 (0.30 g, 1.40 mmol) was dissolved in 5 ml of anhydrous THF (5 ml). The flask was capped with a septurn, placed under an I coverage of N2, and cooled in a dry ice / 2-propanol bath. Was it added? a solution of LDA (1.71 ml, 1.8 m) by syringe and the reaction mixture was stirred for 0.5 h. A solution of benzaldehyde of 4-methoxy I (0.21 g, 1.54 mmol) in 5 ml of anhydrous THF was added via syringe. The reaction mixture was stirred for 1 h. The ice bath was removed and the reaction was allowed to stir overnight at rt. Water was added and the reaction mixture was diluted with EtOAc. The layers separated. The organic layer was washed with water and dried with Na2SO4, the solvent was evaporated and the crude product was purified by instantaneous sgc using 1: 1 EtOAc: Hexanes to give 0.28 g of 653. H NMR (400 MHz, CDCl 3) d 7.42 (s, 1 H), 7.37-7.32 (m, 2H), 6.89- I 6.94 (m, 2H), 6.02 (s, 1 H), 5.38 (broad s, 1 H), 4.55 (s, 2H), 3.86 (s, 3H) 3.28 i (s, 1 H), 1.49 (s, 9H).

Part D: < ' Compound 653 (0.28 g, 0.80 mmol) was dissolved in triethylsilane (2 mi) and TFA (0.6 mi). The reaction mixture was refluxed for 3 h and then allowed to cool to rt and stirred overnight. The reaction mixture i was concentrated. Methanol was added and the reaction mixture was concentrated. Lithium hydroxide (10 ml, 1.0 M jac) and dioxane (10 ml) were added.

The reaction mixture was stirred for 3 h then partially concentrated.

EtOAc was added and the layers separated. The organic layer was washed with water and dried with Na2SO4, the reaction mixture was concentrated to give 0. 23 g of compound 654. 1 HMNR (400 MHz, CDCl 3) 5 7.44 (s, 1 H), 7.19 (d, J = 9 Hz, 2 H), 6.89 (d, J = 9 Hz, 2 H), 4.16 (s, 2 H), 4.1 1 j (s, 2 H), 3.84 (s, 3 H), 1.77 (s broad, 2H).

I Parts E and F: j I Compound 654 was transformed into code 655 using i the procedures described in Example 2. Data pair 655: 1 H NMR (400 i MHz, CDCI3) 7.41 -7.26 (m, 5H) , 7.22-7.14 (M, 4H), 6.89-6.81 (m, 2H), 5.50- (5 The reaction mixture was stirred overnight under argon at room temperature and was diluted with EtOAc. The organic layer was washed with saturated NaHCO3 I, brine, dried over Na2SO4, and concentrated. Column chromatography on silica gel (EtOAc / hexane, 20:80) was compound 665. Mass calculated for the formula Ci8H22CINO4S 383.1, LCMS observed m / z 384.1 (M + H). · Part B: Compound 665 in MeOH (5 mL) was added K2C03 (50 mg) powder. The mixture was stirred at room temperature for 1 h and the solvent was removed in vacuo. The residue was dissolved in water and acidified with 1N HCl. Extraction was carried out with EtOAc, the combined organic layers were washed with 1 N HCl, brine, dried over Na 2 SO 4, and concentrated to give the compound 666 as an oil (45 mg). Mass calculated for the formula Ci7H2oCINO4S 369.1, LCMS observed m / z 370.1 (M + H).

Part D: To compound 666 (10 mg, 0.027 mmol) in DMF (0.5 ml) was added 229 (11 mg, 0.041 mmol) and HATU (20.5 mg, 0.054 mmol). The reaction mixture I i was stirred at room temperature for 4 h, and diluted with ethyl acetate and water. The organic layer was washed with 1 N HCl, saturated NaHCO3 and brine. It was dried over Na 2 SO, and concentrated, giving compound 667 as an oil. Mass calculated for the formula C 29 H 3 O Cl 2 N 2 O 3 S 2 588.1, LCMS observed m / z 589.1 (M + H).

Part E: Compound 667 was dissolved in 0.5 ml of ITFA / H20 (80:20) and stirred at room temperature for 2 h. The reaction mixture was quenched with ACN / H20 (50:50) and concentrated in vacuo. Purification by reverse phase preparatory LC gave compound 668 as a white solid.

HPLC-MS t R = 6.97 min (UV254 nm, 10 min), Calculated mass for the formula C 26 H 26 Cl 2 N 2 O 3 S 2 548.1, LCMS observed m / z 549.1 (M + H).

EXAMPLE 16B Part A: i A 1 (204 mg, i mmol) in DMF (2 ml) was opened 229 (320 mmol, 1.2 mmol) and HATU (570 mg, 1.5 mmol). The mixture | reaction was stirred overnight at room temperature, and diluted with ethyl acetate and Water. The organic layer was washed with 1 N HCl, saturated NaHC03j, and brine.

It was dried over Na 2 SO 4, and concentrated, giving 669 as an oil slightly yellow (280 mg, 66%).

Part B: To a solution of 669 (280 mg, 0.54 mmol) in THF (5 ml) was added Lawesson's reagent (202 mg, 0.5 mmol) in portions. The mixture of The reaction was stirred overnight under argon at room temperature, and I diluted with EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4, and concentrated. Column chromatography on silica gel (EtOAc / hexane, 20:80) gave compound 670. Calculated mass for the formula C2oH22CINO4S 439.1, LCMS observed m / z 440.1 (M + H).

Part C: To 670 in MeOH (5 mL) was added K2C03 Jen powder (50 mg). The The mixture was stirred at room temperature for 1 h and the solvent was removed at room temperature. empty. The residue was dissolved in water and acidified with H 1N. It was extracted with EtOAc. The combined organic layers were washed with HCl 1, brine, dried over Na2SO4, and concentrated to give compound 671 as an oil (80 mg). Mass calculated for the formula d7H2oCINO4S 425.1, LCMS | observed m / z 426.1 (M + H). iit I Part D: j To compound 671 (10 mg, 0.027 mmol) j in DMF (0.5 ml) was added racemic 2- (3-chlorophenyl) pyrrolidine (6.5 mg, 0.035 mmol) and HATU (17.5 mg, 0.046) mmol). The reaction mixture was stirred at room temperature for 4 h, and diluted with ethyl acetate and water. The organic layer was washed with 1 N HCl, saturated NaHCO 3, and brine. It was dried over Na 2 SO 4, and concentrated, giving compound 672 as an oil. Mass calculated for the formula C29H3oCl2N203S2 588.1, LCMS observed m / z 589.1 (M + H).

Part E:! I i i Compound 672 was dissolved in 0.5 ml of TFA / H2O (80:20) and stirred at room temperature for 2 h. The reaction mixture was deactivated with ACN / H20 (50:50) and concentrated in vacuo. The purification by LC Reverse phase preparative gave compound 673 as a white solid.

HPLC-MS t R = 7.04 min (?? 25 nm, 10 min), Mass calculated for the formula C 26 H 26 Cl 2 N 2 O 3 S 2 548.1, LCMS observed m / z 549.1 (M-I H).

The following compounds were prepared by the methods I described above. The Lav sson reagent was replaced by the reagent of Belleau.

Compound 675 was prepared as described in Example 4A Part C. j I I I I Part A: To 675 (1.34 g, 3.38 mmol) in DMF (0 mL) was added 4-hydroxybenzylamine (0.5 g, 4.06 mmol), DIEA (0.71 mL, '4.06 mmol) and HATU (1.54 g, 4.06 mmol). The reaction mixture was stirred overnight room temperature. The reaction mixture was diluted with water and the layer aqueous was extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated. The purification by column chromatography (SiO2, 80% EtOAc / hexane) gave 676 (1.41 g, 83%).

HPLC-MS t R = 1.56 min (?? 25 nm); Mass calculated for the formula C25H28FN3O7 501.2, LCMS observed m / z 502.1 (M + H).

Part B: To a mixture of 676 (50 mg, 0.1 mmol), triphenylphosphine (79 mg, 0. 3 mmol), 3-hexin-1-ol (33 μl, 0.3 mmol) in THF (0.5 ml) at 0 ° C was added DEAD (47 μ ?, 0.3 mmol). The reaction mixture was heated to room temperature environment and stirred for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated. The purification by column chromatography (SiO2, 20% EtOAc / hexane at 100% EtOAc) gave 677 (9 mg, 15%). HPLC-MS tR = 2.09 min (UV254 nm) j Mass calculated for the formula C3iH36FN3O7 581.3, LCMS observed m / z 582.2 (M + H).

Part C: To 677 (9 mg, 0.02 mmol) in methanol (0.5 ml) was added hydrazine anhydrous (2 μ ?, 0.04 mmol). The reaction mixture was stirred overnight room temperature. The solvents were removed in vacuo and the material was dried frozen to give 678 as a white powder (mg). HPLC-MS tR = 1.89 min (UV254 nm); Mass calculated for the formula C27H32FN3O5 497.2, LCMS observed m / z 498.2 (M + H). ! Part C:: To compound 682 (33 mg, 0.06 mmol) in methanol (2 mL) was added 7.0 M ammonia in methanol (2 mL). Mix! reaction was stirred for 1 hour and concentrated. Purification by HPLC preparatory Reverse phase gave 683 (8 mg). HPLC-MS t R = 4.28 min (UV254 m, 10 min); Mass i calculated for the formula C ^ H ^ s ^ Os 424.2, LCMS observed m / z 425.2 i (M + H). | The following compounds were prepared using the procedures described in Examples 17A and 17B.

I I and the mixture was stirred overnight before draining the solution and the resin I was washed with 5 cycles of MeOH, DCM and THF to give the resin 692 after vacuum drying overnight.

Step A2: To a pre-swollen 692 resin (150 mgj, 1 mmol / g) in anhydrous THF was added benzylalcohol (5 eq) and PPh3 (7 eq) in 1.5 ml of THF and ADDP (5 eq) in 0.5 ml of DCM. The reaction was stirred at room temperature over the weekend. The reaction solution was drained and the resin was washed with 5 cycles of MeOH, DCM and THF and dried under vacuum before being embedded in NMP followed by the addition of 1.5 ml of | 1 M NMP solution of compound 48. The reaction mixture was stirred overnight before draining the solution and the resin was washed with 5 cycles of MeOH, DCM and THF and dried in vacuo to give resin 694.

Step B: Resin 694 was previously inflated in DCM, before adding 1-Phenylpiperazine hydrochloric salt (695) (6 eq) followed by the addition of PyBrop (3 eq) and DIEA (9 eq) in 3 ml of DCM. The solution of the reaction is it stirred overnight before it was drained and the resin was washed with 5 cycles of MeOH, DCM and THF before being treated with 10% hydrazine in methanol for 2h. Then, the resin was further washed with 5 cycles of MeOH, DCM and THF followed by cleavage using 50 of TFA in DCM. The splitting solution was evaporated and the residue was parked with a t system EXAMPLE 17D s s empty. Then, the resin was imbibed in anhydrous DCM (25 ml) before adding 769 (6 eq, salt HCI) and DIEA (9 eq) followed by the addition of PyBrop. The reaction was stirred at t.a. during the night before draining the solution and the resin it was washed with 5 cycles of MeOH, DCM and THF and dried under vacuum to give resin 770 (0.9 mmol / g charge).

Step B:! I I To a previously swollen resin 770 (0 0 095 g, 0.9 mmol / g) in I Anhydrous DCM was added anhydrous Cu (OAc) 2 (3 eq), 771 (5 eq), sieves Molecular 4 A (particle size 5 microns, 1?!? mg) and DIEA (7eq) in 2 ml of anhydrous DCM. The reaction was stirred for 48 h before draining the mixture and the resin was washed with 5 cycles of H2O, MeOH, DCM and THF before being treated with 10% hydrazine in methanol for 2 h. The resin was washed then I EXAMPLE I Part A: Following the procedure described in Example 1 Part A, 1 (163 mg, 0.8 mmol), 2S-phenyl-pyrrolidine (798) (Burgess, L.E., Meyers, A.I., J.

Org. Chem. 1991, 56, 2294) (147 mg, 0.8 mmol), DIEA (560 μ ?, 3.2 mmol) and HATU (304 mg, 0.8 mmol) was mixed together in DMF (2 mL). The purification by column chromatography (SiO2, 5% -20% EtOAc / DCM) gave 799 as an oil (15 mg, 43%). HPLC-MS t R = 1.82 min (UV254 nm); dough calculated for the formula C18H23NO5 333.2, LCMS observed m / z 334.1 (M + H).

Part B: Following the procedure in Example 1, Part B was saponified the material from Part A. 800: HPLC-MS tR = 1.54 rjiin (UV nm); dough calculated for the formula C17H21 NO5 319.1, LCMS Observed m / z 320.2 (M + H).

Part C: Compound 800, 2-phenoethylamine (6 μ? 0. 05 mmol), DIEA (18 μ ?, 0.103 mmol) and HATU (19 mg, 0.05 mmol) following the procedure described in Example 1 Part A. 801 !: HPLC-MS tR = 2.01 min (UV254 nm); mass calculated for the formula C23H2 ^ N204S 428.2, LCMS i observed m / z 429.2 (M + H). j Part D: Compound 801 was dissolved in 90: 10 FA: water (2 ml) and stirred for 4 hours. The reaction mixture is! deactivated with 1: 1 Acetonitrile: water (4 mL) and concentrated. The purification by LC preparatory phase reversed gave 802 as a bjanco powder (9 mg, 50%, 2 i steps). HPLC-MS t R = 1.54 min (UV254 nm); mass calculated for the formula C2oH24N2O4S 388.2, LCMS observed m / z 389.2 (M + H).

Compound 2 (42 mg, 0.14 mmol), 2-phenypyrrolidine (22 mg, 0.15 mmol), DIEA (63 μ ?, 0.36 mmol) and HATU (61 mg, I 0.16 mmol) were mixed together following the procedure described in Example 1 Part A. The The desired isomer was separated by reverse phase preparatory LC to give 803 as a white solid. HPLC-MS tR = 1.96 imin (UV254 nm); mass i calculated for the formula C23H28N2O4S 428.2, LCMS observed m / z 429.1 (M + H). | Part ?: Compound 803 was deprotected using the procedure described in Example 1 Part D to give 804 as a white powder (5 mg, 19% 2 steps). HPLC-MS t R = 1.50 min (?? 254 nm); mass calculated for the formula C20H24N2O4S 388.2, LCMS observed m / z 389.2 (M + H). reaction methanol (50 ml) was added. Sodium borohydride (1.04 g, i 27.5 mmol) was added in portions. Once the bubbling was stopped, the mixture of The reaction was stirred for 1 hour at room temperature. Added one 50% solution of sodium hydroxide (5 ml) to the mixed and stirred during the night. The reaction mixture was filtered to remove the precipitate and solids they were washed with ethyl acetate. The filtrate was concentrated in vacuo. The mixture of The crude reaction was dissolved in ethyl acetate and water. The watery layer possessed a pH of 9. The layers were separated and the organic layer1 was washed with solution of brine, dried over sodium sulfate and concentrated in vacuo to give an orange oil The product was purified by column chromatography (Si02, 20% ethyl acetate / hexane to 20% ethyl acetate hexane + 2% triethylamine) to give 811 as a polar yellow oil (927 mg, 52%). 1 H i NMR (400 MHz, CDCl 3) d 7.4 - 7.3 (m, 4 H), 7.24 (m, 1 H), 3.60 (d, 1 H, J = i 2.4, 10.4 Hz), 3.21 (m, 1 H ), 2.81 (dt, 1 H, J = 3.2, 10.8 Hz), 1.90 (m, 1 H), 1.81 (m, 1 H), 1.68 (m, 1 H), 1.56 (m, 3H); HPLC-MS t R = p.73 min (MS); dough calculated for the formula CnH 5N 161 .1, LCMS observed m / z 162.1 (M + H).

Part B: To 48 (108 mg, 0.5 mmol) in DCM (3 ml) sje added 81 1 (80 mg, 0. 5 mmol). The reaction mixture was stirred overnight before pouring it? in HCl 1.0 N and extracted with DCM. The combined organic layers were dried over sodium sulfate, concentrated and lyophilized to give 812. as a white solid (1 19 mg, 63%). Calcium mass for the formula i C19H23N07 377.2, LCMS observed m / z 378.1 (M + H). mg, 78%). 2-chloro-benzyl ester of 1- (2-chloro-benzyl) -1H-pyrazole-5-carboxylic acid (817A): 1 H NMR (400 MHz, CDCl 3) d 7.61 (d, 1 H, J = 2.0 Hz) , 7.37 (m, 3H), 7.31 - 7.1 1 (m, 4H), 7.02 (d, 1 H, J = 2.0 Hz), 6.53 (dd.1 H, J = 2.0, 7.6 Hz), 5.91 (s, 2H), 5.39 (s, 2H). HPLC-MS t R = 2.40 min (UV254 nm); mass calculated for the formula C18H1 CI2N202 360.0, LCMS observed m / z 361 .0 (M + H). 2-chloro-benzyl ester of 1- (2-chloro-benzyl) -1H-pyrazole-3-carboxylic acid (817B): 1 H NMR (400 MHz, CDCl 3) d 7.51 (m, 1 H), 7.44 ( d, 1 H, J = 2.4 Hz), 7.40 (m, 2H), 7.27 (m, 4H), 7.08 (dd, 1 H, J = 1.6, 7.6 Hz), 6.87 (d, 1 H, J = 2.4 Hz), 5.54 (s, 2H), 5.51 (s, 2H); HPLC-MS tR = 2.22 min (UV254 nM); I mass calculated for the formula C18Hi4Cl2N2O2 360.0, IICMS observed m / z i 361 .0 (M + H). ! Part B: To 817B (685 mg, 1.90 mmol) in THF (10 mL) was added 1.0 M LiAIH4 (1.1 mL, 1.14 mmol) with ice cooling. The reaction mixture I was stirred for 1 hour. The reaction was quenched with water (1 ml), 3 M NaOH? (1 mi) and water (3 mi). The organic layer was decanted and the precipitate was washed with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (Si02, 1: 1 DCM: EtOAc) dioi 818 as an I i oil (350 mg, 83%). 1 H NMR (400 MHz, CDCl 3) d 7.42 (d, 1 H, | J = 2.4 Hz), 7.39 (dd, 1 H, J = 2.4, 8.0 Hz), 7.25 (m, 2H), 7.02 (dd, 1 H, J = 1 .6, 7.2 Hz), 6.30 (d, 1 H, J 2. 4 Hz), 5.43 (s, 2H), 4.73 (s, 2H), 2.5 (bs, 1 H, OH); HPLC-MS tR = 1.29 min (UV nm); mass calculated for the formula CnHnplN20 222.1, LCMS observed m / z 223.1 (M + H).

Part C: A 81 8 (350 mg, 1.57 mmol) in toluene (5 ml) was added phosphorus tribromide (163 μ ?, 1.73 mmol). The reaction mixture was heated to reflux in an oil bath previously heated for 5 minutes.

The mixture was cooled, poured on ice and extracted! with EtOAc. The combined organic layer was washed with bicarbonate solution and brine, dried over sodium sulfate and concentrated to give 819 how a white solid (414 mg, 93%). 1 H NMR (400 MHz, CDCl 3) d 7.39 (m, 2 H), 7.25 (m, 2 H), 7.00 (dd, 1 H, J = 2.0, 7.2 Hz), 6.36 (d, 1 H, J = 2.4 Hz), 5.41 (s, 2H), 4.53 (s, 2H); HPLC-MS t R = 1.96 min (UV254 nm); mass calculated for the formula Cn H10BrCIN2 284.0, LCMS observed m / z 285.1 (M + H).! Part D: To 81 9 (412 mg, 1.44 mmol) in DMF (5 rnl) was added phthalimide (255 mg, 1.73 mmol) and cesium carbonate (515 mg, 1.5 mmol). The mixture of ! The reaction was stirred overnight at room temperature. The solids are they were removed by filtration and the filtrate was concentrated. The residue dissolved in EtOAc and water. The layers separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The purification by column chromatography (SiO2, 5% EtOAc / DCM) gave 820 as a solid (418 mg, 82%). HPLC-MS t R = 1.96 min (UV2d4 nm); calculated mass for the formula 351.1, LCMS observed m / z 352.2 (M + H).

Part E: i A To 820 (418 mg, 1.19 mmol) in ethanoi (20 mL) was added hydrazine I monohydrate (231 μ ?, 4.75 mmol) and the reaction was heated to reflux for 3 hours. The mixture was cooled and diluted with 50% EtOAc / hexanes (40 mL). The solids were removed by filtration and washed thoroughly with 50% EtOAc / hexanes (30 ml). The filtrate was concentrated. The residue was dissolved in EtOAc and washed with water and brine, dried over sodium sulfate and concentrated to give 821 as a semi-solid I (205 mg, 78%). 1 H NMR (400 MHz, CDCl 3) d 7.39 (m, 1 H), 7.38 (d, 1 H, J = 2.0 Hz), 7.23 (m, 2H), 6.92 (dd, 1 H, J = 2.0, 7.2 Hz), 6.22 (d | 1 H, J = 2.0 Hz), 5.39 (s, 2H), 3.91 (s, 2H); HPLC-MS t R = 0.91 min (UV254 nm)! mass calculated for the formula CnH 2CIN3 221.07, LCMS observed m / z 222 ^ 1 (M + H).

Part F: i I A 821 (49 mg, 0.22 mmol) in DMF (2 mL) was added 230 (67 mg, 0. 2 mmol), DIEA (77 μ ?, 0.44 mmol) and HATU (84 mg, 0.2 μ mmol). The mixture of reaction was stirred overnight. The DMF was removed under vacuum and the residue was dissolved in EtOAc. The organic layer was washed with bicarbonate solution, HCI 0. 1 N, and brine, dried over sodium sulfate and concentrated. The purification by column chromatography (SiO2, 80% EtOAc / Hex) gave 822 as a solid (70 mg, 65%). HPLC-MS t R = 1.80 min (UV254 nm); mass calculated for the formula C27H27CIN406 538.2 LCMS observed m / z 539. 2 (M + H).

Part G: j A mixture of 822 (70 mg, 0.13 mmol) and sodium carbonate was stirred. potassium (90 mg, 0.65 mmol) in MeOH (2 mL), for 1 hour. The reaction diluted with EtOAc and poured into brine solution. Additional salt t was added and the layers separated. The aqueous layer was extracted! with EtOAc. The layer organic compound was dried over sodium sulfate and concentrated to give 823 as a white solid (45 mg, 76%). 1H NMR (4Ó0 MHz, DMSO-d6) d 8. 05 (t, 1 H, J = 6.0 Hz), 7.70 (d, 1 H, J = 2.0 Hz), 7.46 (de, 1 H, J = 2.0, 8.0 Hz), I 7.36 - 7.27 (m, 6H ), 6.94 (dd, 1 H, J = 2.0, 7.6 Hz), 6.2 ^) (d, 1 H, J = 2.0 Hz), I 5.68 (d, 1 H, J = 6.8 Hz), 5.35 (s, 2H), 5.06 (d, 1 H, J = 14-4 Hz), 5.03 (d, 1 H, J = 7.6 Hz), 4.91 (d, 1 H, J = 14.4 Hz), 4.76 (d, 1 H, J = 15J6 Hz), 4.62 (dd, 1 H, J = 2.8, 7.6 Hz), 4.61 (d, 1 H, J = 14.8 Hz), 4.26 (m, 3H); BPLC-MS tR = 1.55 min i (UV254 nm); mass calculated for the formula C23H23CIN O4 454.1, LCMS i observed m / z 455.2 (M + H).

Part A: To the amine of Weinreb 824 (prepared using De's method Luca, L; Giacomelli, G .; Taddei, M. J. Org. Chem. 2001, 66, 2534) (200 mg, 0.85 mmol) in THF (15 mL) was added (trimethylsilyl) acetylide lithium (4.3 mL, 2.14 mmol) by dripping at 0 ° C. The reaction mixture was stirred! for 1 hour then i was diluted with EtOAc (50 ml). The mixture was washed with HCl .1 N (50 ml), dried on sodium sulfate and concentrated. Purification by chromatography Column (SiO2, 20% EtOAc / Hex) gave 825 (91 mg, 04%).

Part B: A mixture of 825 (71 mg, 0.33 mmol), di (2-chloro-phenyl) -hydrazine dihydrochloride (89 mg, 0.39 mmol) and potassium carbonate (200 mg) was stirred. mg, 1.64 mmol) in methanol (5 mL) at reflux for 12 hours. The mixture of The reaction was cooled and diluted with EtOAc (50 mL) and water (50 mL). The layer organic was separated, dried over sodium sulfate and concentrated. The purification by column chromatography (SiO2, 20% EtOAc / Hex) gave 826 (50 mg, 15%). HPLC-MS tR = 2.10 min (ELSD); | mass calculated for the formula C17H22CIN3O2 335.1, LCMS observed m / z 336.2 (M + H). i J Part C: i Compound 826 (45 mg, 0.13 mmol) was dissolved in 25% of TFA / DCM (4 mL) and stirred for 30 minutes. The solvents were removed at vacuum and the material was used without further purification. The residue dissolved in DMF (5 ml) and 230 (25 mg, 0.07 mmol), DIEA (300 μl, 1.68 mmol) were added. and HATU (32 mg, 0.09 mmol). The reaction mixture was stirred overnight.

The DMF was removed in vacuo and the residue was dissolved in EtOAc and water. The layer organic was separated and washed with 0.1 N NaOH, 0.1 N HCl and brine, dried on sodium sulfate and concentrated. Compound 827 was used without additional purification. j Part D: j Compound 827 (-25 mg, 0.05 mmol) was dissolved in methanol (5%). mi) and a solution was added over potassium carbonate (50 mg) in water (1 my). The reaction was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate and brine. The organic layer was separated, dried over Sodium sulfate and concentrated. Purification by reverse phase preparative LC gave 828 as a white powder (15 mg, 65%). 1 H NMR (400 MHz, DMSO-de) d 7.81 (d, 1 H, J = 8.0 Hz), 7.70 (d, 1 H, J = 1.6 Hz), 7.47 (dd, 1 H, J = 1 .6, 7.6 Hz), 7.35 - 7.26 (m, 6H), 6.89 (dd, 1 H, J = 1 .6, 7.2 Hz), 6.29 (d, 1 H, J = 2.0 Hz), 5.38 (s, 2H), 5.04 (d, 1 H, J = 15.2 Hz), 4.97 (m I, 2H), 4.90 (d, 1 H, J = 14.0 Hz), 4.76 (d, 1 H, J = 16.4 Hz), 4.61 (m, 2H), 4.27 (d, 1 H, J = 2.4 Hz), 1.39 (d, 3H, J = 6.8 Hz); HPLC-MS t R = 4.25 min (UV254 nm, 10 min); mass calculated for the formula C 24 H 25 CIN 4 O 4 468.2, LCMS observed m / z 469.1 (M + H). i 3H, J = 7.2 Hz). j Part B:; ? A 838 (135 mg, 0.26 mmol), PdCI2 (dppf) | (22 mg, 0.03 mmol), potassium phosphate (1 66 mg, 0.78 mmol) in dioxane (5 ml) under an atmosphere of argon, was benzyl-9 - ?? (0.5 M in THF, 1.3 ml, OJ65 mmol). Mix of reaction was heated to 60 ° C overnight. The reaction mixture it was filtered through a pad of Celite and the bed was rinsed with ethyl acetate. ethyl. The filtrate was concentrated. The crude product was dissolved in methanol (5 ml) and potassium carbonate (4 mg) was added. The reaction mixture was stirred for 1 hour, filtered and concentrated to give 839 as a solid (50 mg, 42%). H NMR (400 MHz, DMSO-d6) d 7.97 (d, 1 H, J = | 7.6 Hz), 7.34 - 7.10 (m, 13H), 5.03 (d, 1 H, J = 14.4 Hz), 4.90 (m, 2H), 4.72 | (d, 1 H, J = 16.8 Hz), 4. 58 (m, 2H), 4.20 (d, 1 H, J = 3.2 Hz), 3.87 (s, 2H), 1.37 (d, 3H, J = 7.2 Hz); HPLC-MS ?: = 1.89 min (UV254nm); mass calculated for the formula C27H28N2O4 t 444.2, LCMS observed m / z 445.1 (M + H). j EXAMPLE 21 B The reaction was stirred at rt for 2.5 h under N2. Boc anhydride (7.45 g, 34.1 mmol) and EtOAc (25 mL) were added and the reaction mixture was stirred at low N 2 J for 1.5 h. The reaction mixture was diluted with EtOAc and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layer combined was washed with citric acid, water, and brine, then dried with MgSO4. The solvents were evaporated and the brutp product was purified by instant sgc using a gradient of 5% -10% EtOAc / hexanes as the mobile phase. White solid 842 (7.95 g) was obtained as product. MS (El) m / z M + Na Obs 324.01.

Part C: Compound 842 (1.1 g, 3.69) and 4-pyridinoboronic acid (0.55 g, 4.48 mmol) in 1-propanol (8 ml) were suspended and stirred for 25 hours. min at 40 ° C. Palladium (II) acetate (55 mg, 0.24 mmol) and water were added (4 mL), followed by sodium carbonate (0.47 g, 4.43 mmol) and triphenylphosphine (197 mg 0.75 mmol). The reaction mixture was stirred under N2 at 80 ° C for 21 h. The reaction mixture was allowed to cool to rt and was diluted with EtOAc and NaHCO3 0.5 M. The layers were separated and the layer to uosa was extracted with EtOAc. The combined organic layer was washed with brine, dried with? MgSO 4, filtered and concentrated to give an orange solid. The product crude was purified by sgc using 30% EtOAc / hexanes, followed by % EtOAc / hexanes with 2% added diisopropylethylamine, followed by 40% EtOAc / hexanes as the mobile phase. The product was obtained solid white 843 (0.71 g). MS (El) m / z M + H Obs 299.10.

Part A: I A 500 ml Schlenck flask equipped with an agitator bar i was dried with flame under N2 flow, covered with a septum, and allowed to cool to rt. A solution of n-butyl lithium in hexanes (55 ml, 2. 5 Molar, 137.4 mmol) by syringe. The flask was cooled in a dry ice / 2-propanol bath. Tetramethylethylene diamine (TMEDA-19.0 g, Personal Chemistry "Companion". The resulting material was filtered through i Celite which was washed with EtOAc. The filtrate was partitioned between EtOAc and water. The organic layer was washed with water and treated with Na2SO4 and activated carbon I Darco. The mixture was filtered and concentrated until dried. The gross product it was purified by sgc using 60:40 hexanes: EtOAe as the mobile phase.

Compound 849 was obtained as a yellow oil (224 mg) which was crystallized at rest, m / z Obs. M + Na 350.93. j i Part C: Compound 849 (224 mg, 0.682 mmol) was dissolved in 2.8 ml of CH2Cl2 and 1.2 ml trifluoroacetic acid. The reaction mixture was stirred at for 2 hours, then concentrated until dried) The crude product was purified by sgc using CH 2 Cl 2: MeOH (NH 3) 9: 1 as the mobile phase for give 1 10 mg of 850 as an oil, m / z Obs. M + H 229.10 Parts D and E: Compounds 851 and 852 were prepared by procedures similar to those described in Example 1, Parts D and E. Data for 851: m / z Obs. M + H 574.05, Data for 852: m / z Obs. M + Na 51 1 .91. i Compound 853 was synthesized using the procedures described in Example 1. í I Part A: j Compound 853 (25 mg, 0.050j mmol) was dissolved in THF (1 ml) and PdP (t-Bu3) 2 (5 mg, 0.0097 mmol) was added under an argon atmosphere. HE added 6-methoxy-2-pyridylzinc bromide (0.5 M in THF, 0.2 ml) and reaction i was stirred at 50 ° C overnight. The reaction mixture was filtered over a Celite bed and then evaporated under reduced pressure. The purification by reverse phase preparatory LC gave a whitish solid 854 (10 mg, i 38%) after lyophilization. HPLC-MS tR = 6.138 qin (UV254 nm, 10 min); i mass calculated for the formula C3iH3 CIN305 563.2, observed licMS m / z 564. 1 (M + H).

Part B: Compound 854 (10 mg, 0.0188 mmol) was dissolved in MeOH i (0.3 mL) and TFA (4 mL) and stirred for 2 hours at room temperature. He solvent was removed to give the crude product 855 (9.36 | mg, 95%). HPLC-MS tR = 5.098 min (UV254 nm, 10 min); calculated mass for the formula C28H30CIN3O5 523.1, LCMS observed m / z 524.1 (M + H).

EXAMPLE 21 E 85ß YES Compound 856 was synthesized using the Suzuki procedures described in Example 12.

Part A: : Compound 856 (160 mg, 0.30 mmol) was dissolved in acetonitrile i (5 mL) and sodium iodide (140 mg, 1.0 mmol) was added followed by trimethylsilylchloride (105 mg, 1.0 mmol). Water (0.1 ml) was added and the reaction mixture was stirred at reflux for 4 hours. The reaction was deactivated with water I I saturated solution of ammonium chloride and warmed to room temperature. The mixture was diluted with ethyl acetate (i p ml) and the layers were they separated. The organic layer was washed with water and brine. It dried on Sodium sulfate and concentrated. Purification by chromatography in column (SiO2, 5% EtOAc / hexane) gave 881 (19 mg, 59%). HPLC-MS tR = | 2.28 min (UV254 nm,); mass calculated for the formula | Ci6H19NO2S2 321 .09, LCMS observed m / z 322.2 (M + H).

Part B: i To 881 (66 mg, 0.2 mmol) was added 4N HCl in dioxane (1 mL). The reaction mixture was stirred for 1 hour. The solvents were removed at vacuum and the crude product was used without further purification. HPLC-MS tR = 1 .12 min (UV nm); mass calculated for the formula C 1 1 H 1 1 NS2 221 .0, LCMS observed m / z 222.1 (M + H). Part C: I A 563 (56 mg, 0.16 mmol) in DMF (2 mL) was added 882 (66 mg, 0. 26 mmol), DIEA (82 μ ?, 0.46 mmol) and HATU (78 mg, 0.24 mmol). Mix of reaction was stirred overnight at room temperature. The mixture of The reaction was diluted with ethyl acetate (20 ml) and water (20 ml). The layers are separated and the aqueous layer was extracted with ethyl acetate. The layers combined organic washes with sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. Compound 883 (43 mg, 48%) was used without further purification. HPLC-MS t R = 2.40 I min (UV nm); mass calculated for the formula C 28 H 29 Cl 2 O 4 S 2 556.1, LCMS i observed m / z 557.0 (M + H).

Part D: Compound 883 (25 mg, 0.04 mmol) was dissolved in TFA: water 80:20 (1 ml) and stirred for 1.5 hours. The reaction was deactivated with 1: 1 of water: acetonitrile (1 ml) and the solvents were removed in vacuo. The purification by reverse phase preparatory LC gave 884 ran a white solid (5 Part A: A mixture of 1,1 '-dibromo-p-xylene (885) (528 mg, 2.0 mmol), phthalimide (294 mg, 2.0 mmol) and cesium carbonate (717 mg, 2.2 mmol) in DMF (5 ml) for 4 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM and washed with 1-bicarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated. Recrystallization from 75% EtOAc / hexanes removed the dialkylated product. The mother liquor was concentrated and the monoalkylated product 886 was isolated by column chromatography (S¡O2, 50% DCM / Hex) as a white solid (10 mg, 16%). 1 H NMR (400 MHz, CDCl 3) d 7.84 (d, 2 H J = 2.4 Hz), 7.72 (d, i 2H, J = 2.4 Hz), 7.41 (d, 2H, J = 7.2 Hz), 7.34 (d, 2H, J = † 7.2 Hz), 4.84 (s, 2H), 4. 46 (s, 2H). ! Part B: A mixture of 886 (10 mg, 0.33 mmol), 2-methylbenzimidazole (44 mg, 0.33 mmol) and cesium carbonate (14 mg, 0.35 g. mmol) in DMF (5 mL) overnight at room temperature. The mixture of reaction was filtered and concentrated. The residue was divided between solution bicarbonate and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated to give 887 as a whitish solid (120 mg, 95%). 1 H NMR (400 MHz, CDCl 3) d 7.82 (m, 2H), 7.70 (m, 2H), 7.37 (d, 2H, J = 8.0 Hz), 7.25 - 7.18 (m, 4H), 7.00 (d, 2H, J = 8.7 Hz), 5.30 (s, 2H), 4.82 (s, 2H), 2.57 (s, 3H). ! Part C: A mixture of 887 (120 mg, 0131 mmol) and hydrate was heated hydrazine (61 μ ?, 1.26 mmol) in ethanol (10 ml) to reflux for 3 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and it was washed with bicarbonate solution. The aqueous layer was extracted with ethyl acetate i. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated to give 888 as a yellow cap (31 mg, 40%). 1 H NMR (400 MHz, CDCl 3) d 7.72 (dd, 1 H, J = | 1.2, 8.4 Hz), 7.51 (dd, i 1 H, J = 3.2, 6.4 Hz), 7.26 - 7.17 (m, 4H), 7.01 (d, 2H, J | = 8 Hz), 5.30 (s, 2H), 3. 85 (s, 2H), 2.60 (s, 2H), 2.57 (s, 3H).

Part D: A mixture of 888 (31 mg, 0.1 2 mmol), 5.4% (40 mg, 0.1 mmol), DIEA (38 μ ?, 0.22 mmol) and HATU (46 mg, 0.1 2 mmol) in DMF (2 mL) was stirred i overnight. The DMF was removed in vacuo. The residue was dissolved in acetate of ethyl, washed with bicarbonate solution and brine,! dried over sulfate Part 0 Part A: ! I IA 193 (200 mg, 0.57 mmol) in DC 1 (5 ml) was added i propargylamine (62 mg, 1.13 mmol), DIEA (396 μl, 1.7 mmol), DMAP (7 mg, 0.06 mmol). ) and EDC (140 mg, 0.74 mmol). The reaction mixture was stirred I I overnight at room temperature. The reaction mixture was diluted formula C2oH23CIN204 390.1, LCMS observed m / z 391.1 (M + H).

Part B: To 892 (20 mg, 0.05 mmol) in DMF (1 mL) was added 4-chloro-iodobenzene (24 mg, 0.10 mmol), copper iodide (1) j (1 mg, 0.005 mmol), and PdCI2 (Ph3P) 2 (1.8 mg, 0.003 mmol) and triethylamine (1 ml). The reaction mixture i was stirred overnight at 50 ° C under a largon atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N HCII, dried over Sodium sulfate and concentrated. The material was used without further purification. I 893: HPLC-MS tR = 2.28 and 2.32 min (UV254 nm); mass calculated for the formula C26H26Cl2N2O4 500.1, LCMS observed m / z 501.1 (M + hl. I i Part C: ¡¡ Compound 893 was dissolved in TFA: water 4: 1 (2 mL) and stirred at room temperature for 1.5 hours. The reaction was deactivated with 1: 1 of water: acetonitrile (2 ml) and concentrated. Purification by reverse phase preparative LC i gave 894 as a solid (2 mg). HPLC-MS t R = i 5.02 min (UV254 nm 10 min); mass calculated for the formula C23H22CI2N204 reaction was heated in a sealed tube under N2 at 80 ° C for 2 h. Mix of reaction was allowed to cool to rt. EOAc and regulator were added 0.1 M sodium phosphate pH 7.0. The layers separated. The organic layer it was washed with water and dried with MgSO 4, the solvent was evaporated and the crude product was purified by sgc using 3: 1 EtOAc: hexes as the mobile phase to give 20 mg of compound 896. MS (El) m / z Obs MÍH 467.19.

L- 0 ambient. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed on 0.1 N NaOH and brine, dried over sodium sulfate and concentrated. The material mmol), HOBt (1.82 g, 13.5 mmol) and triethylamine (3.8 mL, 27.0 mmol) in DCM (50 ml) overnight. The reaction mixture was diluted with DCM and washed with 1 H HCl, water, bicarbonate solution and brine, dried over Sodium sulfate and concentrated. The recrystallization of the acetate mixture ethyl gave 906 as a solid (1.72 g, 61%). 1 H NMR (400 MHz, CDCl 3) d 7.83 (m, 2H), 7.70 (m, 2H), 7.42 (d, 2H, J = 8.2 Hz), 7.29 (d, 2H, J = 8.2 Hz), 4.79 (s, 2H). HPLC-MS t R = 2.05 min (UV254 nm); mass calculated for formula j C15H10BrNO2 315.0, LCMS observed m / z 316.0 (M + H).

Part B: A mixture of 906 (100 mg, 0.32 mmol), pyrrolidine was stirred. (34 mg, 0.48 mmol), potassium phosphate (171 mg, 0.80 mmol), Pd2 (dba) 3 (8 mg, 0. 008 mmol) and 2- (dicyclohexylphosphino) biphenyl (1 1 mg, 0.032 mmol) in dioxane (3 ml) under an argon atmosphere at 90 ° C overnight. The mixture of reaction was filtered through Celite and concentrated, The yellow residue was | purified by column chromatography (SiO2, 5% EtOAc / DCM) to yield 907 (82 mg, 84%). HPLC-MS tR = 2.13 min (UV254nmj; mass calculated for I the formula C19H18N2O2 306.1, LCMS observed m / z 307.2 (M + H).

Part C: To 907 (82 mg, 0.268 mmol) in ethanol: DCM 1: 1 (4 mL) was added hydrazine monohydrate (52 μ ?, 1.07 mmol). The reaction mixture was heated to reflux overnight. The precipitate was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated to give 908 as a white solid (23 mg, 49%). HPL.C-MS tR = 0.86 min (UV254nm); mass calculated for formula C H16N2 176.1, LCMS observed m / z 177.1 (M + H).

Part D: A mixture of 554 (30 mg, 0.076 ^ mmol), 908 (17.3 mg, 0. 098 mmol), DIEA (40 μ ?, 0.226 mmol), DMAP (1 mg) and HATU (37 mg, 0.098 mmol) in DMF (1 mL) overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers are washed with 0.1 N NaOH, water and brine, dried over sodium sulfate and they concentrated. Compound 909 was used without further purification Part E: To 909 in methanol: water 3: 1 (2 mL) was added carbonate of potassium (20 mg). The reaction mixture was stirred for 30 minutes. The The reaction mixture was partitioned between ethyl acetate and water. The organic layer I was separated, washed with brine, dried over sodium sulfate and concentrated. Purification by reverse phase preparatory LC gave 910 i i as a solid (2 mg). HPLC-MS t R = 3.57 min (U 254 nm 10 min); mass i I calculated for the formula C25H30CIN3O4 471.2, LCMSl observed m / z 472.2 (M + H). | column chromatography (SiO2, 30% ethyl acetate / hexanes at 50% ethyl acetate / hexane) gave the product as an impure white solid (450 mg). Further purification by column chromatography (SiO2, i dichloromethane at 5% ethyl acetate / dichloromethane) (J. 911 as a solid (295 mg, 70% purity). 1 H NMR (400 MHz, acetone-d 6) d 8.97 (bs, 1 H, NH), 8. 16 (d, 1 H, J = 2.4 Hz), 7.76 (d, 2H, J = 8.4 Hz), 7.42 (?, 2H, J = 8.8 Hz), 6.27 (d, 1 H, J = 2.4 Hz), 4.55 (d, 2H, J = 5.6 Hz), 2.28 (s, 3H; HPLC-MS tR = 1 .62 min (UV254 nm); mass calculated for the formula C13H-12F3N3O 283.1, LCMS observed m / z 284.2 (M + H).

Part B: A 911 (1 65 mg, 0.43 mmol) in methanol 1: 1 (2 ml) was added 1 0% potassium carbonate in methanol: water 2: 1 (7 ml). The mixture | of reaction was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over sodium sulfate and concentrated to give 912 as a white solid (69 μg, 86%). HPLC-MS t R i i = 0.75 min (UV254 nm); mass calculated for formula C H13N3 1 87.1, LCMS observed m / z 1 88.1 (M + H).

Part C:! i A 193 (65 mg, 0.18 mmol) in DMF (2 ml) s, and added 912 (38 mg, 0.2 mmol), DIEA (70 μl, 0.4 mmol) and HATU (76 mg, 0.2 μl mmol) . The reaction mixture was stirred overnight at room temperature. The mixture of The reaction was poured into water and extracted with ethyl acetate. Organic and combined layers were washed with 0.1 N NaOH and brine, dried over sulfate! of sodium and concentrated. Compound j 913 was used without further purification. HPLC-MS tR = 2.05 and 2.09 min (UV254 nm); mass calculated for formula C28H3iCIN4O4 522.2, LCMS observed m / z 523.2 (M + H).

Parts C v D: Compounds 917 and 918 were prepared by methods similar to those described in Example 14 - Parts D and?. Data for 917:? ? NMR (400 MHz, CDCl 3) d 7.98-7.62 (m, 4H), 7.46-7.13 (m, 8H), 6.68-6.47 (m, I 2H), 5.86-5.41 (m, 2H), 5.24-5.10 (m , 2H), 4.05-3.48 (jn, 2H), 2.22-1.79 (m, 10H), 1.58-1.55 (m, 2H). Data for 918: 1H NMR (400 MHz, CDCI3) d 7.96 (s, 1H), 7.80 (s, 1H), 7.75-7.59 (m, 2H), 7.48-6.95 (m, 8H), 6.52 (s, 1H), 5.32-5.13 (m, 2H), 4.97-4.05 (m, 2H), 3.99-3.68 (m, 3H), 2.46-1.80 (m, 4H), 1.62-1.51 (m, 3H); MS (El) m / z Obs. M + H 449.1.

I I HATU (50 mg, 0.13 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured! in water and extracted with ethyl acetate. The combined organic layers were washed with NaOH 0. 1 N and brine, dried over sodium sulfate and concentrated. He Raw material was used without further purification. 953: mass calculated for the formula C26H27CIN404S 526.1, LCMS observed m / z 527 1 (M + H).

Part B: Compound 953 was dissolved in TFA: water 4: 1 (2 mL) and stirred at room temperature for 2 hours. The reaction was deactivated by the Added acetonitrile: water 1: 1 (4 mL) and the solvents were removed in vacuo.

Purification by preparatory LC of revelation phase gave 954 as a white solid (21 mg). HPLC-MS t R = 4.21 min (UV2k4 nm, 10 min); dough calculated for the formula C23H23CIN4O4S 486.1, LCMS observed m / z 487.1 (M + H).

EXAMPLE 26B Biaryl bond of C-C Part A: To the 4-aminomethyl-benzoic acid methyl ester (955) (2 g, 9.92 t mmol) in dichloromethane (25 ml) was added Bob anhydride (2.27 g, 10.4 mmol) and triethylamine (2.76 ml, 19.84 mmol). The reaction mixture was stirred during night. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulfate and concentrated to give 956 as a white solid (2.40 g, 91%). HPLC-MS tR = 1.76 min (UV254nm); dough calculated for the formula Ci4H 9NO4 265.1, LCMS observed m / z 288.2 (M + Na).

Part B:! j Compound 957 (257 mg, 80%) was synthesized following the procedure described in Example 10B Part A. HPLC-MS tR = 1.77 min (UV254nm); mass calculated for the formula Ci Hi8CINO3 283.1, LCMS observed m / z 306.1 (M + Na). ! Part C: j To 957 (49 mg, 0.17 mmol) in DMF (2 mL) was added thioformamide (21 mg, 0.35 mmol) and pyridine (50 μ?). The reaction mixture was stirred for 72 hours The mixture was diluted with ethyl acetate, washed with hydroxide sodium 0.1 N, water and brine, dried over sodium sulfate and concentrated. i Purification by column chromatography (S02, 25% ethyl acetate / hexanes) gave 958 (25 mg, 50%). HPLC-MS tR = 1.80 min (UV254nm); dough m / z 291 .1 Compound 958 (25 mg, 0.084 mmol) was stirred in dichloromethane (2 ml) and TFA (1 ml) at room temperature for 1 hour. The Solvents were removed under vacuum to give 959 as an oil (26 mg). 1 HOUR NMR (400 MHz, CD3OD) d 9.07 (d, 1 H, J = 2.0 Hz), 8. ?|3 (d, 2H, J = 8.4 Hz), 7. 96 (d, 1 H, J = 1 .6 Hz), 7.52 (d, 2H, J = 8.0 Hz), 4.16 (s, | 2H). i or I Part E: i | To 193 (23 mg, 0.065 mmol) in DMF (2 mL) was added 959 (26 mg, 0.084 mmol), DIEA (34 μ, 0.20 mmol) and HATU (32 μg, 0.084 mmol). The The reaction mixture was stirred overnight at room temperature. The The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with 0.1 N NaOH and brine, dried over sodium sulfate and concentrated. The raw material was used without additional purification. 960: HPLC-MS tR = 2.00 and 2.05 min (UV254 nm); dough calculated for the formula C27H28CIN3O4S 525.2, LCMS observed m / z 526.1 (M + H).

Part F: Compound 960 was dissolved in TFA: water 4: 1 (2 ml) and stirred at room temperature for 2 hours. The reaction was deactivated by the Added acetonitrile: water 1: 1 (4 ml) and the solvents were removed in vacuo. i Purification by reverse phase preparatory LC gave 961 as a white solid (14 mg). HPLC-MS t R = 4.17 min (UV254 nm, 10 min); dough calculated for the formula C24H2.4CIN3O4S 485.1, LCMS j observed m / z 486.1 i (M + H). ! Part A: To 4- (tert-butoxycarbonylamino-methyl) -benzoic acid (962) (500 mg, 1.99 mmol) in tetrahydrofuran (5 ml) in a bath of; ice was added DIEA (347 μ ?, 1.99 mmol). The reaction mixture was stirred for 15 minutes and added ethyl chloroformate (190 μ ?, 1.99 mmol). The reaction mixture was stirred for an additional 15 minutes and amoriiac in dioxane (0.5 i i M, 4.18 ml, 2.09 mmol) was added. The reaction mixture was heated to room temperature environment and stirred for 2 hours. The solvent was removed under vacuum and the The residue was partitioned between ethyl acetate and water. The layers separated and the The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. i The combined organic layers were washed with salmira, dried over sodium sulfate and concentrated to give 963 as a white solid (540 mg), which contained some anhydride mixed as an impurity. H i NMR (400 MHz, CD3OD) d 7.81 (d, 2 H, J = 8.0 Hz), 7.35 (d, 2 H, J = 8.4 Hz), i 7.21 (bs, 1 H, NH), 4.28 (s, 2 H) ), 1 .47 (s, 9H).

Part B: A 963 (500 mg, 2.0 mmol) in tetrahydrofuran (20 mL) was added Lawesson's reagent (485 mg, 1.2 mmol). The reaction mixture was stirred overnight at room temperature. The solvent is removed under vacuum and the The residue was dissolved in ethyl acetate. The mixture was washed with 0.1N sodium hydroxide, water and brine, dried over sodium sulfate. sodium and concentrated until a yellow residue. Purification by column chromatography (SiO2, 40% ethyl acetate / hexanes) gave 964 a pale yellow I solid (432 mg, 81%). 1 H NMR (400 MHz, CDCl 3) d 7.8,4 (d, 2 H, J = 8.4 Hz), i 7.32 (d, 2 H, J = 8.4 Hz), 4.36 (d, 2 H, J = 5.6 Hz), 1 .48 (s, 9H).

Part C: I A 964 (70 mg, 0.263 mmol) in DMF; (2 ml) was added chloroacetaldehyde (50% in water, 41 mg, 0.526 mmol). The reaction was shaken overnight at room temperature. An additional 2 j equivalents of chloroacetaldehyde was added and the reaction was stirred for 24 hours. The reaction was not yet complete, so the mixture heated up up to 50 ° C for 2 days. The mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide, water and brine, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, % ethyl acetate / hexanes) gave 965 (31 mg). HPLC-MS tR = 1.84 min (UV254 nm); mass calculated for the formula Ci5H18 202S 290.1, LCMS observed m / z 291 .1 (M + H).

I Part D: Compound 965 (31 mg, 0.106 mmol) was stirred in dichloromethane (2 ml) and TFA (1 ml) at room temperature for 1 hour. The Solvents were removed under vacuum to give 966 as an oil (60 mg). 1 HOUR NMR (400 MHz, CD3OD) d 8.03 (d, 2H, J = 8.8 Hz), 7.9 | 0 (d, 1 H, J = 3.2 Hz), 7. 65 (d, 1 H, J = 3.6 Hz), 7.56 (d, 2H, J = 8.8 Hz), 4.18 (s, 2H).

! Part E: i To 193 (29 mg, 0.082 mmol) in DMF (2 ml) was added 966 (32 mg, 0.106 mmol), DIEA (43 μ ?, 0.25 mmol) and HATU (40 mg, 0.106 mmol). The The reaction mixture was stirred overnight at room temperature. The The reaction mixture was poured into water and extracted with ethyl acetate. The Combined organic layers were washed with NaOH cj.1 N and brine, dried over sodium sulfate and concentrated. The raw material was used without additional purification. 967: HPLC-MS tR = 2.03 and 2.08 min (UV254 nm); dough calculated for the formula C27H28CIN3O4S 525.2, LCMS j observed m / z 526.1 (M + H).

Part F: Compound 967 was dissolved in TFA: water | 4: 1 (2 ml) and stirred room temperature for 2 hours. The reaction was deactivated by the Added acetonitrile: water 1: 1 (4 mL) and the solvents were removed in vacuo. i Purification by reverse phase preparatory LC gave 968 as a white solid (15 mg). HPLC-MS t R = 4.21 min (UV54nj 10 min); dough calculated for the formula C24H24CIN3O4S 485.1, LCMs j observed m / z 486.1 (M + H).

Piperidine-aryl compounds EXAMPLE 27 A Step 1 . A mixture of tert-butylester of piperidin-methylmethylcarbamic acid (977) (2.5 g, 1.66 mmol), 2-fluoro-3-cyanobenzene (1.55, 12.8 mmol) and DIEA (3 ml, 17.5 g. mmol) in NMP (5 njil) under an atmosphere of Argon, overnight, at 120 ° C. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and He concentrated. Purification by column chromatography (Si02, 25% ethyl acetate / hexanes) gave a white solid (3.1 g). j Step 2: To the material from Step 1 (2 g) in dichloromethane (5 ml) to 0 ° C TFA (5 ml) was added. The mixture was stirred at room temperature during 1 hour. The mixture was deactivated with acetonitrile and corjicentro. The residue is dissolved in ethyl acetate, washed with sodium carbonate solution and brine, dried over sodium sulfate and concentrated to give 978 as an oil that solidified to a waxy solid (920 mg). HPLC-MS tR = 0. 63 min (UV254 nm); mass calculated for the formula Ci3H17N3 215.1, LCMS observed m / z 216.2 (M + H). j Part B: To 978 (120 mg, 0.55 mmol) in DMF (2 mL) was added 230 (167 mg, 0.5 mmol), DIEA (0.21 mL, 1.2 mmol) and HATU (21 mg, 0.55 mmol). The mixture was stirred for 3 hours at room temperature. The mixture of The reaction was diluted with ethyl acetate, washed with saturated sodium bicarbonate I and brine, dried over sodium sulfate and concentrated. The I material was used without further purification. \ Part C: j A 979 in methanol (4 ml) was added 7.0 N ammonia in methanol (2 mi) The mixture was stirred for 2 hours at room temperature and concentrated. The purification by preparatory LC of | Reverse phase gave 980 as a white powder (80 mg) in lyophilization. HPLC-MS tR = 4.03 min (UV25 nm); mass calculated for the formula 025? 2? ? 4 448.2, LCMS observed m / z 449.2 (M + H). j Part A: A mixture of 977 (200 mg, 0.93 mmol), 3-iodothiophene i (981) (294 mg, 1.4 mmol), copper iodide (1) (36 mg, 0.19 mmol), proline (43) was stirred. mg, 0.37 mmol) and potassium carbonate (258 mg, 1.87 mmol) in DMSO (1.5. mi) overnight, at 80 ° C, in a jar of 4 ml. The reaction mixture is diluted with ethyl acetate and washed with water (3X) and brine, dried over Sodium sulfate and concentrated. Purification by chromatography in column (SiO2) 25% ethyl acetate / hexanes) gave 982 (94 mg, 34%).

Part B: Compound 982 (42 mg, 0.14 mmol) was dissolved in DCM (2 mL) and TFA (1 ml). The mixture was stirred for 1 hour and concentrated to give 983? in quantitative performance. HPLC-MS t R = 0.35 min (UV254 nm); dough calculated for the formula Ci0H16N2S 196.1, LCMS stored m / z 197.2 (M + H).

Part C: Compound 984 was prepared according to the procedure described in Example 27A Part B. HPLC-MS tR = 1.36 min (UV254nm); mass i calculated for the formula C26H31 N3O6S 513.2, LCMS Observed m / z 514.2 i (M + H).

Part D: j Compound 985 was prepared according to the method described in Example 25 Part E. HPLC-MS tR = 2.85 min (Uy254nm, 10 min); dough calculated for the formula C22H27N304S 429.2, LCMS | observed m / z 430.1 (M + H). followed by DIEA (2.5 ml, 14.4 mmol). The reaction was adjusted to 120 ° C overnight. The cooled reaction mixture was deactivated with water and extracted! with ethyl acetate. The combined organic layers washed with solution of bicarbonate and brine; dried over sodium sulfate and they concentrated. Purification by column chromatography (SiO2, 25% I ethyl acetate / hexanes) gave a white solid 987 (1.5 g, 81%). HPLC-MS Í = 1.95 (UV254nm); mass calculated for the formula Ci5Hje 2O2 258.14, LCMS observed m / z 259.1 (M + H).

Part B: i I Diisopropylamine (0.330 mL, 2.32 mmol) was dissolved in THF (20 mL). mi) and cooled in an ice bath. A solution of n-BüLi (2.5M in hexanes, 1 ml) was added dropwise and stirred for 15 minutes. The mixture of The reaction was then cooled to -78 ° C and a solution of compound 987 (400 mg, 1.6 mmol) in THF (1 ml) was added dropwise. The continued stir at this temperature for 30 minutes before adding drip a solution of iodomethane (450 mg, 3.2 mmol) in THF (10 mL). The reaction it was stirred for 30 minutes at this temperature and then j the hour at temperature ambient. The reaction was quenched with water and extracted with ethyl acetate.

The combined organic layers were washed with bicarbonate solution and brine; were dried over sodium sulfate and concentrated to give the 988 product which was used without further purification. jHPLC-MS tR = 2.10 (UV254nm); mass calculated for the formula C 16 H 20 I 2 O 2 272.15, LCMS I observed m / z 273.2 (M + H).

Part C: Compound 988 was dissolved in THF (20 mL) and lithium borohydride (60 mg, 2.6 mmol) was added. The reaction mixture was refluxed for 5 hours. The cooled reaction mixture was deactivated with water and extracted with ethyl acetate. The combined organic layers were washed with bicarbonate solution and brine; dried over sodium sulfate and they concentrated. Purification by column chromatography (S1O2, 50% ethyl acetate / hexanes) gave a white solid 989 (300 mg). HPLC-MS t R = 1.57 (UV254 nm); mass calculated for the formula C14Hi8N2O 230.1 LCMS observed m / z 231.3 (M + H).

Part D: | Compound 989 (300 mg, 1.3 mmol) was dissolved in toluene (5 mi) and phosphorus tribromide (0.06 ml, 0.52 mmol) was added. The reaction stirred at reflux for 3 hours. The cooled reaction was deactivated with water and it was extracted with ethyl acetate. The organic cdmbinated layers were washed with bicarbonate solution and brine; dried over sodium sulfate and concentrated to give the 990 product that was used without further purification.

Part E: Compound 990 was dissolved in DMF (10 ml) and added cesium carbonate (850 mg, 2.6 mmol) and phthalimide (190 mg, 1.3 mmol) and it stirred during the night. The reaction was deactivated with water and extracted with ethyl acetate. The combined organic layers were washed with a solution of bicarbonate and brine; They were dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, 25% ethyl acetate / hexanes) gave a white solid 991 (90 mg). HPI4C-MS tR = 2.14 min (UV254 nm); mass calculated for formula C22H21 359.1, LCMS observed m / z 360.1.

Part F: Compound 991 (90 mg, 0.25 mmol) was dissolved in ethanol (3 mi) and hydrazine hydrate (0.5 ml) was added. The reaction was stirred for 3 hours and the solids filtered. The solvent evaporated j to give the product desired 992 which was used without further purification. í Part G:! Compound j 992 was dissolved in DMF (5 ml) and added compound 230 (84 mg, 0.25 mmol) and HATU (14 mg, 0.30 mmol) and stirred overnight. The reaction was quenched with water and extracted with acetate of ethyl. The combined organic layers were washed with a solution of bicarbonate and brine; dried over sodium sulfate and concentrated. i Purification by column chromatography (SiOj, ethyl acetate) gave a white foam 993 (100 mg). HPLC-MS tR = 1.99 | min (UV254 nm); dough calculated for the formula C3oH34N406 546.2, LCMS observed m / z 547.2.

Part H: Compound 993 (100 mg, 0.1 | 82 mmol) was dissolved in methanol (5 ml) and potassium carbonate (100 mg) was added and stirred for 30 minutes. minutes The reaction was quenched with water and extracted with ethyl acetate.

The combined organic layers were washed with bicarbonate solution and brine; They were dried over sodium sulfate and concentrated. The purification by preparatory reverse phase LC gave a white solid 994 (7 mg, 8%) after lyophilization. HPLC-MS R = 4.32 min (UV254 nm, 10 min); dough calculated for the formula C26H3oN404 462.23, LCMS observed m / z 463.1 i (M + H). The following table contains the compounds that were prepared i using the procedures described in Example 27 A-C. Compounds I such as 1002 were prepared from the chloropyridyl precursor using the procedures described in Example 27A Part A. i stirrer, dried with flame under N2 flow, covered; with a septum, and it was allowed to cool to ta. Compound 1042 (0.50 g, 2.02) was added mmol) and the flask was coated. Anhydrous THF (8.5 ml) was added via syringe and the flask was cooled in a dry ice / 2-propanol bath. Added sec butyl lithium (1.6 m, 2.34 mmol) by syringe. The reaction mixture is left under stirring at -78 ° C for 30 m. Iodoethane (180 μ ?, 2.25 was added mmol) and the reaction mixture was stirred for 2 hrs. Iodoethane was added Additional (80 μl, 1.0 mmol) and the reaction mixture was stirred for 45 minutes. The reaction mixture was deactivated with 1.0 M sodium phosphate buffer pH 7.0 and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and brine, then dried with MgSO 4 and concentrated to an oil Clear. The crude product was purified by column chromatography (SiO2) 0% -20% EtOAc / hexanes) to give 0.12 g of compuekto 1043. MS (El) m / z M + Na Obs 298.15. ! Part C: Compound 1043 (0.12 g, 0.43 mmol) was dissolved in 10 ml of 4 M HCl in dioxane. The reaction mixture was stirred at rt for 2.25 h. The Reaction mixture was concentrated until dried white solid 1044 (12 mg). MS (El) m / z Obs M + H 176.12. ! Part D: Compound 1044 (104 mg, 0.49 mmol) and 1 (0.120) were dissolved g, 0.588 mmol) in CH2Cl2 (2 mL). Diisopropylethylamine (200 μ ?, 1.12) was added mmol), followed by PyBrop (249 mg, 0.78 mmol). The reaction mixture is left in agitation overnight at ta low N2. The reaction mixture is diluted with CH2Cl2 then washed with phosphate buffer! Sodium 1.0 M pH 7. 0, NaHCO3 aq, and brine. The organic layer was dried with MgSO4 and concentrated for a clear oil. The purified crude product was purified by column chromatography (SiO2, 0% -40% EtOAc / hexanes) to give 0.16 g of compound 1045. MS (El) m / z Obs M + H 362.08. i I Part E: I i I Compound 1045 (0.15 g, 0.42 mmol) was dissolved in dioxane (1.6 mi) and water (0.4 mi). Lithium hydroxide (19 mg, 0.45 mmol) was added. The reaction mixture was stirred at rt for 2 h 15 m. The solution was concentrated j to give 1046 as a clear oil. MS (El) m / z Obs. M + H 348.09.

Part F: i I Compound 1046 (69 mg, 0.19 mmol) and 845 (51 mg, 0.22 mmol) in DMF (1 mL) and diisopropylamine (1?!? μ ?, 0.58 mmol). HE added PyBrop (108 mg, 0.338 mmol) and the reaction was stirred overnight to ta. The reaction mixture was diluted with EtOAc and washed with 1.0 M sodium phosphate buffer pH 8.0 and brine. The organic layer was dried with i I I I MgSO and concentrated to a yellow oil. The crude product was purified by TLC prep. on silica plates using CH2C 2: MeOH 95: 5 as the mobile phase. Compound 1047 was obtained as a clear acetone (74 mg). MS (El) m / z Obs M + H 528.20.

Part G: Compound 1047 (74 mg, 0.j14 mmol) was dissolved in 5 ml of Trifluoroacetic acid solution: water 9: 1. The reaction mixture was stirred at for 3 h 10 m, then concentrated until dry. The crude product was purified by column chromatography (S¡02, 0% -7% MeOH / CH 2 Cl 2) to give 26 mg of compound 863. MS (El) m / z Obs M + H 488.1.

Compound 1048A, B was prepared from Boc-proline OMe using the above alkylation procedures and the thiazole ring is constructed as described in Example 10A.

(S02) 10% ethyl acetate / dichloromethane) gave the product as a solid orange (27 mg). HPLC-MS t R = 1.78 min (UV254 nm); mass calculated for the formula C20H20N2O5S2 432.1, LCMS observed m / z 433.0 (M + H).

Part C:! I i Compound 1052 was prepared following the procedure described in Example 2 Part B. HPLC-MS tR = 1.39 imin (UV254 nm); mass I calculated for the formula Ci6H 6N2O3S2 348.1, LCMS observed m / z 349.0 (M + H).

Part A: Sodium hydride (95%, 1 15 mg, 4.55 mmol) in DME (10 ml) under argon, triethylphosphonacetate was added dropwise. In a few minutes the reaction mixture cleared. After 1 hour, the aldehyde 1055 i (400 ul, 4.55 mmol) was added. After 15 minutes water and diethyl ether were added to the reaction mixture. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated to give 1056 as an oil. orange (666 mg, 80%). 1 H NMR (400 MHz, CDCl 3) j 5 7.92 (d, 1 H, J = 3.2 Hz), 7.79 (d, 1 H, J = 16.0 Hz), 7.43 (d, 1 H, J = 3.2 Hz), 6.71 (d, 1 H, J = 16.0 Hz), 4.29 (q, 2H, J = 7.5 Hz), 1 .36 (t, 3H, J = 7.5 Hz). | Part B: To ester 1056 (84 mg, 0.46 mmol) in THF (2 mL) was added 1 .0 M lithium hydroxide solution (0.5 ml, 0.5 mmol). The reaction mixture It stirred during the night. The reaction mixture was acidified with I solution HCl 1.0 N and extracted with ethyl acetate. During the extractions, added sodium chloride to the aqueous layer. The combined organic layer dried over sodium sulfate and concentrated to give 1057 as a film (65 mg, 92%). 1 H NMR (400 Hz, CDCl 3) d 7.97 (d, 1 H J = 3.0 Hz), 7.89 (d, 1 H, J = 15.7 Hz), 7.49 (d, 1 H, J = 3.0 Hz), 6.75 (d, 1 H, J = 15.7 Hz).

Part C: Compound 1058 was prepared from compound 1057 (32 mg, 0.21 mmol) using the standard HATU coupling strategy described in Example 2 Part A. Purification by column chromatography (Si02, 50% ethyl acetate / hexane) gave the product as a film (35 mg, 63%). HPLC-MS t R = 1.35 min (UV254 nm); mass calculated for the formula i C12H12N2OS2 264.0, LCMS observed m / z 265.1 (M + H).

Part D: Compound 1059 was prepared using a method of Sharpless modified dihydroxylation (Chem. Rev. 1994¡ ,, 94, 2483). Take care a flask with (DHQ) 2PHAL (10 mg, 10 mol%), K3Fe (CN) 6 (128 mg, 0.39 i mmol), potassium carbonate (54 mg, 0.39 mmol), metharosulfonamide (24 mg, 0.26 mmol) and potassium tetraoxide and osmium dihydrate (1 mg, 2 mol%). Alkene 4 (35 mg, 0.13 mmol) in tert-jbutanol: water (1: 1, 2.5) was added to the solids. my). The reaction mixture was stirred overnight at room temperature.

The reaction mixture was cooled in an ice bath and sodium metabisulfite j (38 mg, 0.2 mmol) was added. The mixture was stirred for 30 minutes. The The reaction mixture was diluted with ethyl acetate and water. The layers are separated and the aqueous layer was extracted with ethyl acetate. The organic layer Part A: Compound 1062 was prepared following the procedures described in Example 1.

HPLC-MS t R = 1.69 min (UV254 nm); mass calculated for formula of NaOES 400.2, LCMS observed m / z 401 .2¡ (M + H).

Part B: j Compound 1062 (198 mg, |? .69 mmol) and ammonium acetate (1.9 g, 24.7 mmol) in acetic acid (6 mL) were heated overnight at 10 ° C to 10 ° C. The reaction mixture was concentrated. The residue was suspended in DCM and the solids were removed by filtration. The filtrate was concentrated to give a product mixture protected from acetonide and 1063. The residue was treated with 80% TFA: water (2 ml) and stirred overnight. The solvents are they eliminated. Purification by preparative HPLC gave 1063 (11 mg, 4%) as a salt of TFA. HPLC-MS t R = 0.79 min (UV25-j nm); calculated mass for the formula C 13 H 17 N 3 O 3 S 295.1, LCMS observed m / z 296.1 (M + H).

I Part A: Compound 1 064 was prepared following the procedures described in Example 1. '· HPLC-MS t R = 1.77 min (UV254 nm); mass calculated for formula C2iH24N205S 416.14, LCMS observed m / z 417.i1 (M + H).

Part B:! Compound 1064 (216 mg, 0.52 mmol) and ammonium acetate (2 g, 25.9 mmol) in acetic acid (6 mL) were heated overnight at 10 ° C.

The reaction mixture was concentrated. The residue was suspended in DCM and the solids were removed by filtration. The filtrate was concentrated and purified by reverse phase chromatography (Gilson) to give 1065 (80 mg, 30%) as a TFA salt (80% purity). HPLC-MS t R = 1.38 min (UV254 nm); mass calculated for the formula C21 H23N3O3S 397.1, LCMS observed m / z i 398.2 (M + H). ! Part C: A mixture of compound 1065 (63 mg, 0.127 mmol) was stirred, iodomethane (10 μ ?, 0.16 mmol) and cesium carbonate (206 mg, 0.634 mmol) in DMF (6 mL) overnight at room temperature, the reaction mixture was concentrated. The residue was suspended in ethyl acetate and the solids removed by filtration. The filtrate was concentrated to give the crude product protected from acetonide. The residue was treated with 90% TFA.water (3 ml) i i and stirred for 3 h at 50 ° C. The solvents were removed. The purification by preparative HPLC it gave 1066 (12 mg, 19%) as a TFA salt.

HPLC-MS † R = 2.87 min (10 min; UV25 nm); mass calculated for the formula C19H2i N303S 371.1, LCMS observed m / z 372.1 (M + H).

EXAMPLE 29E Part A: ? According to a modification of a Goker procedure, H. et. to the. (II Drug 1998, 53, 415-420) a mixture of 1-fluoro-2-nitro-benzene (1067) (1.1 mL, 10.4 mmol) and benzylamine (2.35 mL, 21.5 mmol) was heated. in DMF (5 ml) overnight at 80 ° C. The reaction mixture was concentrated to give an orange solid that was filtered, washed with water and dried to give benzyl- (2-nitro-phenyl) -amine (1068) (2.5 g, 100%). 1 H NMR d (400 MHz, i CDCl 3) 8.44 (b, 1 H, NH), 8.22-8.19 (dd, 1 H), 7.41 -7.27 (m, 6H), 6.84-6.81 (dd, 1 H), 6.70-6.66 (m, 1 H), 4.58-4.57 (d, 2H).

Part B: To a solution of benzyl- (2-nitro-phenyl) -amine (1068) (2.5 g, 10.43 mmol) in ethanol (150 ml) and water (10 ml) was added iron (8.7 g, 155.7 mmol) followed by 30 drops of concentrated HCl, and the resulting mixture was heated overnight at reflux. The reaction mixture was deactivated with water, diluted with DCM and the layers separated. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate sodium and concentrated to give a brown oily residue. Additional purification I by column chromatography (SiO2) 20% acetate ethyl / hexanes) gave N-benzyl-benzene-1,2-diamine (1069) as an oil dark yellow (1 .18 g, 57%). 1 H NMR (400 MHz, CDClJ) d 7.41 -7.24 (m, 5H), 6. 82-6.67 (m, 4H), 4.32 (s, 2H), 3.56 (b, 3H, NH).

Part C: Compound 1070 was prepared following the procedures described in Example 29C Part A. HPLC-MS tR = 2.13 min (UV254 nm); dough calculated for the formula C26H29N3O4S 479.2, LCMS filedervada m / z 480.1 (M + H).

Part D: [ A mixture of compound 10 1070 (75 mg, 0.156 mmol) and p-toluenesulfonic acid monohydrate (30 mg, was heated at reflux overnight. 0. 156 mmol) in toluene (3 mL). The reaction mixture was concentrated to a residue identified as the product deprotected from acetonide by LC-MS. Further purification by reverse phase chromatography gave 1071 (40 mg, 48%) as a TFA salt (95% purity). HPLC-MS t R = 3.52 min (10 min; UV254 nm); mass calculated for the formula C23H23N3O3S 421.1, LCMS observed m / z 422.2 (M + H). The following compounds were synthesized by procedures described in Example 29C-E. . , 14. 4 mmol) in 45 ml of THF, nBüLi was added dropwise (9 ml, 14.4 mmol, 1.6 M solution in hexane), and the resulting solution was stirred at -78 ° C for min. Then, DMF (1.12 ml, 14. 4 mmol) was added dropwise, followed by THF (5 mL) and the resulting mixture was allowed to warm slowly until room temperature, and stirred overnight. The reaction mixture is deactivated by the addition of silica gel (3 g), concentrated, and the The resulting aqueous mixture was diluted with DCM and loaded onto a Silica gel. Flash chromatography (3% ethyl acetate / DCM) gave oxazole-2-carbaldehyde (1075) (165 mg, 12%) as a yellow oil; 1 H i NMR (400 MHz, CDCl 3) d 9.79 (s, 1 H), 7.9 (s, 1 H), 7.46 (| s, 1 H).

Part B: Compound 1076 was prepared from compound 1075 (165 mg, 1.7 mmol) using the procedure described in Example 29B Part A.

Purification by column chromatography (SiO2, 20% ethyl acetate / hexane) gave the product as a yellow solid (107 mg, 34%); 1 H NMR (400 MHz, CDCI3) d 7.69 (s, 1 H), 7.45 (d, 1 H, J = 16.0 Hz), 7.27 (s, 1 H), 6.74 (d, 1 H, J = 16.0 Hz), 4.29 (q, 2H, J = 7.3 Hz), 1 .36 (t, 3H, J = 7.3 Hz). i i Part C:! Compound 1077 was prepared from compound 1076 (107 mg, 0.58 mmol) using the procedure described in Example 29B Part B.

The process gave the product as a pale yellow solid (77 mg, 85%). 1 HOUR NMR (400 MHz, DMSO-d6) d 12.9 (s, 1 H), 8.25 (s, 1 H), 7.44 (s, 1 H), 7.27 (d, 1 H, J = 16.0 Hz), 6.62 (d, 1 H, J = 16.0 Hz). | Part D: I i I Compound 1078 was prepared from Compound 1077 (165 mg, 1.7 mmol) using the procedure described in Example 29B Part C. After the standard HATO coupling process, the solid residue was triturated with 1: 1 DCM / hexane, filtered and washed with DCM / hexane. 1: 1 to give 1078 (123 mg, 70%) as a pale yellow solid; 1 H NMR (400 MHz, DMSO-d6) d 8.49 (t, 1 H), 8.20 (s, 1 H), 7.69-7.66 (dd, 1 H), 7.49-7.44 (m, 1 H), í 7.38 (s, 1 H), 7.20-7.16 (dd, 1 H), 7.14 (d, 1 H, J = 16.01Hz), 6.94 (d, 1 H, J = 16. 0 Hz), 3.41-3.38 (d, 2H), 3.16 (t, 2H), 2.72 (t, 2H), 1.81-1.78 (d, 2H), 1.64-1.58 (m, 1H), 1.40-1.30 (m , 2H). HPLC-MS t R = 1.63 jnin (UV254 nm); mass calculated for the formula Ci9Hi9FN4O2354.15, LCMS observed m / z 355.1 (M + H).

Part E: Compound 1079 was prepared from compound 1078 (118 mg, 0.33 mmol) using the procedure described in Example 29B Part D. Purification by column chromatography (SiO2, 5% MeOH / DCM) gave the product as a white solid (28 mg, 22%); 1 H NMR (400 MHz, DMSO-d 6) d 8.02 (s, 1 H), 7.88 (t, 1 H), 7.69-7.66 (dd, 1 H), 7.48-7.43 (m, 1 H), 7.20-7.16 (dd, H ), 7.14 (s, 1H), 5.83-5.81 (d, 1H), 5.72-5.70 (d, 1H), 4.93-4.90 (dd, 1H), 4.23-4.21 (d of d, 1H), 3.38-3.36 (d, 2H), 3.04 (t, 2H), 2.69 (t, 2H), 1.77-1.72 (d, 2H), 1.62-1.56 (m, 1H), 1.32-1.23 (m, 2H) .19F NMR ( 400 MHz, DMSO-de) d -120.6 ppm. HPLC-MS tR - 3.32 min (10 min; UV254 nm); mass calculated for the formula C19H2iFN4O4388.15, LCMS observed m / z 389.2 (M + H).

EXAMPLE 30 EXAMPLE 30A A mixture of 2- (5-bromo-pentyl) -isoindole-1,3-dione (1080) (2.0 g, 6.77 mmol), 2-trifluoromethyl-1 H- was stirred overnight at room temperature. benzoimidazole (1.2 g, 6.45 mmol) and potassium carbonate (1.78 g, 12.9 mmol) in NMP (5 mL). The reaction mixture was divided between ethyl acetate and water, and the resulting organic layer was washed with water, brine, dried over sodium sulfate and concentrated to give an oil. i Further purification by column chromatography (S1O2, 25% ethyl acetate / hexanes) gave compound 1082 as a colorless oil (1.88). g, 73%). 1 H NMR (400 MHz, CDCl 3) d 7.88-7.86 (d, 1 l | l), 7.85-7.83 (m, 2H), 7. 73-7.71 (m, 2H), 7.49-7.34 (m, 3H), 4.31 (t, 2H), 3.72 2H), 1 .99-1 .92 (m, 2H), 1 .80-1 .73 (m, 2H), 1 .53-1 .45 (m, 2H).

Part B: To a solution of compound 1082 (1.88 g, 4.68 mmol) in EtOH (50 ml) was added hydrazine monohydrate (0.45 ml, 9.36 mmol) and the mixture The resulting mixture was heated for 3 h at 60 ° C, during which time a white precipitate was formed. The reaction mixture was filtered, washed with EtOH and the filtrate was concentrated. The residue was suspended in ether, stirred for 10 min. at room temperature, it was filtered and washed with ether, and the resulting filtrate was concentrated to give compound 1083 as an oil (1.10 g, 87%). 1H NMR (400 MHz, CDCI3) d 7.90-7.88 (d, 1 H), 7.46-7.37 (m, 3H), 4.33 (t, 2H), 2.76 (t, 2H), 2.02-1.40 (m, 6H).

Part C: Compound 1084 was prepared from 1083 and 230 following the procedures described in Example 2.

Part D: I Compound 1085 was prepared following procedures i described in Example 2, HPLC-MS t R = 4.14 min (I oj min; UV254 nm); mass i calculated for the formula C25H27F3N4O4 504.2, LCMS (observed m / z 505.1 (M + H).

EXAMPLE 30B J. W. et. al { J. Org. Chem. 1982, 47, 2027-2033), a mixture of 2- (2-amino-ethylsulfanyl) -ethanol (1086) (1.82, 15 mmol) and phthalimide (2.22 g, 15 mmol) in toluene was heated ( 35 ml) at reflux overnight. The reaction mixture was concentrated to a residue, which was purified by column chromatography (SiO2, 25% ethyl acetate / DCM at 50% ethyl acetate / DCM) to give compound 1087 as an off-white solid (2: 98). g, 79%). 1H NMR (400 MHz, CDCl 3) d 7.87-7.85 (m, 2H), 7.75-7.72 (m, 2H), 3.94 (t, 2H), 3.80 (t, 2H), 2.89-2.82 (m, 4H).

Part B: According to a modification of a procedure by Nair, S. A. et. to the. . { Synthesis 1995, 810-814), to a cold solution of compound 1087 (628 mg, 2.5 mmol) and carbon tetrabromide (1.04 g, 3.12 mmol) in DCM (25 mL) was added triphenylphosphine (920 mg, 3.5 mmol) in two portions for 10 min. The reaction mixture was allowed to warm to room temperature and was stirred overnight at room temperature. The mixture was concentrated and the resulting residue was purified by column chromatography (SiO2, 30% ethyl acetate / hexanes) to give compound 1088 as a white solid (733 mg, 93%). 1 H NMR (400 MHz, CDCl 3) d 7.88-7.86 (m, 2 H), 7.75-7.73 (m, 2 H), 3.92 (t, 2 H), 3.53 (t, 2 H), 3. 4 (t, 2 H) 2.90 (t, 2H).

Part C: Compound 1089 was prepared following the procedures described in Example 30A, Part A. 1 H NMR (400 MHz, CDCl 3) d 7.89-7.87 (d, 1 H), 7.86-7.84 (m, 2H), 7.74- 7.72 (m, 2H), 7.58-7.56 (d, 1 H), 7.46 (t, 1 H), 7. 38 (t, 1 H), 4.52 (t, 2H), 3.92 (t, 2H), 3.02 (t, 2H), 2.89 (t, 2H); 19 F NMR (400 MHz, CDCl 3) d-64.7 ppm.

Part D: To a solution of compound 1089 (250 mg, 0.6 mmol) in DCM (5 ml) was added m-chloroperoxybenzoic acid (336 mg, | 1.5 mmol) and the mixture The resulting mixture was stirred overnight at room temperature. The mixture of The reaction was diluted with DCM, washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated to give compound i 1090 (284 mg) as a white solid which was used without purification. additional. H NMR (400 MHz, CDCl 3) d 7.92-7.90 (d, 1 H), 7.90-7.88 (m, 2H), 7. 78-7.76 (m, 2H), 7.66-7.62 (d of t, 1 H), 7.54-7.51 (t of d, 1 H), 7.46-7.44 (t I of d, 1 H), 4.89 (t, 2H), 4.20 (t, 2H), 3.65 (t, 2H), 3.46 (t, 2H); 19F NMR (400 MHz, CDCl 3) d -62.5 ppm. j Part E: j Compound 1091 was prepared following procedures I described in Example 30A, Part B. 1 H NMR (400 MHz, CDCl 3) d 7.91 -7.89 i (d, 1 H), 7.63-7.61 (d, 1 H ), 7.51 -7.48 (t of d, 1 H), 7.44-7.40 (t of d, 1 H), 4.90 (t, 2H), 3.71 (t, 2H), 3.31 (t, 2H), 3.12 (t, 2H); 19 F NMR (400 MHZ, CDCl 3) d- 62.5 ppm. ! Part F: Compound 1092 was prepared following the procedures described in Example 27A, Part B, and used without further purification.

HPLC-MS tR = 1.65 min (UV25i, nm); mass calculated for the formula C28H29F3N408S 638.17, LCMS observed m / z 639.1 (M + H). of 3,3-dimethylglutaric anhydride (1094) (7.1 g, 50 mmol) and methanol (40 ml), during the night, at reflux. The reaction mixture was concentrated to give the Compound 1095 as a colorless oil (8.46 g, 97% j.H NMR (400 MHz, CDCI3) d 3.70 (s, 3H), 2.50 (s, 2H), 2.48 (s, 2H), 1 .16 (s, 6H) Part B: To an ice-cold solution of the compound 109 I5 (8.46 g, 48.5 mmol) in DCM (30 mL), oxalyl chloride (7 mL, 80 mmol) was added dropwise, followed by DMF (2 drops) and the resulting mixture was heated for 3.5 h at reflux. The reaction mixture was concentrated to give the corresponding acid chloride (4-chlorocarbonyl-3,3-dimethyl-butyric acid methyl ester) as a brown oil (7.89 g, 84%) that was used without further purification in the next step.

To a freezing solution of ammonia in 1,4-dioxane (30 ml of a solution containing 2.2 g of ammonia dissolved in 100 ml of 1,4-dioxane, 38.8 mmol approx.) was added dropwise a solution of methyl ester of 4-chlorocarbonyl-3,3-dimethyl-butyric acid (3 g, 15.5 mmol) in 1,4-dioxane (3 ml) and once the addition is complete, the resulting white suspension is stirred 45 min at room temperature. The reaction mixture was diluted with ethyl acetate, filtered and concentrated to give compound 1096 as a yellow viscous oil (2.62 g, 97%). 1 H NMR (400 MHz, CDCl 3) d 3.71 (s, 3H), 2.43 (S, 2H), 2.31 (s, 2H), 1 .14 (s, 6H).

Part C: j To an ice-cold solution of LAH (42 mL, 1 M sol in THF, 42 mmol) and a solution of compound 1096 (2.02 g, 1 1.6 mmol) was added dropwise to the solution.

THF and the resulting mixture was heated overnight at reflux. The reaction mixture was cooled to 0 ° C and deactivated by the dropwise addition of brine, when a solid similar to the paste was formed. E. This solid was crushed and was sonicated several times with ethyl acetate, and the extracts The combined organics were concentrated to give compound 1097 as a oil (1 .17 g, 76%). H NMR (400 MHz, CDCl 3) d 3.7 '(t, 2H), 2.71 (t, 2H), 1 .53 (t, 2H), 1 .41 (t, 2H), 0.92 (s, 6H).

Part D: Compound 1098 was prepared following the procedures described in Example 30B, Part A. HPLC-MS tR = 1.88 min (UV254 nm); mass calculated for the formula C15H19NO3 261 .14, L¡CMS observed m / z 26 262.0 (M + H).

Part E:; j Compound 1099 was prepared following the procedures described in Example 30B, Part B. 1 H NMR (400 MHz, CDCl 3) d 7.84-7.82 (m, 2H), 7.71 -7.69 (m, 2H), 3.70-3.66 (m, 2H), 3.47-3.42 (m, 2H), 1 .97-1.92 (m, 2H), 1.61 -1 .57 (m, 2H), 1.03 (s, 6H).

Part F: Compound 1100 was prepared following the procedures described in Example 30B, Part C. 1 H NMR (400 MHz, CDCl 3) d 7.89-7.87 (d, 1 H), 7.86-7.84 (m, 2H), 7.73-7.71 (m, 2H), 7.5-7.57 (d, 1 H), 7.47-7.43 (t of d, 1 H), 7.39-7.35 (t of d, 1 H), 4.46-4.41 (m, 2H), 3.79-3.75 (m, 2H), 1 .89-1 .85 (m, 2H), 1 .74-1 .69 (m, 2H), 1 .18 (s, 6H); 19F NMR (400 MHz, CDCI3) d-62.7 ppm.

Part G: Compound 1101 was prepared following the procedures described in Example 30B, Part E. HPLC-MS tR = 1 .13 min (UV254 nm); i mass calculated for the formula C 5H2oF3N3 299.16, LCMS observed m / z 300. 1 (M + H).

Part H: Compound 1102 was prepared following Jo, the procedures described in Example 27A, Part B, and used without further purification. i HPLC-MS t = 2.0 min (UV254 nm); mass calculated for the formula C3i H35F3N406 616.25, LCMS observed m / z 617.2 (M + H).

Part I: j Compound 1 103 was prepared following the procedures described in Example 27A, Part C. HPLC-MS tR = 4.52 min (10 min, UV254 column (SiO2, 50% ethyl acetate / hexanes) gave a white solid 1 116 (1.02 g, 56%). HPLC-MS tR = 0.95 (UV254nm); mass calculated for formula i C12H18N203 238.1, LCMS observed m / z 239.2 (M + H).

Part B: Compound 1116 (1.02 g, 4.2 mmol) was dissolved in THF (25 mL) and cooled in an ice bath. Potassium t-butoxide (1.5 g, 1 3.2) was added mmol) in portions and the reaction mixture was stirred for 10 minutes. HE drip added a solution of p-toluenesulfonyl chloride (1.91 g, 1 0.8 mmol) in THF (5 mL) and the reaction was stirred 30 minutes at 0 ° C and 30 minutes at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with HCI solution 1 N, bicarbonate solution and brine; dried over sodium sulfate and they concentrated. Purification by column chromatography (SiO2) 50% ethyl acetate / hexanes) gave a white solid | 1117 (0.750 g, 48%).

HPLC-MS t R = 1.87 min (UV254 nm); mass calculated for the formula Ci 9 H 22 N 2 O 4 S 374.1, LCMS observed m / z 375.1 (M + H). i Part C:! Compound 1117 (750 mg, 2: 0 mmol) was dissolved in DMF (10 mi) and phthalimide (441 mg, 3.0 mmol) and cesium carbonate (1.95 g, 6. 0 mmol) and stirred overnight. The reaction mixture was deactivated with water and extracted with ethyl acetate. The combined organic layers were washed with 1 N HCl solution, bicarbonate solution and brine; They were dried over sodium sulfate and concentrated. The solid residue is recrystallized from ethyl acetate / hexanes to give 11-18 (500 mg, 72%) as a white solid. HPLC-MS tR = 1.63 (UV254 nm); mass calculated for Formula C20H19N3O3 349.1, LCMS observed m / z 350.2 (M + H) Part D: Compound 1118 (10 mg, 0.29 mmol) was dissolved in ethanol (3 mL) and hydrazine hydrate (0.10 mL) was added. The reaction was stirred for 3 hours at room temperature. The solids were removed by filtration and the solution was evaporated under reduced pressure. The residue was dissolved in 1 N NaOH solution and extracted with ethyl acetate. The combined organic layers were washed with brine; were dried over sodium sulfate and concentrated to give compound 1119 which was used without further purification Part E: Compound 1119, 230 (97 mg, 0.29 mmol), DIEA (0.125 mL, 0.7 mmol) and HATU (133 mg, 0.348 mmol) in D F (3 mL) were combined and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with 1 N HCI solution, bicarbonate solution and brine; were dried over sodium sulfate and concentrated to give compound 1120 which was used in the next step without further purification. HPLC-MS t R = 1.68 min (UV254 nm); mass calculated for formula C28H32N4O7 536.2, LCMS observed m / z 537.3 (M + H).

Part F: Compound 1120 was dissolved in methane! (5 ml) and potassium carbonate (150 mg) was added and stirred for 30 minutes. The reaction it was deactivated with water and extracted with ethyl acetate. The organic layers combined were washed with 1 N HCl solution, bicarbonate solution and brine; They were dried over sodium sulfate and concentrated. The purification by reverse phase preparatory LC gave 1121 as a white solid (16 mg) after lyophilization. HPLC-MS t R = 3.48 min (UV254 nm, 10 min); I mass calculated for the formula C24H28N4O5 452.2, LC- S observed m / z 453. 1 (M + H). | in THF, 4 mL, 4 mmol) by drip and the reaction was stirred after 10 minutes to this temperature before heating to room temperature and stirred for 30 additional minutes Boron trifluoroetherate (864 mg, 4 mmol) was added and the solution was stirred for 2 hours. The reaction was deactivated with 1 N HCl and washed with diethyl ether. The aqueous layer was made basic by the addition of 1N NaOH solution and then extracted with ethyl acetate. The combined organic layers i were washed with brine; were dried over sulfate sodium and concentrated to give compound 1 125 that was used without further purification. 1 I Part B: Compound 1125 was dissolved in DMF (5 ml) and added compound 230 (50 mg, 0.140 mmol) and HATU (69 mg, 0.182 mmol) and stirred overnight. The reaction was quenched with water and extracted with acetate of ethyl. The combined organic layers were washed with 1 N HCl, bicarbonate and brine; They were dried over sodium sulfate and concentrated.

Purification by column chromatography (Si02, 50% acetate) ethyl / hexanes) gave a white solid 1126 (60 mg, 81%). HPLC-MS tR = 1 .928 (UV254 nm); mass calculated for the formula C25H25BrN206 528.0, LCMS observed m / z 529.1 (M + H).

Part C: Compound 1126 (60 mg, 0. "427 mmol) was dissolved in eOH (5 ml) and potassium carbonate (100 mg) was added, followed by stirring for 30 minutes. The reaction was quenched with toluene and extracted with ethyl acetate. The combined organic layers were set with bicarbonate solution and brine; They were dried over sodium sulfate and concentrated.

Purification by reverse phase preparatory LC gave a white solid 1127 (10 mg, 15.8%) a lyophilization. HPLCMVIS tR = 4.192 min i (UV254 nm, 0 min); mass calculated for the formula C2iHi > iBrN204 444.0, LCMS observa observed m / z 445.1 (M + H). ' Part D: Compound 1 127 (7.6 mg, 0.017 mmol) was dissolved in dioxane (2 ml) and Pd (dba) 3 (3 mg), triienyl phosphine (4.4 mg, 0.017 mmol), potassium phosphate (8 mg, 0.0377 mmol), and 2-methylphenyl boronic acid (4.3 mg, 0.034 mmol) were added. under a nitrogen atmosphere. The reaction mixture was heated to 90 ° C overnight and then filtered over a bed of Celite and concentrated. Purification by reverse phase preparative LC gave a white solid 1 128 (5 mg, 65%) a lyophilization. HPLC-MS t R = 4.0 4,095 min (UV254 nm, 10 min); mass calculated for formula C28H28 204 456. 2, LCMS observed m / z 457.3 (M + H). I Acid methyl ester hydrochloride: 2-amino-3-thiophen-2-yl-propionic acid (1130) (120 mg, 0.54 mmol) in DMF (2 ml) was added 230 (150 mg, 0. 45 mmol), DIEA (160 uM, 0.9 mmol) and HATU (205 mg, 0.54 mmol). The The reaction mixture was stirred overnight at room temperature, and diluted with ethyl acetate and water. The organic layer was washed with 1N HCl, saturated NaHCO3 and brine. It was dried over Na2SO4 and concentrated, resulting in compound 1131.

Part B: Compound 1131 was dissolved in 5 ml of IMeOH, added ml of 10% aqueous solution of K2CO3. A stirring at room temperature environment during acidified with HCI the organic layer laughed, giving compuest the formula C ^ Hso ^ OeS 404.1, LCMS observed m / z 405.0 (M + H).

Part C: Compound 1132 (40 mg, 0. 1 mmol) was added in 1 ml of DMF with carbodiimide PS resin (17 mg, 1.28 mmol / g charge, 0.15 mmol) and dimethylaminopyridine (3 mg, 0.024 mmol). A shaking during overnight at 50 ° C, the solid was filtered, and the solution was concentrated in vacuo. The purification by reverse phase preparatory LC gave compound 1133 as a white solid. HPLC-MS t R = 3.59 min (UV254 nm, 10 min), Mass calculated for the formula C25H26CIN304S 386.1, LCMS jobservada m / z 387.0 (M + H). ! EXAMPLE 33B Part A: To 2-benzylamino-ethanol (1135) (0.676 g, 4. mmol) in DMF (10 mL) was added 230 (1.0 g, 3 mmol), and HATU (1.71 g, 4.5 mmol). The mixture of The reaction was stirred overnight at room temperature, and diluted with ethyl acetate and water. The organic layer was washed with 1 N HCl, saturated NaHCO 3 I and brine. It was dried over Na2SO4, and concentrated, giving the compound 1136 (1.1 g, 80%). Mass calculated for the formula C25H28N2O7 468. 2, LCMS observed m / z 469.1 (M + H). i Part B:: Compound drip 1136 (468 mg, 1 mmol) and DIEA was added (261 mL, 1.5 mmol) in CH 2 Cl 2 (5 mL) with mesyl chloride (116 mL, 1.5 mmol) at 0 ° C. A stirring at 0 ° C for 10 min, the reaction mixture was left under stirring at room temperature for 1.5 hours, then concentrated until it dried up. The residue was extracted with ethyl acetate, washed with HCl 1 N, saturated NaHCO 3 and brine. Dried over Na2SO4, and concentrated, room temperature for 2 hrs. concentrated to remove the solvent, it was then dissolved in EtOAc and water. The organic layer was washed with 1N HCl, saturated NaHCO3, brine, and concentrated. The purification by LC Reverse-phase high school gave 1138 as a white solid. HPLC-MS t R = I 3.89 min (UV254 nm, 10 min), Mass calculated for formula C21H22N20 366. 16, LCMS observed m / z 367.1 (M + H).

Part A: Step 1: Added (R) - Boc-prolinol (1139)! (2.0 g, 9.94 mmol) in THF (5 mL) in NaH (0.437 g, 60% in mineral oil, 10.93 mmol) in 10 mL of THF at n ° C. After stirring at 0 ° C for 10 min, bromide was added allyl (1.32 g, 10.93 mmol). The reaction mixture was allowed to stir overnight at room temperature. After filtration, the solution is concentrated until dried, the residue was captured with EtOAc, washed with 1 N citric acid, saturated NaHCO3, and brine, dried over Na2SO4, and concentrated, giving a colorless oil (2.30 g, 96%).

Step 2: The above material was added dropwise in CH2CI2 (10 μm) with 3 ml of TFA at 0 ° C. After stirring at room temperature I for 1 h, the solution was concentrated. The residue was dissolved in EtOAc, washed with concentrated Na2CO3, brine, dried over Na2SO4, and concentrated, giving compound 1140 as a colorless oil (1.06 g, 75% for the 2 Steps).

Part B: Step 1: To compound 1140 (500 mg, 3.5¼ mmol) in DMF (10 mi) was added 1 (867 mg, 4.25 mmol) DIEA (1.48 ml, 8.5 jmmol) and HATU (1 .616) g, 4.25 mmol) at 0 ° C. After stirring at room temperature for 5 h, The reaction mixture was diluted with ethyl acetate and water. The organic phase it was washed with 1 N citric acid, saturated NaHC03, and salrhuera. It was dried over Na2SO4, and concentrated. The purification in column j (SiO2, EtOAc / hexane 40:60) gave a colorless oil (650 mg, 57%). j Step 2: The previous material was treated with 5 ml of TFA / H20 (80:20) at 0 ° C. After stirring at room temperature for 2 h, concentrated until it dried. Column purification (Si02, EtOAc / hexanes i 70:30) gave compound 1141 (500 mg, 88%) as a colorless oil.

Part C: | I Step 1: To compound 1 141 (250 mg, 0.87 mmol) in toluene (20 mi) was added dibutyltin oxide (217 mg, 0.87 mmol). The reaction mixture was refluxed for 1 h, using a Dean-Stark device for the azotropic removal of water. After cooling to room temperature, the solvent was disintegrated until reduced pressure was reduced. He The resulting oil was dried under vacuum for 2 h.

Step 2: CsF (198 mg, 1.30 mmol) was added to the previous oil.

The mixture was then placed under vacuum for 2 h. N-Allyl bromide (220 mg, 1.83 mmol) in DMF (10 mL) was added at 0 ° C. After shaking At room temperature under argon for 30 h, the reaction mixture was concentrated, and then it was captured with EtOAc. The solution | was washed with solution saturated KF, and brine, dried over Na2SO4, and concentrated. The organic layer I was washed with 1 N HCl, saturated NaHCO3, brine, and concentrated. The column chromatography (Si02, EtOAc / hexane 60:40) gave compound 1142 | as a colorless oil (130 mg, 45%). Mass calculated for the formula Ci 6 H 25 NO 6 327.17, LCMS observed m / z 328.1 (M + H).

Part D: Compound 1142 (10 mg, 0.33 mmol) was added in dichloromethane (200 ml) with second-generation Grubbs catalyst (Scholl, M .; Ding, S .; Lee, C.W .; Grubbs, R.H., Org. Lótt, 1999, 1, 953-956).

After stirring at room temperature under argon for 3.5 h, the solution was concentrated under reduced pressure. Column chromatography (SiO2l EtOAc) gave 143 as a white solid (60 mg, 60%), mass calculated for the formula Ci4H21NO6 299.14, LCMS observed m / z 300.1 (M + H).

Part E: To 1143 (60 mg, 0.2 mmol) in EtOAc (10 mL) was added 10% of Pd / C (10 mg). The reaction mixture was allowed to stir at room temperature under H2 for 2 h, then concentrated. Column chromatography (SiO2, EtOAc) gave 1144 as a white solid (50 mg, 83%), mass calculated for the formula Ci4H23N06 301.15, LCMS observed m / z 302.1 (M + H).

Part F: Compound 1144 (20 mg, 0.067 mmol) in MeOH (2 mL) was mixed with solid K2CO3 (20 mg, 0.14 mmol). After stirring at room temperature for 5 h, the reaction mixture was concentrated, and captured with EtOAc and water. It was acidified with 1N HCl. The organic layer was separated, washed with brine, dried over Na2SO4) and concentrated to give 1145 as a white solid (12 mg, 63%), mass calculated for the formula C13H21NO6 287.1, LCMS observed m / z 288.1 (M + H).

Part G: j A mixture of 1145 (12 mg, 0.042 mmol), 978 (13.5 mg, 0.063 mmol), DIEA (0.018 mL, 0.1 mmol) and HATU (24 mg, 0.063 mmol) in DMF (1 mL) was stirred. overnight at room temperature, and then diluted with ethyl acetate and water. The organic layer was washed with 1 N HCl, saturated NaHCO 3, and brine. It was dried over Na2SO4, and conjuced. Purification by reverse phase preparatory LC gave 1146 as a white solid. HPLC-MS t R = 4.22 min (UV25 nm, 10 min), mass calculated for the formula sodium bicarbonate, water, and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (S1O2, 33% EtOAc / hexane) to give a white solid (10% rrjg, 33%). HPLC-MS tR = 1.89 min (UV254 nm); mass calculated for the formula C18H22N2O4 330.2, LCMS observed m / z 353.2 (M + Na).

Step 2: Compound 1 148 was prepared from the material of the step 1 following the procedure as described in fel Example 27 Part A Step 2.

Part B: Compound 1 149 was prepared following the procedure according to described in Example 27 Part A step 1, HPLC-MS tR = 1.96 min (UV254 I i nm); mass calculated for the formula C20H17N3O2 331 .1, LCMS observed m / z 332. 2 (M + H).

Part C: Compound 1 149 (0.33 mmol) and hydrate were refluxed of hydrazine (65 μ ?, 1.34 mmol) in ethanol (3 ml) for hours. The reaction mixture was cooled and filtered. The filtrate was concentrated and 150 was used without further purification. 'I | i Parts D v E:! Compounds 1 151 and 1 152 were prepared following the procedures described in Example 5 Parts D and jE. Data for 1 151: HPLC-MS t R = 1.78 min (UV254 nm); mass calculated for formula I C28H30N4O6 518.2, LCMS observed m / z 51 9.2 (? +. Data for 1 152: i HPLC-MS tR = 1.52 min (?? 254 nm); mass calculated for the formula i through a Celite bed. The filtrate was washed with hydroxide solution of 1 N sodium and brine, dried over sodium sulfate and concentrated to give 1 154 as an oil (14 mg, 32%). HPLC-MS tR = 0.22 min (UV254 J; mass calculated for the formula C12H18N2 190.2, LCMS observed m / z 191.2 (M + H).

Parts B and C: Compounds 1155 and 156 were prepared following the Part A: iij Step 1: A mixture of tert-butylester of acetidin-3-ylmethylcarbamic acid (1157) (20 mg, 0.107 mmol), 4-chloro-1-iodobenzene (38.4 mg, 0.161 mmol) was stirred. ), copper iodide (4.0 mg, 0.021 mmol), L-proline (4.8 mg, 0. 042 mmol) and potassium carbonate (29.6 mg, 0.214 rmol) in DMSO (2 ml) under an argon atmosphere at 80 ° C overnight. The reaction mixture is The mixture was diluted with EtOAc, washed with water and brine, sodium and concentrated. HPLC-MS t R = 2.13 min (UV254 nm) i mass calculated for i I the formula C15H2iCIN2O3 296.1, LCMS observed m / z 297.2 (M + H).

Step 2: Compound 1161 was prepared from the material of the Step 1 following the procedure as described in Example 27 Part A Step 2.

Parts B v C: Compounds 1162 and 1163 were prepared following the procedures described in Example 5 Parts D and E. Data for 1162: I HPLC-MS t R = 1.93 min (UV254 nm); mass calculated for the formula? C26H28CIN306 513.2, LCMS observed m / z 514.2 (M + H). Data for 1 163: HPLC-MS t R = 1.63 min (UV254 nm); mass calculated for the formula C22H24CIN304 429.2, LCMS observed m / z 430.1 (M + H). for the formula C21 H23CIIN3O4 543.0, LCMS observed m / z 544.0 (M + H).

Part A: Compound 1165 was prepared from 1164 and acid styrenylboronic using the coupling conditions described in I Example 3 Part F. HPLC-MS tR = 2.1 1 min (UV254 nm); mjasa calculated for Formula C29H30CIN3O4 51 9.2, LCMS observed m / z 520.0 | (M + H).

Part B: A mixture of 1165 (10 mg, 0.02 rhmol) and palladium on carbon (10% by weight, 2 mg) in THF (2 ml) was stirred under hydrogen (atmospheric pressure) overnight. The reaction mixture was filtered through Celite and concentrated. Purification by prep LC gave 1166 as an off white solid (5 mg). HPLC-MS t R = 5.42 min (UV? 54 nm, 10 min); mass calculated for the formula C29H32CIN3O 521.2, LCMS observed m / z 522.2 (M + H).

Part A: Compound 1172 was prepared from 189 using the procedures described in Example 2A Part B. HPLC-MS tR = 4.83 min i (UV254 nm 10 min); mass calculated for the formula C 1 H 2 BrCIN 3 O 4 S 501.0, i LCMS observed m / z 502.0 (M + H). ! Part B: Compound 1173 was prepared using the procedures described in Example 36 Part A. HPLC-MS t R = 5.37 min (UV254 nm, 10 min); mass calculated for the formula C27H28CIN3O4S 525.2, LCMS observed m / z 526. 2 (M + H). p 1 observed m / z 516.0 (M + H). I I Part B:! Compound 1175 was prepared using the procedures described in Example 36 Part A. HPLC-MS tR = 2.29 min (UV254 nm,); dough calculated for the formula C28H3oCIN304S 539.2, LCMS j observed m / z 540.2 (M + H). | EXAMPLE 37C To 3-chloro-2-methylbenzoic acid 1189 (4.95 g, 0.0290 mol) j dissolved in DMF (70 ml) was added cesium carbonate (14.18 g, 0.0435 mol) and methyl iodide (5.35 g, 2.3 ml, 0.0377 mol) ). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated, and EtOAc (200 ml) was added. The organic solution was washed with water (2 x 100 mi), dried (MgSO 4), filtered and concentrated to give 4.43 g (83%) of the 1190 product as a yellow oil. MS for M-CI: 149 mi) was added n-bromosuccinimide (5.1 1 g, 0.287 mol) and benzoyl peroxide (0.58 g, 0.00239 mol). The reaction mixture was refluxed for 16 h, then cooled to room temperature. The solid was removed by filtration and washed with CH 2 Cl 2. The filtrate was concentrated to give 7.80 g of product I 1193 with succinimide as a yellow oil and solid mixture.

Step 4 To compound 1196 (1.00 g, 5.97 mmol) suspended in dry THF (15 mL) was added borane (1 M in THF, 14.9 mL, 14.0 mmol). The reaction mixture was heated to reflux for 5 h then cooled to 0 ° C. HE carefully added in portions EtOH (15 ml) and potassium carbonate (2 g). The reaction mixture was refluxed for 16 h, then cooled to 0 ° C, and (tBOC) 2 O (1.95 g, 8.95 mmol) was added. The reaction mixture it was stirred at room temperature for 3 h, then concentrated. Added water (30 ml), and the aqueous solution was extracted with 3 x 30 ml of CH 2 Cl 2, The The combined organic extracts were dried (MgSO-j), filtered and concentrated. The crude product was purified by silica gel flash chromatography (eluent: 5% EtOAc-CH 2 Cl 2) to give 0.56 g (37%) of the product 1199 as a yellow oil. MS for? +1 -tBu: 198. with the The following intermediaries will be prepared in accordance with the procedure of Example 2 I with the procedure EXAMPLE 39 Hydrazinamide Aqueous NaOH. After filtration, the organic layer was separated, dried over Na2SO, and concentrated. Column chromatography (SiO2l EtOAc / hexane, 20:80) gave 1216 as a colorless oil.

Part B: Compound 1217 was prepared according to the procedure described in Example 2A Part A of 1216 (15 mg, 0.1 mmol).

Part C: Compound 1217 was dissolved in 1 ml of MeOH, 0.5 was added my NH3 7N in MeOH. After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo. The purification by LC Reverse phase preparative gave compound 1218 as a white solid.

HPLC-MS t R = 5.09 min (UV25 nm, 10 min). Mass calculated for the formula C25H26CIN3O4S 499.1, LCMS observed m / z 500.0 (M + H).

Part C: A 1220 (105 mg, 0.36 mmol) in DMF (2 m) was added 230 (100 mg, 0.3 mmol), DIEA (750 μ ?, 0.6 mmol) and HATU (137 mg, 0.36 mmol). The reaction mixture was stirred overnight at room temperature, and diluted with ethyl acetate and water. The organic layer was washed with 1 N HCl, Saturated NaHC03, and brine. It was dried over Na2SO4, and concentrated, giving 1221.! Part D: Compound 1221 was dissolved in 4 mL of eOH, 2 mL of 7N NH3 in MeOH was added. After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo. Purification by reverse phase preparatory LC gave 1222 as a white solid. HPLC- S t R = 3.59 min (UV254 nm, 10 min), Mass calculated for the formula C24H29N306S 488. 2, LCMS observed m / z 488.1 (M + H). I EXAMPLE 41 ) from to. (Heterocyc sta reference: Part C: Compound 1036 was synthesized using the procedure found in Example 2A, Part B. Purification by reverse phase preparatory LC gave a white solid after lyophilization. HPLC-MS t R = I I 3.39 min (UV254 ??, 10 min); mass calculated for the formula C23H27FN6O4 470.2, LCMS observed m / z 471.2 (M + H).

EXAMPLE 41 B m . 4 mmol) followed by p-toluenesulfonyl chloride (d.35 g, 17.7 mmol) in portions. The reaction mixture was stirred for 3 hours at room temperature and then quenched with water and extracted with methylene chloride.

The combined organic layers were washed with 1 N HCl solution, bicarbonate solution and brine; were dried over sodium sulfate and concentrated to give the desired product 1231 (3.85 g), which was used without further purification. HPLC-MS tR = 1.26 min (UV254nm) masa mass calculated for the formula C Hi5N03S 241.08, LCMS observed m / z 242.2 (M + H). Part B: j j Compound 1231 (3.82 g, 15.78 mmol) was dissolved in chloride of methylene (100 ml) and pyridinium chlorochromate (6.7 g, 31 mmol) was added. followed by crushed molecular sieves (3.5 g). The reaction was stirred overnight and then diethyl ether (150 ml) was added and the agitation for an additional hour. The solids were filtered and the solvent was evaporated under reduced pressure. Purification by chromatography in column (S02, 50% ethyl acetate / hexanes) gave a white solid 1232 (3.20 g, 84%). HPLC-MS tR = 1.43 min (UV254) ', mssa calculated for the formula CnH13NO3S 239.06, LCMS observed m / z 240.1 (M + H).

Part C: The reactions were carried out using methods of Heterocycles, Vol. 41, No. 7, 1995.

Part D: The reaction was carried out using the procedure that was found in Example 2A, Part A. 1234: HPLC-MS t R = j 1702 min (UV254 p?); Í mass calculated for the formula C27H3o N506S 571.19, LCMS observed m / z i 572.2 (M + H). I Part E: j The reaction was carried out using the procedure found in Example 2A, Part B. The purification by preparatory LC of reverse phase gave a white solid after lyophilization. 1035: HPLC- MS t R = 3.66 min (UV254?, 10 min); mass calculated for the formula C23H26FN504S 487.2, LCMS observed m / z 488.2 (M + H) with water (1 x 50 ml) followed by brine (1 x 50 ml) The organic layer is dried over MgSO4, filtered and concentrated. The rification by column chromatography (SiO2, 10% Et2O / hexane followed by 15% Et20 / hexane) gave the desired compound 1238 as light oil (9.7 g, 83%).

LCMS m / z: 233.1 (M + H).

Part B: A solution of the pH regulator 8 was prepared by means of the titration of 0.1 M sodium phosphate solution (300 ml) with 1 M HCl for a final pH of 8. To a mixture of compound 1238 in regulator solution of pH 8 esterase was added (41 units / mg, 15 mg, 615 units). NaOH aq. 1 N (6.5 ml) by syringe for a period of 3.5 hours to the reaction mixture to maintain the pH of the mixture of reaction in the range of 7.9-8.2. The reaction mixture was extracted with Et2O (2 x 50 mi). The aqueous layer was acidified to pH 3 using 12 N HCl then extracted with EtOAc (4 x 25 mL). The combined organic layers were dried I! on MgSO4, filtered and concentrated in vacuo to give the compounddesired 1239 (1.36 g, 72%). LCMS m / z: 219.1 (M + H).

Part C: To a solution of compound 916 (0.1 g, 0.535 mmol) in DMF i (1.5 mL) was added compound 1239 (0.092 g, 0.5 mmol), triethylamine (0.2 mL, 1.4 mmol) and HATU ( 0.365 g, 0.96 mmol). The reaction mixture was stirred for 18 hours and then diluted with CH2Cl2 (5 mL) and washed with aq. NaOH 0.5 N (3 ml). The organic layer was dried over MgSO4 and concentrated. Purification by column chromatography (Si02, 30% EtOAc / hexane followed by 40% EtOAc / hexane) gave compound 1240 as a white foam (0.162 g, 67%). LCMS m / z 388.1 (M + H).

Part D: To a solution of compound 1240 (0.175 g, 0.452 mmol) in THF (2 mL) and MeOH (2 mL) at 0 ° C was added LiOH aq. 1.0 M (0.91 mL, 0.91 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was acidified with aq. HCl. 1 N (0.95 mL) and diluted with brine (1.5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over MgSO 4 and concentrated to give compound 1241 as a white foam (0.182 g, 100%). LCMS m / z: 374.1 (M + H).

Part E: To a solution of compound 1241 (0.179 g, 0.48 mmol) in DMF (3 ml) was added 2-phenylpii rotidine hydrogen chloride salt (0.092 g, 0.5 mmol), triethylamine (0.2 ml, 1.4 mmol) and HATU (0.365 g, 0.96 mmol). The reaction mixture was stirred for 4.5 hours and then diluted with EtOAc (10 mL) and washed with water (1.5 mL) followed by brine (1.5 mL!). The organic layer was dried over MgSO4 and concentrated. The residue was purified by plate chromatography prep. (SiO2, 66% EtOAc / hexane). Two were isolated diastereomeric compounds 1242. Diastereomeric Compound 1242A (0.067 g, 28%), LCMS m / z 503.1 (M + H) and the diastereomeric compound 1242B (0.095 g, 28%), LCMS m / z 503.1 (M + H).

Part F: To a solution of compound 1242A (?.? G, 0.1 19 mmol) in CH2CI (1 mL) was added TFA (4 mL) followed by water (0.5 mL). The reaction mixture was stirred at 80 ° C for 3 hours and then concentrated. The residue was purified by column chromatography (SiO2) % MeOH / CH2Cl2) to give 1243A (0.012 g, 22%), LCMS m / z 463.1 (M + H).

To a solution of compound 1242B (0.088 g, 0.18 mmol) in i CH2Cl2 (1 mL) was added TFA (4 mL) followed by water (0.5 mL). The mixture of The reaction was stirred at 23 ° C for 18 hours and then concentrated. The residue was purified by column chromatography (S¡O2, % MeOH / CH2Cl2) to give 1243B (0.05 g, 66%), LCMS 'm / z 463.1 (M + H).

Part A: To a solution of compound 1239 (200 mg, 0.917 mmol) and 2-phenylpyrrolidine (177 mg, 0.96 mmol) in CH 2 Cl 2 (5 mL) at 23 ° C was added DIEA (0.35 ml, 2.01 mmol) followed by PyBOP (0.367 g, 1.1, 46 mmol) and the mixture of reaction was stirred for 18 hours. The mix of writing was concentrated and the residue was purified by column chromatography (SiO2, 20% EtOAc / hexane followed by 30% EtOAc / hexane) to give the compound desired 1244 as an oil (0.16 g, 50%). LCMS m / z. 348.1 (M + H).

The combined organics were dried (Na2SO4), filtered and concentrated. The The mixture of the crude product was used without further purification.

A mixing solution of the crude product prepared was stirred above and sodium azide (0.75 g, 1 1 .5 mmol) in a mixture of MeOH solvent (15 ml) / DMF (15 ml) / DMSO (15 ml), at room temperature environment, for 24 hours. The reaction was diluted with H2O and EtOAc. The layer The organic phase was removed, and the aqueous phase was extracted with EtOAc (1 x). The organic The combined extracts were washed with H2O (3x), brine (1x), dried (Na2SO4), filtered and concentrated. The resulting brown oil! it was purified by chromatography on silica gel to give 1249 (1.2 g, | 4.25 mmol, 47% production in two steps). MS m / e: 283.1 (M + H).

Step 2: To a solution of 1249 (1.2 g, 4.2 mmol) in THF (20 mL) a Room temperature was added PPh3 (1.1 g, 4.2 mmol). The reaction was stirred at room temperature for 1 hour, at which time H20 was added (2 my). The resulting mixture was stirred for 24 hours. After the concentration, the mixture was captured in Et20 and 0.25 N HCl. The organic phase was was removed, and the aqueous phase was made basic with sat Na2CO3. and it was extracted with EtOAc (4x). The combined organics were dried (Na 2 SO 4), filtered and concentrated. The compound was purified by gel chromatography of silica to give 1250 (0.51 g, 47% yield). MS m / é: 257.1 (M + H). with 1 N HCl and diluted with EtOAc. The organic layer was removed and the phase aqueous was extracted with EtOAc (3x). The combined organics were dried (Na 2 SO 4), filtered and concentrated. The compound was used without further purification and I. j To the crude mixture of the product prepared above in CH2Cl2 (2 mL) was added NMM (0.200 mL, 1.82 mmol) and EDCI (0.100 g, 0.52). mmol), and HOBt (0.059 g, 0.38 mmol). This mixture ! it was stirred for 1 0 minutes, at which time NH4CI (0.100 g, 1.86 mmol) was added. After After 72 hours of stirring, the reaction was deactivated with H2O and diluted with EtOAc. The organic layer was removed, and the aqueous phase was extracted with EtOAc.

The combined organics were dried (Na2SO4), filtered they concentrated. The residue was purified by silica gel chromatography to give 1253 (0.062 g, 61% yield in two steps). MS m / e: 529.1 (M + H). ! Step 6: To a solution of 1253 (0.050 g, 0.095 mmol) in CH2Cl2 (2 ml) cooled to 0 ° C, DIEA (0.050 ml, 0.28 mmol) was added followed by TFAA j (0.030 ml, 0.22 mmol). The reaction was stirred at 0 ° C for 3 hours and then was deactivated with 1 N NaOH. The organic layer was removed, and the aqueous phase was removed. acidified with 1 N HCl to pH ~ 4. The aqueous phase was then extracted with EtOAc. (3x) The combined organics were dried (Na2ScLi), filtered and they concentrated. The residue was purified by silica gel chromatography to give 1254 (0.042 g, 0.082 mmol, 88% yield). MS m / e: 51 1 .1 (M + H).

Step 7: Compound 1255 was prepared in a similar manner from 1253 as set forth above in the Example | 12B. MS m / e: 489.1 (M + H). I Step 8: i I Compound 1256 was prepared in a similar manner from 1254 as set forth above in Example 12A. MS m / e: 471 .1 Brown. MS m / e: 268.1 (M + H).

Step 10: j Compound 1259 was prepared in a similar manner from j 1258 as set forth above in Example 12B. MS m / e: 569.1 (M + H).

Step 12: Compound 1261 was prepared in a similar manner from 1260 as set forth above in Example 12A MS m / e: 528.1 (M + H).

H), 3.79 (br s, 1H), 1.50 (d, J = 6.2 Hz, 3H). Mass caked for the formula C7H8BrNO 200.98, LCMS observed m / z 202.0 (M + H).

Part B: Düsopropyl azodicarboxylate (1.2 g, 6 mmol) in THF (5 g) was added. mi) to a solution of 1263 (1.0 g, 5 mmol), phthalimide (0.88 g, 6 mmol) and triphenylphosphine (1.57 g, 6 mmol) in 20 ml of THF. After shaking during overnight at room temperature, the reaction mixture was concentrated until It dried. Then, it was dissolved in 30 ml of ethanol, added with monohydrate of Hydrazine (5 ml) was heated to reflux for 3 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved with ethyl acetate and HCl 1 N. The aqueous phase was extracted again with ethyl acetate. The extract organic was discarded. The aqueous phase was added with 1 N NaOH to pH 12. It was extracted with EtOAc (30 ml x 3). The ester extract was mixed, washed with brine, dried over Na2SO4, and concentrated, giving 1264 (0.61 g, 61%). 1 H NMR (CDCl 3, 300 MHz), d 8.58 (s, 1 H), 7.75 (dd, J = 8.1, 2.0 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 1 H), 4.15 (q, J = 6.5 Hz, 1 H), 1.43 (d, J = 6.5 Hz, 3H). Dough calculated for the formula C7H9BrN2 199.99, LCMS observed m / z 201 .0 (M + H). I Part C: | j To 1264 (400 mg, 2 mmol) in DMF (5 mL) was added 563 (707 mg, 2 mmol), and HATU (912 mg, 2.4 mmol). The reaction mixture was stirred for overnight at room temperature, and diluted with ethyl acetate and water. The organic layer was washed with saturated NaHCO3, and brine. It was dried over Na2SO4, and concentrated to give 1265 (600 mg, 56%). Mass calculated for mi) and potassium t-butoxide (1.0 g) was added and stirred at reflux for 24 hours. The solvents were removed under reduced pressure and the reaction was quenched with water and extracted with chloroform. The layer! aqueous was acidified and It was extracted with chloroform. The combined organic layers were dried over sodium sulfate and concentrated to give a yellow solid 1272 (1.1 g, 74%). HPLC-MS t R = 0.76 min. (UV254 nm); mass calculated for the formula C5H4 BrNO 1 72.95, LCMS observed m / z 1 74.0 (M + H). mi) and compound 1270 (93 mg, 0.370 mmol), potassium phosphate were added (108 mg, 0.51 mmol), triphenylphosphine (10 mg), and Pd (dba.) 3 (5 mg) and stirred 90 ° C at night. The reaction was filtered through Je Celite and purified i i by column chromatography (EtOAc) to give the desired product 1274 as a white solid (60 mg, 75%). HPLC-MS t R = 1.64 (UV254 nm); mass calculated for the formula Ci9H24N203 328.18, LCMS observed m / z 329.2 (M + H).

Part E: Compound 1274 (60 mg, 0.183 mmol) was dissolved in methylene (4 mL) and TFA (1 mL) was added. The reaction mixture was stirred for 1 hour and then the solvent was removed under reduced pressure. The residue was dissolved in DMF (5 ml) and compound 563 (63.5 mg, 0.183 I mmol), HATU (90.5 mg, 0.2379 mmol), and DIEA (0.5 mlj and stirred overnight were added.) The reaction was quenched with water and extracted with ethyl acetate.

The combined organic layers were washed with 1 N HCl solution, bicarbonate solution and brine; They were dried over sodium sulfate and concentrated. The purification of the residue by column chromatography (EtOAc) gave compound 1275 as a white solid (87 mg, 85%). HPLC-MS t R = 1.81 min. (UV254 nm); mass calculated for the formula C31 H34CIN3O5 563.22, LCMS observed m / z 564.1 (M + H).

Part F: Compound 1276 was synthesized using procedures similar to Example 1, Part D. HPLC-MS tR = 1.48 min. (UV254 nm) mass calculated for the formula C28H30CIN3O5 523.19, LCMS observed m / z 524.2 (M + H).

EXAMPLE 46 Part A: Compound 1277 was prepared from 305 according to the procedures described in Example 4A Part A.

Part B: To 1277 (150 mg, 0.44 mmol) in THF (5 mL) was added lithium hexamethyldisilazide (1.0 M, 0.66 mL, 0.66 mmol) at 0 ° C. The mixture of reaction was stirred for 10 minutes. To the reaction mixture was added Methyl iodide (0.034 ml, 0.53 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1.0 N citric acid, saturated sodium bicarbonate and brine, dried over sodium concentrated. The residue was dissolved in DCM (5 ml) and treated with 4N HCl in dioxane (2 ml). The reaction was stirred at room temperature and concentrated.

Compound 1278 was used without further purification.

Part C and D: j Compound 1280 was obtained from 1278 and 230 using the procedures described in Example 4A Part D and J. E. Data for 1280: HPLC-MS Í = 5.05 min. (UV254 nm, 10 min); Calcined mass for the formula I C25H25CIN2O4S 484.1, LCMS observed m / z 485.0 (M + H).

Compound 2000 was prepared according to the procedures in U.S. Patent 5,371, 09. I Compound 2001 was prepared using the procedures described in Examples 2 and 27. HPLC-MS tR = njiin. (UV254 nm); mass calculated for formula C21 H24FN3O7 449.2, LCMS observed m / z 450.1 (M + H).

Part A: Compound 2002 was prepared using the coupling conditions described in Example 2, HPLC-MS tR = 1.60 min. (UV254 nm); mass calculated for the formula C28H30FN5O6 551.2, LCMS observed m / z 552. 1 (M + H). j Part B: Compound 2002 was dissolved (50 mg) in methanol (2 mL). To this solution was added 7.0 M ammonia in methanol (2 mL). The reaction mixture was stirred for 1 hour at room temperature and concentrated. Purification by preparatory LC, and conversion of the hydrochloride salt gave 2003 as an off-white solid (32 mg). HPLC-MS tR = 1.35 min. (UV254 nm); mass calculated for the formula C2 H26FN504 467.2, LCMS observed m / z 468.1 (M + H).

Compound 2004 was prepared according to the procedures in US Patent No. 5,371,090. Compound 2005 was prepared using procedures described j in Examples 1 and 27.

Part A: Compound 2006 was prepared using the coupling conditions described in Example 1, HPLC-MS R = 1.40 min. (UV254 nm); 2008 sulfonyl chloride (2.44 g, 9.8 mmol) was dissolved in dioxane (40 ml) and cooled in an ice bath. S! E bubbled gas ammonia in the reaction mixture for 10 minutes. The mixture of The reaction was warmed to room temperature and filtered. The filtrate is concentrated. The crude product was recrystallized from ethyl acetate / hexanes i to give 2009 as a whitish solid (1.74 g). 1 H NMR (400 MHz, DMSO- d6) d 7.09 (s, 2H), 6.74 (s, 1 H), 3.80 (s, 3H), 2.57 (s, 3H), 2.48 (s, 3H), 2.08 (s, 3H); HPLC-MS t R = 1.43 min. (UV254 nm); calcified mass for the formula C10H15NO3S 229.1, LCMS observed m / z 230.1 (M + H).

Part B: Sodium hydride (95%, 131 mg, 5.19 mmol) in DMF (10 ml) was added sulfonamide 2009 (596 mg, 2.6 mmol). The reaction mixture is heated to 70 ° C and stirred for 45 minutes. To this mixture was added 2,3-bis (chloromethyl) pyrazine (2010) (Yoshiizumi, K. et al. Bioorg, Med.Chem.I 2003, 11, 433) (448 mg, 2.53 mmol) in DMF (3 ml). The reaction mixture is heated at 70 ° C overnight. The reaction mixture was cooled and poured in water The aqueous layer was salted and extracted with chloroform. The organic The combined extracts were washed with water, dried over sodium sulfate and concentrated. Purification by column chromatography (Si02, 30% ethyl acetate / hexanes) gave sulfonamide recovered 2009 (218 mg) and 201 1 (245 mg). HPLC-MS t R = 1.82 min. (UV254 nm); calculated for the Formula C 6H19N303S 333.1, LCMS observed m / z 334. i! (M + H).

Part C:: A mixture of sulfonamide 201 1 (245 mg, 0.73 mmol) was stirred, anhydrous methanesulfonic acid (3 ml) and thioanisole: trifluoroacetic acid 1: 9 (3 mi), for 3 hours, at room temperature. The reaction mixture was poured on ice and treated with 50% sodium hydroxide (10 ml). The aqueous layer The 2014 compound was prepared according to the procedure in Helv. Chim. Acta. 1986, 905-907.

Part B: i Acetyl chloride (20 ml) was added dropwise to methanol (130 ml) chilled in an ice bath. This solution was then added to the compound 2014 (5.00 g, 31.8 mmol) and stirred overnight at reflux. The solvent is The mixture was removed under reduced pressure and the residue was partitioned between ethyl acetate and 1 N NaOH. The organic layer was washed with brine, dried over sodium sulfate, sodium, and concentrated to give 2015 (5.0 g). H NMR (400 MHz, CDCI3) d 3.72 (s, 3H), 3.69 (s, 3H), 2.77 (t, 2H), 2.5 (t, 2H), 1.32 (s, 6H).

Part C: The compound 2015 (5.00 g, 24 mmol) was dissolved in THF (60 ml) and saturated sodium bicarbonate (60 ml) and cooled in an ice bath. HE added methyl chloroformate (2.93 g, 31.2 mmol) per drop and the reaction was stirred at room temperature overnight. The reaction mixture is divided between ethyl acetate and water. The organic layer was washed with 1 N HCl, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. Purification by column chromatography (Si02, 20% of ethyl acetate / hexanes) gave 2016 (5.5 g). 1 H NMR (400 MHz, CDCl 3) d 3.72- 3.68 (m, 9 H), 3.65-3.6 (t, 2 H), 2.66 (t, 2 H), 1.5 (s, 6 H).

Part D: Compound 2016 (1.66 g, 6.36 mmol) sp dissolved in THF (20 mi) and cooled on an ice bath. Hydride was added in portions potassium (35% in oil, 1.12 g, 9.54 mmol) and stirring was continued for 2 hours. hours at room temperature. The reaction was slowly deactivated with water, acidified to pH 3, and extracted with ethyl acetate. The organic layers The combined extracts were dried over sodium sulfate and conentrated (1.5 g). An i portion of the residue (350 mg) was dissolved in MeOH (5 ml) and 6N HCl (5 ml) and stirred at reflux for 3 hours and at room temperature overnight. He solvent was evaporated under reduced pressure and partitioned between ethyl acetate and Water. The organic layer was washed with water, dried over sodium sulfate, and concentrated to give 2017 (150 mg). 1 H NMR (400 MHz, CDCl 3) d 3.72-3.55 (m, 5H), 2.5 (t, 2H), 1.4-4.25 (m, 6H). J Part E: i According to a modification of a Fukui procedure, H. et al. (Heterocycles 2002, 56, 257-264) a mixture of ketone 2017 (200 mg, 1.17 mmol) and?,? - dimethylformamide dimethyl acetal (3 mL) was heated at 100 ° C for 2 h, and then concentrated to give enamino-ketone 2018 (244 mg, 92%) as a yellow solid. 1 H NMR (400 MHz, CDClj.). D 7.32-7.31 (m, 1 H), 4. 54-4.51 (d, 2H), 3.78-3.22 (d, 3H), 3.12 (s, 6H), 1.48 (s | 3H), 1.40 (s, 3H).

! Part F: j According to a modification of a Fukui procedure, H. et al. (Heterocycles 2002, 56, 257-264) heated up a mixture of enamino-ketone 2018 (690 mg, 3.05 mmol) and formamidine acetate (3.17 g, . 5 mmol) in ethanol (15 ml) for 3 days, and then concentrated. The residue it was partitioned between dichloromethane and water, and extracted with dichloromethane. The The combined organic extracts were concentrated to give an oil which was subjected to chromatography (SiO2, 50% -80% ethyl acetate / hexane) to give pyrimidine 2019 (334 mg, 53%). 1 H NMR (400 MHz, CDCl 3) d 9.15 (s, 1 H), 8.67 ii (s, 1 H, broad), 4.76-4.71 (d, 2 H), 3.84-3.77 (d, 3 H), 1.75. (s, 3H), 1 .67 (s, 3H). environment for 2 days and filtered to remove the white precipitate. The filtrate i was concentrated and the residue was dissolved in ethyl acetate, washed with solution of sodium bicarbonate, water and brine, dried over sodium sulphate sodium and concentrated to give 2023 as a light yellow oil (2.4 g, 64%). 1 H NMR (400 MHz, CDCl 3) d 3.74 (s, 3 H), 3.69 (s, 3 H), 3.46 (d, J = 3.2 Hz, 2H), 3.14 (m, 1 H), 2.45 (m, 2H), 1 .1 5 (d, J = 7.2 Hz, 3H).

Part B: Compound 2023 (2.42 g, 13 mmol) was dissolved in THF (20 mL) 1 and saturated sodium bicarbonate (20 mL) and cooled in an ice bath. HE Methyl chloroformate (1.2 ml, 15 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The reaction mixture is divided between ethyl acetate and water. The organic layer was washed with 1 N HCl, saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated to give 2024 (2.9 g). I i I Part C: Compound 2024 (1.30 g, 5.26 mmol) was dissolved in THF (20 mi) and cooled on an ice bath. Hydride portions were added in j potassium (35% in oil, 1.12 g, 9.54 mmol) and the mixture was stirred at room temperature and overnight. The reaction was quenched slowly with water, acidified to pH 3, and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. Purification by column chromatography (Si02 [25% acetate ethyl / hexane) gave an oil (1.27 g). This oil (1.27 g) j was dissolved in MeOH (5 ml) and HCl 6N (5 ml) and stirred at reflux overnight. The mixture extracted with ethyl acetate and the combined organic layers were washed with solution of sodium bicarbonate, water and brine, dried over sulphate of sodium and concentrated to give 2025 (663 mg). 1 H NMR (400 MHz, CDCI3) d 4.5 (bs, 1 H), 3.95 (m, 1 H), 3.78 (s, 3 H), 3.70 m, 1 H), 2.73 (m, 1 H), 2. 25 (m, 1 H), 1.28 (m, 3H).

Part D: Compound 2026 was prepared from the material of part C according to the procedures described in Example 47D Part E and i Part F. ?? NMR (400 MHz, CDCl 3) d 9.13 (s, 1 H), 8.61 | m, 1 H), 5.24 (m, 1 H), 4. 88 - 4.64 (m, 2H), 3.82 (m, 3H), 1.59 (m, 3H).

Part E: A mixture of compound 2026 (300 mg, mmol), powdered potassium hydroxide (600 mg, 10.7 mrhol) and monohydrate of hydrazine (1.0 ml, 21 mmol) in ethylene glycol (5 ml) at 100 ° C overnight.

The reaction mixture was cooled to rt, poured into brine and extracted several times with dichloromethane. The combined organic extracts were washed with brine and concentrated to give compound 2027 (105 mg, 54%). o- 2030 Part A: To a solution of compound 2028 (0.29 g, 0.63 mmol) in CH 2 Cl 2 at 0 ° C was added 70% m-CPBA (0.31 g, 1.26 mmol) and the reaction mixture was warmed to room temperature and stirred for 1 hour. It was diluted with CH 2 Cl 2 (5 mL) and washed with a solution of water (6 mL) and concentrated NH 4 OH (0.5 mL). The aqueous layer was extracted with Cl C (3 x 10 mL) and 5% I of MeOH / CH 2 Cl 2 (2 x 5 mL). The organic layer was dried over MgSO4, filtered and concentrated. Purification by column chromatography (SiO 2, 5% MeOH / CH 2 Cl 2) gave the desired product with some impurities. The impure product was dissolved in EtOAc (15 mL) and washed with NH40 10% (5 mL). The aqueous layer was extracted with CH2Cl2 (3 x 5 mL). The combined organic layers (EtOAc and CH 2 Cl 2) were dried over MgSO 4, filtered and! were concentrated to give the desired compound 2029 (0.25 g, 92%). j i Part B: Compound 2030 was obtained from compound 2029 using the TFA deprotection procedure as described in Example 1 The following compounds were prepared using the procedures described above.

Part A: Compound 2061 was synthesized according to the procedures of U.S. Patent 5,037,834.

Part A: i A mixture of ketone 2066 (4.0 g, 20 mmol), morpholine (7.5 ml, 85 mmol) and p-1-toluenesulfonic acid monohydrate (160 mg, 0.84 mmol) in benzene was heated at reflux for 3 days. 30 mi) using a Dean-Stark trap. The mixture was then washed with saturated sodium bicarbonate solution and concentrated to give 2067 as a yellow oil (4.36 g, 65%). 1 H NMR (400 MHz, CDCl 3) d 4.58 (s, 1 H, broad), 3.96-3.95 (m, 2 H), 3.77-3.73 (m, 4H), 3.55 (t, 2H), 2.83-2.80 (m, 4H), 2.18 (t, 2H), 1.49 (s, 9H).

Part B: According to a modification of a procedure of Gündisch, D. et. to the. (Bioorg, Med. Chem. 2002, 10, 1-9) a mixture was heated of enamine 2067 (2.27 g, 8.48 mmol) and 1, 3,5-triazine (688 mg, 8.48 mmol) in 1,4-dioxane (10 ml) at 100 ° C in a sealed tube overnight. Mix The reaction mixture was concentrated and subjected to chromatography (SiO2, 50-65% of ethyl acetate / hexane) to give pyrimidine 2068 as a yellow oil (665 mg, 35%). 1 H NMR (400 MHz, CDCl 3) d 9.01 (s, 1 H), 8.49 (s, 1 H), 4.64 (s, 2 H), 3. 80 (t, 2H), 3.00 (t, 2H), 1.54 (s, 9H). HPLC-MS tR = 1.32 min. (UV254 nm); mass calculated for the formula Ci2H17N302 235.1, LCMS observed m / z 236. 1 (M + H).

Part C: Compound 2068 j (100 mg) was deprotected using the procedures described in Example 48C to give the amine 2069 as a yellow solid (68 mg, 78%). 1 H NMR (400 MHz, DMlSO-d 5) d 9.67 (s, 2H, broad), 9.01 (s, 1 H), 8.67 (s, 1 H), 4.33 (t, 2H), 3.50-3.45 (m, 2H), 3.09 (t, 2H).

HPLC-MS t R = 0.18 min. (UV25 nm); mass calculated for the formula C7H9N3 . 1, LCMS observed m / z 36.2 (M + H).

EXAMPLE 49 EXAMPLE 49A Part A: Compound 2086 was prepared according to the procedure in Org. Lett. 2002, 4, 24, 4353-4356.

Part B: Compound 2087 was prepared according to the procedure in Org. Lett. 2002, 4, 24, 4353-4356, 1 H NMR (400 IvJHz, CDCI3) d 7.05 (t, 2H), 5.1 (bs, 2H), 2.15 (m, 2H), 1.4 (s, 9H), 1.3 (m, 2H).

Part C: I I i Compound 2087 (80 mg, 0.30 mmol) was dissolved in 4 M HCl in dioxane (2 ml) and stirred at room temperature for 1 hr. The reaction it was diluted with diethyl ether (5 ml) and the resulting solid was filtered to give 2088 as an HCI salt (45 mg).

EXAMPLE 49B Part A: Compound 2090 was prepared according to the procedure in Bioorg. Meó. Chem. 2002, 10, 5, 1 197-1206.

Part B: Compound 2091 was prepared according to the procedure in Bioorg. Med. Chem. 2002, 10, 5, 197-1206, 1 H NMR (400 MHz, CDCl 3) d 9. 00 (s, 1 H), 8.40 (s, 1 H), 5.10 (bs, 1 H), 4.70 (bs, 1 H), 4 ^ .10 (m, 2H), 3.40 (bs, 1 H), 2.50 (s, 1 H), 2.40-2.30 (m, 2H), 1.80 (m, 2H), 1.75 (| n, 2H), 1.25 (m, 3H).

Part C: Compound 2091 (350 mg, 1.5 mmol) was dissolved in ethylene glycol (4 mL) and KOH (0.5 g) and hydrazine monohydrate (1 mL) were added and stirred at 100 ° C for 12 hours. . The reaction mixture was poured into brine and extracted with methylene chloride. The combined organic layers were washed with water, dried over sodium sulfate and concentrated to give 2092 (150 mg). 1 H NMR (400 MHz, CDCl 3) d 9.00 (s, 1 H), 8.40 (s, 1 H), 4.30 (d, 1 H), 4.00 (t, 1 H), 3.20 (m, 1 H), 2.80 (m, 1 H), 2.20-2.10 (m, 2H), 2.00-1.90 (m, 2H), 1.80-1.60 (m, 2H). ! The following compounds were prepared using the procedures described above. cesium carbonate (358 mg, 1.1 mmol) in NMP (5 ml), at room temperature, overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water (2x) and brine, dried over sodium sulfate and concentrated. Purification by column chromatography (Sicj2, hexanes to 2% ethyl acetate / hexanes) gave 2101 (232 mg) as an oil. 1 H NMR (400 MHz, CDCl 3) d 7.53 (m, 1 H), 6.70 (m, 2 H), 4.40 (q, 2 H, J = 8.0 Hz).

Part B: Compound 2102 was prepared according to the procedures in Example 27B Part A. HPLC-MS t R = 2.10 min. (UV254 nm); mass calculated for the formula C19H26F4N203 406.2, LCMS observed m / z 407.2 (M + H).

Part C: Compound 2102 (8 mg, 0.02 mmol) was dissolved in DCM: TFA 3: 1 (4 mL) and stirred for 1 hour at room temperature. The solvent was removed in vacuo. The residue was dissolved in ether and treated with 1.0 M HCl in ether (1 mL). The solvents were concentrated to give 2103 as a white solid (8 mg). or d n Acetone (20 ml) was stirred at room temperature overnight. Added Additional ethyl iodide (0.24 ml, 3 mmol) was added to the reaction and the mixture was stirred for 24 hours. The mixture was filtered and concentrated.! The residue was divided between water and ethyl acetate. The layers separated. The organic layer is washed with water and brine, dried over sodium sulfate and concentrated to? give 2105 (1 .23 g) as an oil. 1 H NMR (400 MHz, CDCl 3) d 7.07 (m, 2H), 6. 96 (m, 1 H), 6.87 (m, 1 H), 4.12 (q, 2H, J = 7.1 Hz), 1.48 (t, 3H, J = 7.1 Hz).

Part B: To arene 2105 (1.23 g, 8.8 mmol) and TMEDA (1.32 ml, 8.8 mmol) in THF (20 ml) at -78 ° C under argon, s-Búli (1.4 M, 6.3 ml, 8.8 mmol) was added. The reaction mixture was stirred for 2 hours at -78 ° C. To the mix of reaction was added iodine (2.23 g, 8.8 mmol) in THF (10 ml) at -78 ° C. The reaction was stirred for 10 minutes then warmed to 0 ° C. The reaction mixture I i was poured into water and extracted with diethyl ether. The organic The combined extracts were washed with water (2x), 5% sodium hydrogen sulfide and brine, dried over sodium sulfate and concentrated. The crude product 2106 (1.70 g) was a product mixture: starting material 75:25 by 1 H NMR. It was used without further purification. 1 H NMR (400 MHz, CDCl 3) d 7.28 (m, 1 H), 6.94 (m, 1 H), 6.81 (m, 1 H), 4.1 1 (q, 2 H, J = 7 1 Hz), 1 .47 (t, 3H, J = 7.1 Hz).

Part C: Compound 2107 was prepared according to the procedures in Example 27B Part A. HPLC-MS; tR = 2.15 min. (UV254 nm); mass calculated for the formula C-19H29FN2O3 352.2 LCMS observed m / z 353.2 (M + H).

Part D: Compound 2107 (276 mg, 0.78 mmol) was dissolved in DCM FA 3: 1 (4 mL) and stirred for 1 hour at room temperature. The solvent was removed in vacuo. The residue was dissolved in ether and treated with 1.0 M HCl in ether (1 mL). The solvents were concentrated to give 2108 as a white solid (241 mg). 1 H NMR (400 MHz, DMSO-d 6) d 7.89 (bs, NH), 6.97 (m, 1 H), 6.75 (m, 1 H), 6.63 (m, 1 H), 4.04 (q, 2 H, J 6.9 Hz), 3.33 (m, 2H), 2. 76 (m, 2H), 2.62 (m, 2H), 1.80 (m, 2H), 1.70 (m, 1 H¾, 1.38 (m, 2H), 1.32 (t, 3H, J = 7.1 Hz).! Compound 2109 was prepared using described procedures in Example 27, 1 H NMR (400 Hz, CDCl 3) d 7.00-6.80 (m, 4 H), 4.64 (m, i 1 H), 3.55 (m, 2 H), 3.09 (m, 2 H), 2.65 (m, 2 H) ), 1.82 (m, 2¡H), 1.60-1.50 (m, 2H), 1. 49 (s, 9H), 1.42 (m, 1H).

Part A: To Compound 2109 (100 mg, 0.32 mmol); and pyridine (0.026 ml, 0. 32 mmol) in DMF (2 mL) was added NBS (115 mg, 0.64 mmol). The mixture stirred at room temperature for 2 hours and diluted with ethyl acetate.

The mixture was washed with sodium carbonate solution, water and brine, dried over sodium sulfate and concentrated. The purification by column chromatography (S02, 5% ethyl acetate / hexane) gave 2110 i as a white solid (88 mg). 1H NMR (400 MHz, CD ^) d 7.3 (m, 1H), 7.0 (m, 2H), 4.65 (bs, 1H), 3.28 (m, 2H), 3.10 (m, 2H), 2.61 (m, 2H), 1.8 (m, 2H), 1. 65-1.4 (m, 12 H). % ethyl acetate / hexane) to give a pale yellow oil (80 mg).

HPLC-MS t R = 2.14 min. (UV254 nm), mass calculated for C21H32N2O4 376.5, LSMS observed m / z 399.2 (M + Na).

Step 2: The material of step 1 (80 mg) was stirred in HCl 4 N in 1,4-dioxane (2 ml) for 1 hour. The solvent was removed under vacuum and 2114 used without further purification.

Part C: A mixture of 2114, 2,5-difluorobenzonitrile (32.5 mg, 0.234 mmol) and DIEA (0.1 13 ml, 0.637 mmol) in NMP (2 ml) in argon atmosphere it was stirred overnight at 100 ° C. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and He concentrated. Purification by column chromatography (Si02, 25% ethyl acetate / hexane) gave 2115 as a yellow oil (26 mg). 1H NMR (400 MHz, CDCI3) d 7.3 - 7.2 (m, 6H), 7.2 (m, 1 H), 7.0 (m, 1 H), 5.05 (s, 2H), 4. 7 (m, 1 H), 3.52 (m, 2H), 2.77 (m, 2H), 2.15 (m, 1 H), 1.8 (m, 2H), 1.63 (m, 2H), 1.32 (s, 6H).

Part D: A mixture of 2115 (26 mg) and 10% palladium on carbon (5 mg) in ethanol (4 ml) under hydrogen atmosphere was stirred for 3 hours. The The mixture was filtered through a pad of Celite and the filtrate was concentrated to give 2116 as a yellow residue (20 mg), which was used without purification.

Part A: Added methyl (triphenylphosphoranylidene) methyl (104.5 g, 0.31 mmol) to a solution of ?? -Boc-piperidinone (2066) (49.79 g, 0.25 mol) in toluene (625 ml). The resulting reaction mixture was heated to reflux and it was stirred for 17 h. The reaction mixture was then cooled to room temperature and concentrated in vacuum. The resulting residue was then pre-adsorbed onto silica gel and purified by elution through a plug of silica gel with 50% ethyl acetate / hexanes, to give the unsaturated ester 2117 (62.16 g, 0.243 mol) as a white solid.

Part B: Potassium tert-butoxide (450i g, 0.41 mol) was added to a solution of trimethylsulfoxonium iodide (90.0 g, 0.41 mol) in DMSO (700 ml), i in one portion. The mixture was stirred at room temperature for 3 h. He unsaturated ester 2117 (59.64 g, 0.23 mol) was dissolved in DMSO (0.26 L) and added to the reaction mixture. The reaction mixture was stirred for 20 h at room temperature and then added to brine (1 L). Aqueous saturated NH4CI was then added to the reaction mixture to adjust the pH to about 7. The reaction mixture was then extracted several times with ether, the ether extracts were combined, washed with water and brine, dried with anhydrous MgSO4. , filtered and concentrated in vacuo to give ester 2118 (53.5 g, 0.20 mol) as an oil.

Part C: An aqueous solution of LiOH (2N, 200 ml) was added to a solution of ester 2118 (53.5 g, 0.20 mol) in THF (200 ml). The mixture was then stirred at room temperature for 17 h, diluted with water (750 ml) and washed with ether. The ether phase was discarded, and the aqueous phase was acidified to a pH of 3-4 with 6 N HCl. The acidified aqueous phase was then extracted with ether several times. The ether washings were combined, washed with water and brine, dried with anhydrous MgSO4, filtered and concentrated in vacuo to give carboxylic acid 2119 (49.25 g, 0.19 mol) as a white solid.

Part D: Triethylamine (8.7 g, 0.086 mol) followed by ethyl chloroformate (9.4 g, 0.086 mol) was added to a 2119 carboxylic acid solution (20.0 g, 0.078 mol) in acetone (78 ml) at 0 ° C. The resulting mixture is stirred at 0 ° C for 40 minutes. Then, sodium azide (10.2 g, 0.15 mol) in water (50 ml) was added to the mixture. The mixture was then allowed to warm to room temperature and stirred for 4 h. Later, water was added, and then the mixture was extracted several times with CH2CI2. The organic extracts were combined and washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give an oil. The oil was taken up in toluene (200 ml), allyl alcohol (5.5 g, 0.094 mol) was added, and the mixture was heated to reflux and stirred under reflux for 17 h. The reaction mixture was then cooled to room temperature and EtOAc (250 mL) was added. Then, the mixture was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (35% ethyl acetate / hexanes) to give carbamate 2120 (24.4 g, 0.061 mol).

Part E: A solution of HCl / Et20 (2 N, 50 mL) was added to a solution of carbamate 2120 (24.4 g, 0.061 mol) in CH2Cl2 (100 mL). The reaction mixture was stirred overnight and then concentrated in vacuo to give 2121 as a hygroscopic foam (17.4 g, 0.052 mol). 59%).

Part B: The chlorine compound 2123 was dissolved in DMF (100 ml) and treated with NaN3 (10.3 g, 157 mmol), and the mixture was stirred vigorously for 36-48 h. The reaction mixture was then diluted with 100 ml of water and extracted with ethyl acetate (2 x 100 ml). The organic extracts were combined, dried and concentrated to give pure azide 2124 (6.2 g, 87%).

Part C: Azide 2124 (6.2 g, 27 mmol) and triphenylphosphine (15 g, 57 mmol) were dissolved in 100 mL of THF, and then water (6 mL, 333 mmol) was added. The resulting mixture was stirred vigorously for 16-24 h. The solvent was removed and the crude amine 2125 was obtained without further purification.

Part D: The crude amine 2125 and N, N-dimethylaminopyridine (0.66 g, 5.4 mmol) were dissolved in CH2Cl2 (100 mL). To this solution was added di-tert-butyldicarbonate (7 g, 33 mmol), in portions, and the reaction mixture was stirred i i for 16 h. The reaction mixture was then washed twice (50 ml) with water and once with brine (50 ml). The organic phase was isolated and dried, and the solvent was removed under reduced pressure. The crude product was submitted to silica gel chromatography using ethyl acetate: hexane 1: 3 as the eluent solvent. The eluted fractions were combined and concentrated to give 6.9 g of pure carbamate 2126 (84%).

Part E: Carbamate 2126 (1.9 g, 6.3 mmol) was dissolved in methanol (100 ml) and mixed with palladium hydroxide (20%, 0.4 g). The mixture was transferred to a bottle of Parr, which was then charged with hydrogen 138 kPa. Parr's bottle j was stirred for 10 h. The remaining hydrogen was removed under vacuum from the Parr bottle, and the reaction was filtered through Celite. The filtrate was then concentrated to give the pure amine 2127 (1.4 g). | Part A: L! AIH4 was added to dry THF (40 ml) and the mixture was cooled then up to 0 ° C. Then 2128 carbonitrile was drip added to the mixture (0.9 g, 3.8 mmol, in a THF solution of 10 ml). The reaction mixture was allowed to warm to room temperature and was stirred for 48 h, then cooled again to 0 ° C and deactivated by sequential addition of 1 Mi of water, 2 ml of NaOH aq. 0.5 N, and 1 ml of water. The resulting mixture is stirred vigorously for 2 h and then filtered through Celite. The filtering! concentrated to give 2129 pure as an oil (0.9 g, 100%).

Part B: The crude product 2129 and triethylamine (TEA) (0.6 ml, 4.3 mmol) were dissolved in CH2Cl2 (50 ml). Di-tert-butyldicarbonate (0.85 g, 3.9 mmol) to this solution, in portions, and the reaction mixture was stirred for 16 h. The reaction mixture was then washed twice with 50 ml of water and once with 50 ml of brine. The organic phase was dried and the solvent was removed under reduced pressure. The crude product was subjected to gel chromatography of silica using methanol saturated with 2.5% ammonia in CH2Cl2 as the solvent eluent. The fractions eluted and concentrated to give 0.78 g of the carbamate product Part C: Carbamate 2130 (0.8 g, 2. in methanol (60 mi) and treated with palladium hydroxide (20%, 0.08 g). The mixture was transferred to! a bottle of Parr, which was then charged with hydrogen 138 kPa. The bottle of Parr was stirred for 10 h. Hydrogen was removed from the Parr bottle vacuum, and the reaction mixture was filtered through Celite. The filtrate is then concentrated to give the pure amine 2131 (0.6 g). 3-methyl-N-benzyl piperidone (2132) (4.25 g, 20.93 mmol) in DME (150 ml) and cooled to 0 ° C. Ethyl alcohol (2.9 ml) was added to the reaction mixture and potassium tert-butoxide (7 g, 62.4 mmol) and stirred at room temperature During 4 hours. The reaction mixture was poured into ice and extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with brine, dried on anhydrous MgSO 4 and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel (20% ethyl acetate / hexane) to give first 2133 (trans isomer, 1.85 g, 41%), and second 2134 (cis isomer, 1. 05 g, 22%).

Part B: The trans intermediate 2133 (2.0 g, 9.34 mmol) was dissolved in ethyl alcohol (50 ml) and Raney nickel (humid, 5.0 g) was added under N2, followed by the addition of ammonium hydroxide conc. (1.0 mi). The mixture subjected to H2 atmosphere at 345 kPa for 16 hours under vigorous stirring.

The reaction was filtered through Celite under N2 and concentrated. vacuum to give 1.8 g (88%) of the intermediate 2135.

Part C: Intermediary 2135 (1.0 g, 4.6 mmol) was dissolved in alcohol methyl (35 ml). A solution of BOC-anhydride (1.2 g, . 5 mmol) in methyl alcohol (15 ml) at 0 ° C. The resulting mixture was stirred at 0 3C for one hour, then at room temperature for one hour additional. The solvent was removed under vacuum to give a crude product that was purified by silica gel column chromatography using ethyl acetate I as the eluent solvent. The relevant fractions were collected and concentrated under reduced pressure to give 1.1 g (76%) of the intermediate 2136.

(M + Na).

Part B: Compound 2168 was synthesized according to the procedures of Example 0B Part A. HPLC-MS tR =! 1.78 min. (MS); dough calculated for the formula C12Hi8CIN03 259.1, LCMS observed m / z 282.1 (M + Na).

Part C: Compound 2168 (17 mg) was cyclized with N-methylthiourea in DMF (2 ml) to give 2169 (35 mg) according to the procedures of Example 10B Part B. HPLC-MS tR = 1.16 min. (UV nm); mass calculated for the formula C 4 H 21 N 3 O 2 S 295.1, LCMS observed m / z 296.2 (M + H).

Part D: i To Compound 2169 (35 mg) in methanol (2 ml) was added HCI / 4.0 M dioxan (1 ml) with ice bath cooling. The mixture of The reaction was stirred for 1.5 hours and concentrated. The, residue was suspended in DCM (5 mi) and concentrated to give 2170 impure. The material was used without purification.

Part B: To Compound 2172 (2.1 g, 11.6 mmol) in DCM (25 mL) was added DIEA (4.2 mL, 24 mmol) and a solution of BOC-anhydride (3.03 g, 13.9 mmol) in DCM ( 25 mi) with ice bath cooling. The reaction mixture was slowly warmed to room temperature and stirred for the night. The reaction mixture was washed with water, 0.1 N HCI, bicarbonate solution and brine, dried over sodium sulfate and concentrated. Purification by column chromatography (Si02 charged with ethyl acetate and eluted with 30% ethyl acetate / hexane to ethyl acetate) gave 2173 (2.66 g) as an oil. 1 H NMR (400 MHz, CDCl 3) d rotamers 4.40-4.29 (m, 2H), 3.81 and 3.80 (s, 3H), 3.75 -3.64 (m, 1 H), 3. .57-3.50 (m, H) , 2.35 (m, 1 H), 2.1 1 (m, 1 H), 1.48 and 1.44 (s, 9H).

Part C: To Compound 2173 (2.66 g, 10.8 mmol) n DCM (50 mL) in an ice bath was added dropwise triethylamine (1.66 mL, 1.9 mmol) and methanesulfonyl chloride (1.09 mL, 14.1 mmol) . The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was quenched with ice water and the layers separated.

The aqueous layer was extracted with DCM. The combined organic layers were washed with 0.1 N HCl and brine, dried over sodium sulfate and concentrated. Purification by column chromatography (S1O2, 50% ethyl acetate / hexanes) gave 2174 (3.36 g) as an oil. HPLC-MS t R = 1.49 min. (ELSD); mass calculated for the formula C12H21 NO7S 323.1, LCMS observed m / z 346.1 (M + Na). pyridine (0.162 ml, 2.0 mmol) and 150% peroxide were added dropwise. hydrogen (0.161 ml, 2.63 mmol). The ice bath was removed and the mixture The reaction was stirred at room temperature for 1.25 hours. The mixture of The reaction was diluted with ethyl acetate (50 ml), washed with 0.1 N HCl, bicarbonate solution I and brine, dried over sodium sulfate and concentrated to a give 2176 (272 mg) as a yellow oil. HPLC-MS t R = 1.81 min. (MS); i mass calculated for the formula C-i2Hi9N0 241.1, LCMSj observed m / z 264.1 (M + Na).

Part F: Compound 2177 (123 mg) was prepared from 2176 (202 mg, 0.84 mmol) according to the procedure described in Example 10B Part B. HPLC-MS t R = 1.70 min. (MS); mass calculated for the formula CnH16CIN03 245.1, LCMS observed m / z 264.1 (M + Na Part G: Compound 2178 (48 mg) was prepared as described in Example 51 B Part C of compound 2177 (123 mg, 0.5 mmol). HPLC-MS t R = 1.12 min. (UV254 nm); mass calculated for the formula C 13 H 19 N 3 O 2 S 281.1, LCMS observed m / z 282.1 (M + H).

Part H: A mixture of compound 2178 (48 mg, 0.17 mmol) was stirred, TFA (2 mL) and DCM (2 mL) at room temperature durante for 1 hour. The solvents were removed and the residue was dissolved in DCM (5 mL) and concentrated to give 2179 (70 mg). H NMR (400 MHz, CDCl 3) d 9.58 (bs, NH), 6.75 (s, 1 H), 6.26 (d, 1 H, J = 6.3 Hz), 5.92 (d, 1 H, J = 7.5 Hz), 5.77 (m, 1 H), 4.43 (d, 1 H, J = 17.2 Hz), 4.28 (d, 1 H, J = 17.2 Hz), 3.1 1 (s, 3H).

The combined extracts were washed with 1 N HCl, saturated sodium bicarbonate and water, dried over sodium sulfate and concentrated. The ! purification by column chromatography (SiO2, 50% ethyl acetate / hexanes) gave 2181 (0.200 g). HPLC-MS t R = 1.126 min. (UV254 nm); mass calculated for the formula C 0H NO 161.1, LCMS observed m / z 162 (M + H).

Part B: Compound 2181 (0.200 g, 1.24 mmol) was dissolved in THF (10 mL) and a borane solution (2.5 'M in THF, 3 mL) was added dropwise.

The solution was stirred at reflux overnight. The reaction was deactivated with a solution of 1 M sodium hydroxide (2 ml) and methanol (2 ml) and the reflux for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organics were washed with baking soda saturated sodium, water, dried over sodium sulfate and concentrated to give 2182 (65 mg). HPLC-MS tR = 0.595 min. (UV254 nm); calculated mass for the formula Ci0H N 147.1, LCMS observed m / z 14 ^ 8 (M + H).

Part A: The compound 2184 was prepared using a modification of the procedure in J. Med. Chem. 1994, 37, 23, 3878-3881. Compound 2183 i (2.0 g, 12.9 mmol) was dissolved in methylene chloride and cooled in an ice bath. Triethylamine (3.61 ml, 26 mmol) was added followed by the dropwise addition of TMSOTf (2.81 ml, 15.5 mmol). The reaction heated up room temperature and stirred for 30 minutes. It was added slowly saturated sodium bicarbonate to deactivate the reaction and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate. In a separate flask added T1CI4 (1 M in toluene, 20 mL) to methylene chloride (80 mL) at -78 ° C. Acetone (1.2 g, 22 mmol) was added and stirred for 2 minutes. The silylenol ether of the above was added and the reaction was stirred for 4 hours. After warming to room temperature, the reaction was quenched with saturated sodium bicarbonate and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and evaporated. Purification by column chromatography (SiO; 33% ethyl acetate / hexanes) gave 2184 (600 mg). ?? NMR (400 MHz, CDCl 3) d 7.90 (d, 1 H), 7.80 (d, 1 H), 7.55 (d, 1 H), 7.40 (t, 1 H), 3.15 (s, 2 H), 1 .4o | (s, 6H).

Part B: Compound 2184 (600 mg, 2.84 mmol) was dissolved in methylene chloride (2 mL) and pyridine (2 mL) and cooled in an ice bath. TFAA (0.894 g, 4.26 mmol) was added dropwise and stirred 1 hour at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layers were washed with 1 N HCl, saturated sodium bicarbonate, brine, dried over sodium sulfate, and concentrated. The residue was dissolved in methylene chloride (5 mL) and DB¡U (0.5 mL) was added and stirred for 1 hour at room temperature. The reaction mixture was partitioned between methylene chloride and water. The organic layers were washed with 1 N HCl, saturated sodium bicarbonate, brine, dried over! Sodium sulfate, and concentrated. Purification by column chromatography (S1O2, 10% ethyl acetate / hexanes) gave 2185 (460 mg). 1H NMR (400 MHz, CDC) d 7. 90 (d, 1 H), 7.80 (d, 1 H), 7.50 (d, 1 H), 7.40 (t, 1 H), 6.70 (m, 1 H), 2.20 (d, 3 H), 2. 05 (d, 3H).

Part C: Compound 2185 (460 mg, 2.38 mmol) was dissolved in j-nitromethane (295 mg, 4.76 mmol) and benzyltrimethylammonium hydroxide (40% by weight in MeOH, 200 mg) and stirred for 2 hours at room temperature. I The reaction was quenched with acetic acid (1 ml) and divided between diethyl ether and Water. The organic layer was dried over sodium sulfate and concentrated to give 2186 (550 mg). H NMR (400 MHz, CDCl 3) d 7.90 (d, 1 H), 7.80 (d, 1 H), 7. 58 (d, 1 H), 7.40 (t, 1 H), 4.70 (s, 2H), 3.10 (s, 2H), 1.30 (s, 6H).

Part D: i Compound 2187 was prepared according to procedure i in Chem. Ber. 1958, 91, 1978-1980, 1 H NMR (400 MHz, CDCl 3) d 7.38 (m, 1 H), 7.22 (m, 2H), 7.18 (m, 1 H), 4.30 (m, 1 H), 2.90-2 80 (dd, 2H), 2.00 (m, 1 H), 1.50 (m, 1 H), 1.15 (d, 6H).

EXAMPLE 51 G 219Q Part A: Compound 2186 (500 mg, 1.96 mmol and ammonium chloride (104 mg, 1.96 mmol) were dissolved in THF (5 mL) and water (5 mL) and cooled in an ice bath. Zn powder (637 mg, 9.8 mmol) was added in portions and It stirred during the night. The reaction mixture was divided between acetate ethyl and water. The organic layers were washed with sodium bicarbonate Saturated, brine, dried over sodium sulfate, and concentrated. The residue it was dissolved in methylene chloride (10 ml) and m-CPBA (510 mg, 2.94 g) was added. mmol) and stirred for 2 hours. The reaction mixture was divided between methylene chloride and water. The organic layers were washed with bicarbonate saturated sodium, brine, dried over sodium sulfate, and concentrated to give 2188 (300 mg). H NMR (400 Hz, CDCl 3) d 7.80 (m, 1 H), 7.65 (m, 2H), 7.40-7.30 (m, 2H), 3.80 (t, 2H), 2.80 (t, 2H), 1.20 (sj 6H).

Part B: Compound 2188 (300 mg, 1.35 mmol) was dissolved in THF (10 mL). mi) and MeMgBr (3M in THF, 5 rrjil) was added by drip. After shaking for 30 minutes at room temperature the reaction mixture was divided between ethyl acetate and water. The organic layers were washed with bicarbonate of saturated sodium, brine, dried over sodium sulfate, and concentrated to give 2189 (280 mg). H NMR (400 MHz, CDCI3) d 7.53 (t, 1 H), 7.42 (m, 1 H), 7.30-7.20 (m, 2H), 3.20 (m, 2H), 2.00 (m, 2H), 1.55 (s, 3H), 1 .20 (s, 3H), 1.15 (s, 3H).

Part C: Compound 2189 (280 mg, 1.26 mmol) was dissolved in 1 N HCl (10 ml) and Zn powder (0.5 g) was added. The reaction mixture was stirred TMS solution of diazomethane in hexanes (2M, 8.4 ml) until a yellow color persisted. The reaction was quenched with acetic acid until the color cleared and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with 1 N HCl, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give 2192 (3.1 g). The product was used without purification.

Part B: Diisopropylamine (3.9 mL, 28 mmol) was dissolved in THF (20 mL) and cooled to -40 ° C. A solution of n-Buli (2.5M in hexanes, 8.9 ml) was added dropwise and the reaction was stirred for 30 minutes. Compound 2192 (3.1 g, 11.1 mmol) dissolved in THF (10 mL) was added dropwise at -78 ° C and stirred for another 30 minutes. Iodomethane (3.1 g, 22.4 mmol) was added dropwise and the reaction was stirred for an additional hour. The reaction was warmed to room temperature and quenched with brine and extracted with ethyl acetate. The organic layers combined! they were washed with water, brine, dried over sodium sulfate and concentrated to give 2193 (2.5 g). H NMR (400 MHz, CDCl 3) d 7.40-7.20 (m, 5H), 5.20-5.00 (m, 2H), 3.70-3.40 (d, 3H), 3.70-3.60 (m, 2H), 2.20 (m, 1 H), 1.90 (m, 3H), 1.60 (d, 3H).

Part C: Diisopropylamine (1.24 ml, 8.85 mmol) was dissolved in THF (10 ml) and cooled to -40 ° C. A solution of n-Buli (2.5M in hexanes, 3.5 ml) was added dropwise and the reaction was stirred for 30 minutes. This solution was added dropwise to a solution of compound 2193 (450 mg, 1.61 mmol) and chloroiodomethane (1.12 g, 6.44 mmol) in THF (10 mL) at -78 ° C. The reaction was stirred for 30 minutes and then deactivated by the dropwise addition of acetic acid (1 mL) in THF (50 mL). After stirring for 10 minutes, the reaction mixture was partitioned between ethyl acetate and water. The organic layers were washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, 25% ethyl acetate / hexanes) gave 2194 (330 mg). 1 H NMR (400 MHz, CDCl 3) d 7.40-7.20 (m, 5H), 5.20-5.00 (m, 2H), 4.40-4.00 (m, 2H), 3.80-3.60 (m, 2H), 2.20 (m , 1 H), 2 00-1.8 (m, 3H), 1.60-1.40 (m, 3H).

Part D: Compound 2194 (175 mg, 0.59 mmol) was dissolved in DMF (5 mL) and thiourea (91 mg, 1.2 mmol) was added and stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layers were washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and reconciled. Purification by column chromatography (SiO2, 50% ethyl acetate / hexanes) gave 2195 (15 mg). HPLC-MS t R = 1.17 min. (UV254 nm) mass calculated for the formula C16H 9N302S 317.1, LCMS observed m / z 318.1 (M + H).

Part E:! Compound 2195 (15 mg, 0.36 mmol) was dissolved in 30% HBr / AcOH (2 mL) and stirred for 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in water and triturated with diethyl ether. The aqueous layer was lyophilized to give 2196 as a di-HBr salt (100 mg). in dioxane (2 ml) and methanol (0.5 ml) and stirred at room temperature for 1 hr. The reaction mixture was concentrated and triturated with diethylether to give 2201 (74 mg) as an HCl salt. H NMR (400 Hz, DMSO-d6) d . 00 (bs, 1 H), 8.70 (bs, 1 H), 8.30 (s, 1 H), 6.70 (d, 1 H), 4.60 (bs, 1 H), 3.40 (m, 2H), 2.75 (s, 3H), 2.40 (m, 1 H), 2.00-1.80 (m, 3H).

EXAMPLE 51 J Part A Part B i * 2202 '2203 2204 Part A: Compound 2203 was prepared according to a procedure described in J. Org. Chem. 1991, 57, 7034-7038.

Part B: A mixture of 2203 (200 mg. 1. 42 mmol) and zinc powder (278 mg, 4.25 mmol) in hydrochloric acid concentrated (1.4 mi) and water (5.8 mi). The mixture was turned basic with pills of potassium hydroxide, decanted and the aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, they were dried over sodium sulfate and concentrated to give 2204 as a yellow sticky solid (95 mg). 1 H NMR (400 MHz, GDCI 3) d 3.35 (m, 2H), 1. 88 (s, 2H), 1 .66 (s, NBoc 2205 2206 2207 2208 Compound 2205 was prepared using procedures described in Example 10B.

Part A: To the solution of 2-methylaminothiazole 2205 (100 mg, 0.35 mmol) and DMAP (135 mg, 1.0 mmol) in THF (5 mL), 'Boc20 (218 mg, 1.0 mmol) was added. at room temperature. The resulting mixture was stirred overnight and then diluted with ethyl acetate (30 mL). The organics were washed with water, brine and dried over sodium sulfate and concentrated. The residue, which was purified by column chromatography (S02, 20% ethyl acetate / hexanes), gave the protected product 2206 (130 mg) as a semi-oil. HPLC-MS tR = 2.42 min. (UV254 nm); mass calculated for formula C 8H29N304S 383.2, LCMS observed m / z 384.1Í (M + H).

Part B: The solution of thiazole 2206 (150 mg, 0.39 mmol) in THF (5 ml) cooled to -78 ° C, and n-Buli was slowly added (2.5 M in hexane, 0.19 mi, 0.47 mmol). The resulting mixture was stirred at -78 ° C for 30 min, and then iodomethane (0.1 ml, 1.55 mmol) was added. The mixture was stirred during Another 30 min., followed by the addition of saturated NH 4 Cl solution (15 ml).

The aqueous layer was extracted with ethyl acetate. The combined organics are washed with water, brine, dried over sodium sulfate and they concentrated. Purification by column chromatography (Si02, 10% ethyl acetate / hexanes) gave thiazole recovered 220.6 (36 mg) and 2207 (100 mg). HPLC-MS t R = 2.51 min. (UV254 nm); mass calculated for the formula Ci9H31N304S 397.2, LCMS observed m / z 398.2 (M + H).

Part C: To a solution of 5-methylthiazole 2207 (10.0 mg, 0.25 mmol) in 1 dioxane (2 mL) was added HCl (4N in dioxane, 4 mL) followed by water (0.5 mL).

The mixture was stirred at room temperature for 1 hour and concentrated. He Resulting residue 2208 (72 mg) was dried under vacuum and used in the next step without additional purification.

C18H28BrN304S 461.1, LCMS observed m / z 462.1 (M + lll). Part B: i on sodium sulfate, were concentrated and purified by column chromatography (Si02, 10% ethyl acetate |) / hexanes) to give 5-methylsulfide-thiazole 2211 (137 mg) and thiazole 2206 (38 mg) was recovered. HPLC-MS R = 2.62 min. (UV254 nm); mass calculated for the order Ci9H31N304S2 429. 2, LCMS observed m / z 430.1 (M + H).

Part B: A mixture of sulphide 2211 was stirred at room temperature (137 mg, 0.32 mmol) and m-CPBA (-77%, 230 mg, 1.0 mmol) in dichloromethane (10 mi) during the night. Ethyl acetate (80 ml) was added to dilute the mixture and the organic ones were washed with twice saturated pollution of sodium bicarbonate, followed by brine, dried over sodium sulphate sodium, they concentrated. The residue was purified by chromatography on column (SiO2, 20% ethyl acetate / hexanes), and gave 5-methylsulfone-thiazole 2212 (141 mg). HPLC-MS t R = 2.62 min. (UV254 nm); mass calculated for formula 461.2, LCMS observed m / z 406.1 (M + H- f-Bu).

Part C: j Compound 2213 (10 mg) was prepared from 2212 (141 mg, 0.30 mmol) according to the procedure described in Example 51 K Part C. HPLC-MS tR = 0.63 min. (UV254 nm); mass calculated for the formula i C9Hi5N302S2 261 .1, LCMS observed m / z 262.0 (M + H).

EXAMPLE 51 2214 arle 2215 Starting derivative of pyrroline 2214 was prepared by known methods (Billet, M, Schoenfelder, A, Klotz, P .; Mann, A .. Tetrahedron Letters, 2002, 1453).

Part A: Trimethylsilyl iodide (0.44 g, 2.24 mmol) was added dropwise to a solution of 2214 (0.47 g, 1.5 mmol, 20 ml CH 2 Cl 2) at room temperature and stirred for 3 hours. The mixture was cooled to 0 ° C before deactivating with methanol (5 ml). The solvent was removed at reduced pressure to give crude amine 2215, which was used without further purification. mmol) and potassium carbonate (0.13 g, 0.94 mmol) and stirred for 15 minutes. minutes To this mixture was added osmium tetraoxide (0.005 g, 0.02 mmol) and it was stirred for 16 h. The reaction was diluted with ethyl acetate (50 ml) and the The organic extracts were washed once with brine (10 ml), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to give intermediate 2220. (0.1 g, 91%). j Part B: Diol 2220 (0.1 g, 0.28 mmol) was dissolved in acetone (5 ml) and added 2,2-dimethoxypropane (0.045 g, 0.43 mmol), followed by the addition of a catalytic amount of p-toluenesulfonic acid (0. D6 g, 0.03 mmol). The The reaction mixture was stirred at room temperature for 14 h. The solvent was removed in vacuo to give a crude product that was purified by preparative chromatography of silica gel using ethyl acetate / hexane (1/3) as the eluting solvent to give 2221 (0.075 g, 68%).

Part C: I Intermediary 2221 (0.06 g, 0.15 mmol) was dissolved in CH2CI2 (0.5 ml), followed by the addition of trimethylsilyl iodide (0.034 ml, 0.24 mmol) at 0 ° C. The mixture was stirred at t.a. for 2 hours. The reaction it was quenched with methanol (5 ml) and stirred for another 2 hours. The mixture of The reaction was concentrated to give the crude amine 2222, which was used without additional purification.

EXAMPLE 51 Q Part A: Compound 2223 (2.2 g, 13.9 mmol) was dissolved in methylene chloride (25 mL) and triethylamine (3.9 mL, 27.18 mmol), DMAP (100 mg), and di- -butyldicarbonate ( 3.33 g, 15.3 mmol). The reaction mixture was stirred for 5 hours at room temperature and then! it was diluted with water and methylene chloride. The organic layers were washed with 1 N HCl, saturated sodium bicarbonate, water, brine, dried over sodium sulfate and concentrated. Purification by chromatography on the column (SiO2, 33% ethyl acetate / hexanes) gave the desired product j3.0 g). H NMR (400 MHz, CDCl 3) d 4.60 (m, 1 H), 4.20 (q, 2 H), 2.70-2.60 (m, 1 H), 2.50 (m, 1 H), 2. 40-2.30 (m, 1 H), 2.05 (m, 1 H), 1.50 (s, 9H), 1.20 (t, Part B: Compound 2162 (630 mg, 2.44 mmol) was added to f-butoxy-bis (dimethylamino) methane (2224) (0.705 mL, 3.42 mmol, and stirred at 80 ° C. overnight. The excess reagent was removed under reduced pressure to give 2225 which was used without further purification (750 mg). 1 H NMR (400 MHz, CDCI3) d 7.10 (m, 1 H), 4.50 (m, 1 H), 4.30-4.20 (m, 2H), 3.30 (m, 1 H), 3.00 (s, 6H), 2.80 (m, 1 H), 1.50 (s, 9H), 1.30 (m, 3H).

Part C: Compound 2225 (750 mg, 2.4 mmol) was dissolved in ethyl acetate ethyl (12 ml) and 10% Pd-C (200 mg) was added under an argon atmosphere.

The reaction mixture was placed under a hydrogen atmosphere and stirred for 96 hours at room temperature. The reaction was filtered and the solvent was evaporated Purification by column chromatography (SiO2, 33% ethyl acetate / hexanes) gave the desired product (35.0 mg). H NMR (400 MHz, CDCl 3) d 4.50 (m, 1 H), 4.25 (q, 2H), 2.60 (m, 2H) j 1.65 (m, 1 H), 1.50 (s, 9H), 1.32 (t, 3H), 1.28 (d, 3H).

Compound 2226 (200 mg, 0.73 mmol) was dissolved in THF (2 ml) and dimethyl borane sulfide (2M in THF, 1.5 ml) was added. The mixture of The reaction was stirred for 40 hours and then cooled in an ice bath and deactivated slowly with methanol. The solvent was evaporated and the residue purified by column chromatography (SiO2, 33% acetate ethyl / hexanes) to give the desired product (80 mg); ? NMR (400 MHz, CDCI3) d 3.95 (m, 1 H), 3.75-3.50 (m. 3H), 2.75 (t, 1 H), 2.25 (m, 2H), 1.50 (s, 9H), 1 .20 (m, 1 H), 1.00 (d, 3H).

Part E: Compound 2227 (70 mg, 0.32 mmol) was dissolved in acetone (3 mi) and Jones reagent drip (1 ml) was added. The reaction mixture was stirred overnight and then deactivated with methanol. The mixture is then filtered and concentrated. The residue was dissolved in saturated sodium bicarbonate and it was washed with diethyl ether. The aqueous layer was acidified to pfj 2 and then extracted with ethyl acetate. The ethyl acetate layers were dried over sodium sulfate. sodium and concentrated to give the desired product (p5 mg). 1H NMR (400 MHz, CDCl 3) d 4.30-4.20 (m, 1 H), 3.80-3.70 (m, 1 H), 2.95 (m, 1 H), 2.50-2.30 (m, 1 H), 2.25 (m, 1 H), 1.80-1.60 (m, 1 H), 1.50 (d, 9H), 1 .05 (m, 3H).

Part F: I Compound 2228 (370 mg, 1.62 mmol) was dissolved in toluene (2 ml) and methanol (2 ml) and cooled in an ice bath. A solution of I trimethylsilyl diazomethane (2M in hexanes, 1.5 ml) was trickled. The The solution was stirred for 1 hour and then concentrated. The residue dissolved in ethyl acetate and water. The organic layer was washed with 1 N HCl, saturated sodium bicarbonate, brine, dried over sodium sulfate, and concentrated to give the methyl ester 2229 (310 mg).

Part G: Diisopropylamine (1.0 ml) in THF (10 ml) was dissolved in a separate flask and cooled to -78 ° C. A solution of (n-butyl lithium (2.5 M in hexanes, 2.55 ml) was added dropwise and stirred for 30 minutes, this solution was added dropwise to a solution of methyl ester 2229 (310 mg, 1.27 mmol) and chloroiodomethane ( 0.9 g, 5.08 mmol) in THF (5 mL) at -78 ° C. After 30 minutes the reaction was quenched by acetic acid (1 mL) in THF (50 mL) .The reaction mixture was heated to room temperature. The organic layer was dried over sodium sulfate and concentrated, purification by column chromatography (SiO2, 25% ethyl acetate / hexanes) gave the desired alpha-chloro ketone. 2230 (150 mg).

Water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Purification by column chromatography (Si02, ethyl acetate) gave the desired product 2231 (85 mg). HPLC-MS t R = 1.35 min. (UV254 nm); mass calculated for the formula C 5H25N302S 311.1, LCMS observed m / z 312.1 (M + H). ! DMSO-d6) d 9.50 (bs, 1H), 8.70 (bs, 1H), 7.80 (bs, 1H), | 6.70 (s, 1H), 4.50 (m, 1H), 3.30-3.20 (m, 2H), 2.75-2.65 (m, 2H), 2.40 (m, 2H) |, 1.70 (m, 1H), 1.15 (t , 3H), 1.10 (d, 3H). The following compounds were prepared using the procedures described above. eliminated toluene under reduced pressure. The residue was divided between acetate ethyl and water. The combined organic layers were dried over sodium sulfate sodium and concentrated to give 2274 (190 mg). The material was used without additional purification. HPLC-MS tR = 2.21 min. (UV254 nm); calculated mass for the formula C19H24N203 328.2, LCMS observed m / z | 329.2 (M + H).

Part C: Compound 2274 (190 mg, 0.584 mmol) I was dissolved in chloride of methylene (4 ml) and TFA (1 ml) and stirred for 30 minutes. The solvents they were removed to give 2275 as the TFA salt (190 mg).

EXAMPLE 52B Part A: Compound 559 (100 mg, 0.35 mmol) was dissolved in dioxane (5 mg). my). Then boronic acid 2276 (13 mg, 0.52) was added to the solution. mmol), Pd2 (dba) 3 (27 mg, 0.03 mmol), triphenylphosphine (13.7 mg, 0.052 mmol),? potassium phosphate (148 mg, 0.70 mmol), and stirred at reflux overnight. The reaction mixture was cooled to room temperature and filtered, and the Toluene was removed under reduced pressure. The residue was divided between acetate ethyl and water. The combined organic layers were dried over sodium sulfate sodium and concentrated. Purification by column chromatography (Si02, 25% ethyl acetate / hexanes) gave 2277 (80 mg). 1 H NMR (400 MHz, CDCl 3) d 7.50 (d, 1 H), 7.45 (m, 2H), 7.30-7.15 (m, 5H), 7.20-7.10 (m, 2H), 7. 00-6.90 (m, 3H), 4.30 (d, 2H), 1.45 (s, 9H).

Part B: Part A: Compound 2279 (50 mg, 3.08 mmol) was dissolved, cesium carbonate (3.0 g, 9.25 mmol), and 2-bromophenol | (527 mg, 3.08 mmol) in DMF (15 ml) and stirred at 60 ° C for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layers were washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, and they concentrated. Purification by column chromatography (S1O2, % ethyl acetate / hexanes) gave 2280 (400 mg 1 H NMR (400 MHz, I CDC) d 7.50 (m, 1 H), 7.20 (m, 1 H), 6.85 (d, 1 H), 6.80 (t, 1 H), 3.90 (d, 2H), 2. 40 (m, 1 H), 1.85 (m, 2H), 1.60-1.45 (m, 4H), 1.40 (m, 2H).

Part B: Compound 2280 (157 μg, 0.50 mmol) was dissolved, compound 568 (250 mg, 1.02 mmol), Pd2 (dba) 3 (9.1 mg, 0.01 mmol), S-PHOS (8.3 mg, 0.02 mmol), potassium fluoride (350 mg, 3.0 mmol) in dioxane (8 mL) and stirred at reflux overnight. The reaction mixture was cooled to Room temperature was filtered and toluene was removed under reduced pressure.

The residue was partitioned between ethyl acetate and water, The combined organic layers were dried over sodium sulfate and concentrated. The purification by column chromatography (SiO ?, 10% acetate) ethyl / hexanes) gave 2281 (200 mg). 1 H NMR (400 MHz, CDCl 3) d 7.60 (m, 2H), 7. 40 (m, 2H), 7.30 (m, 2H), 7.00 (m, 2H), 4.60 (d, 2H) j3.85 (d, 2H), 2.35 (m, ¡1 H), 1.80 (m , 2H), 1.60 (m, 4H), 1.30 (m, 2H). j Part C: Compound 2281 (100 mg, 0.317 mmol) was dissolved in MeOH (5 ml) and a saturated solution of potassium carbonate (1 ml) was added and the The reaction was stirred for 3 hours. The re-interaction mixture was divided between ethyl acetate and water. The organic layers were washed with baking soda reduced pressure. The residue was partitioned between ethyl acetate and water. The layers The combined organic extracts were dried over sodium sulfate and concentrated. The purification by column chromatography (Si02, 5% acetate) ethyl / hexanes) gave 2283 (240 mg). 1H NMR (400 MHz, DCI3) d 7.70-7.58 (m, i 4H), 7.27-7.23 (m, 1 H), 6.75-6.70 (m, 2H), 4.05 (q, 2H), il .38 ( t, 3H). gave compound 2285 as an oil (0.17 g, 5.7%).

Part B: stirred a mixture of compound 2285 (0.17 g, 0.57 mmol) and LiOH aq. 1 M (1 mL, 1 mmol) in dioxane (3 mL) at room temperature during 18 hours. The reaction mixture was concentrated and water (2 ml) was added and extracted with CH2Cl2 (2.0 mL). The organic layer was dried over MgSO 4, filtered and concentrated. Purification by column chromatogrlaphy (S1O2, 1% MeOH / CH2Cl2 followed by 5% MeOH / CH2Cl2) from compound 2286 as an oil (0.085 g, 71%).

EXAMPLE 52F Pa 2290 2291 2292 Part F Part A: To a solution of compound 2287 (20.6 g, 136.4 mmol) in CH2Cl2 (200 mL) was added triethylamine (27.5 g, 272.8 mmol) and the reaction mixture was cooled to 0 ° C, and added (Boc) 20 (32.7 g, 150 mmol). The mixture was stirred at 0 ° C for 10 minutes and then warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with NH CI aq. sat (100 mL) and dried over MgSO4, filtered and concentrated. Purification by column chromatography (S1O2, 10% EtOAc / hexane followed by 15% EtOAc / hexane) gave compound 2288 as a white solid (32.7 g, 95%).

Part B: added triethylamine (8.8 mL, 63 mmol). The reaction mixture was cooled to 0 ° C and (Boc) 20 (3.77 g, 17.3 mmol) was added. The mixture was stirred room temperature for 1 hour. The reaction mixture was then washed with water (100 ml), NaHCO3 sat. (25 mi) and brine (1? | Mi). The organic layer i was dried over MgSO4, filtered and concentrated. Purification by i column chromatography (Si02, 10% EtOAc / hexanb followed by 15% EtOAc / hexane and 20% EtOAc / hexane) gave compound 2290 as a oil (1.85 g, 62% in two steps).

I Part D: To a solution of compound 2290 (0.45 g, 1.9 mmol) in CH 2 Cl 2 (10 mL) was added a solution of NBS (0.34 g, 1.9 mmol) in CH 2 Cl 2 (10 mL) using a drip funnel. Stirred at room temperature for 3.5 hours and then washed with 10% H2SO4 aq. (10 ml) The organic layer is dried over MgSO4, filtered and concentrated. The purification by column chromatography (SiO2, 100% CH2Cl2 followed by 1% EtOAc / CH2Cl2) gave compound 2291 (0.13 g, 21%).

Part E: To a solution of compound 2291 (0.22 g, 0.7 mmol) in acetone (6 ml) was added K2C03 (0.288 g, 2.1 mmol) followed by a solution of methyl iodide (0.065 ml, 1.05 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The mixture was filtered and concentrated until it dried up. The residue was dissolved in EtOAc (20 mL) and washed with water (2 ml) followed by brine (2 ml). The organic layer was dried over MgSO 4, filtered and concentrated to give compound 2292 (0.2 g, 86%).

Part F: j The compound 2293 was prepared following the procedure described in Example 52E, Part A. 2293 median 2292 2295 Part A: Compound 2295 was prepared from compound 2292 2293 by TFA as described in Example 1.

Part A: Compound 2289 was transformed into compound 2296 by the procedure described in Example 52F Part C and using trifluoroacetic anhydride in place of Boc20.

Part B, C, D: Compounds 2297, 2298 and 2299 were prepared following the procedures described in Example 52F, Part D, E and F, using benzyl bromide and cyclopropyl bromide instead of methyl iodide.

Part E: Compound 2300 was prepared from compound 2299 i following the procedures described in Example 52E, Part B.

EXAMPLE 521 Part B: Compound 2309 (15 g, 80 mmol) was cooled to 0 ° C, and added trifluoroacetic anhydride (35 mL, 250 mmol) slowly under argon. The The mixture was allowed to stir at room temperature for 30 min, then a 55 ° C for 30 min., After which it was cooled to 0 ° C in a bath of ice. Aqueous NaHCO3 solution (10%, 15.0 mL) was added slowly, with watch out. Once the addition was complete, the mixture was allowed to stir room temperature for 6 h. The solution was extracted with dichloromethane, dried over Na2SO4, and concentrated. The residue was purified by i i flash column chromatography on silica gel (EtOAc / hexane 50:50), giving the product 2310 as a white solid ^ 9.2 g, 61%). 1H NMR (400 MHz, CDCI3) d 8.61 (d, J = 1 .9 Hz, 1 H), 7.80 (dd, | J = 7.9, 2.4 Hz, 1 H), 7. 19 (dd, J = 8.3, 0.9 Hz, 1 H), 4.73 (s, 2H), 3.37 (br s, 1 H).

Part C: To a solution of 2310 (9.0 g, 47.86 mmol) in toluene (40 mL) and PBr3 (5 mL, 52.6 mmol) was added dropwise. Once the addition is complete, the The mixture was stirred at 100 ° C for 2 h. It was cooled to room temperature; the solid was collected by filtration to give 2311 as a solid yellow (HBr salt, 14.83 g, 93%). 1H NMR (400 MHz, DMSO-d6) d 9.74 (br, 1 H), 8.66 (d, J = 1.8 Hz, 1 H), 8.06 (dd, J = 8.4, 1.4 Hz, 1 H), 7.19 (dd, J = 8.3, 0. 9 Hz, 1 H), 4.67 (s, 2H).

Part D: To a solution of 2311 (14.83 g, 44.7 mrnol) in DMF at 0 ° C was slowly added CS2CO3 (29.1 g, 89.4 mrnol) and potassium phthalimide (9.1 g, 49. 2 mrnol). The reaction mixture was allowed to stir at room temperature environment for 6h, after this time the solvent evaporated until that dried up The resulting solid was washed with H20. The solid cake is recrystallized from hot EtOH, giving compound 2312 (7.64 g, 54%) as a white solid. H NMR (400 MHz, DMSO-d6) d 8.54 (d, J = 1.9 Hz, 1 H), 8. 00 (dd, J = 8.4, 2.3 Hz, 1 H), 7.90-7.83 (m, 4H), 7.41 (d,, J = 7.8 Hz, 1 H), 4.88 (s, 2H).

Part E: A mixture of Pd (OAc) 2 (45 mg, 0.2 mrnol), 2-bis (tert-butyl) phosphino-biphenyl (120 mg, 0.4 mrnol), compound 2312 (3.17 g, 10 mrnol) was charged. 2-trifluoromethoxyphenyl boronic acid (2.47 g, 12 mrnol) and KF (2.1 g, 36 mrnol), in a 250-ml balloon flask. Then THff (30 ml) was added under argon, and The reaction mixture was allowed to stir at 50 ° C overnight, then of which it was cooled to room temperature, filtered through Celite and He concentrated. Flash column chromatography on silica gel I (EtOAc / hexane (5:95)) gave compound 2313 (3.27 g, 82%) as a solid.

White. H NMR (400 MHz, CDCl 3) d 8.59 (d, J = 1.5 Hz, 1 H), 7.91 -7.89 (m, 2H), 7.77-7.73 (m, 3H), 7.44-7.34 (m, 5H), 5.08 (s, 2H). , Part F: Compound 2314 was prepared according to the same procedure as in Example 52M Part A. HPLC-Mp R = 1.74 min. (UV254 nm); mass calculated for the formula C2iHi3F3N204 41 (4.1, LCMS observed m / z 415.0 (M + H).

Part G: To a solution of compound 2314 (210 mg, 0.51 mmol) in EtOH (10 mL) was added hydrazine (0.5 mL). The solution was refluxed for 3 h, then cooled to room temperature. After removal of the precipitate by filtration, the solution was concentrated. The resulting residue was extracted with Et2O and concentrated, while compound 2315, as a pale yellow oil (160 mg, 91%). HPLC-MS t R = 1.74 min. (UV254 nm); mass calculated for the formula C 13 H 1 F 3 N 2 O 2 284.1, LCMS observed m / z 285.1 (M + H). ! Part A: To compound 2314 (200 mg, 0.48 mmol) ejn acetonitrile (1 ml) was added Et 3 N (0.094 ml, 0.672 mmol) and subsequently Me 3 SiCl (0.225 ml, i 1.69 mmol) under argon. The reaction mixture was stirred at 80 ° C for 48 h,, time after which it was cooled to room temperature and concentrated to the vacuum The residue was dissolved in EtOAc, washed with saturated NaHCO3, brine, dried (Na2SO4), and concentrated. Flash column chromatography (EtOAc / hexane 40:60) gave compound 2316 (130 mg, 64%). HPLC- MS R = 2.06 min. (UV254 nm); mass calculated for the formula C22H12F3N3O3 423. 1, LCMS observed m / z 424.0 (M + H).

Part B: Compound 2317 was prepared using the procedure described in Example 52M Part G. H NMR (400 MHz, CDCI3 d 7.77 (d, J = 8.1 Hz, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.47-7.42 (m, 4H), 4.12 (s, 2H). 1.98 (br s, 2H).

EXAMPLE 520 2314 231 S 2319 Part A: Phosphorus trichloride (0.330 mL, 3.62 mmol) was added to a solution of 2314 (300 mg, 0.72 mmol) in CHCl3 (1 mL). The reaction mixture was stirred at 60 ° C overnight, time after which it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3, brine, dried (Na2SO4), and concentrated. Flash column chromatography (EtOAc / hexane 30:70) gave 2318 (180 mg, 58%). HPLC-MS t R = 2.33 min. (UV264 nm); mass calculated for the formula C2iH12CIF3N203 432.1, LCMS observed m / z 433.0 (M + H).

Part B: Compound 2319 was prepared using the procedure described in Example 52M Part G. HPLC-MS tR = 1.26 min. (UV254 nm); mass calculated for the formula Ci3H 0CIF3N2O 302.0, LCMS observed m / z 303.0 (M + H).

Y Compound 2321 was prepared according to the procedure described in Example 52M, Part D. 1H NMR (400 MHz, DMSO-d6) d 8.19 (d, J = 8.0 Hz, 1 H), 7.92-7.84 (m, 4H), 7.41 (d, J = 8.0 Hz, 1 H), 4.86 (s, 2H) Part C: Compound 2322 was prepared according to the procedure described in Example 52M, Part G. 1H NMR (400 MHz CDCI3) d 7.87 (d, J = 8. 0 Hz, 1 H), 7.41 (d, J = 8.1 Hz, 1 H), 3.93 (s, 2 H), 1 .78 (br s, 2 H) Part D: Compound 2322 (370 mg, 1.67 mmol in THF (10 mL) was added dropwise into the solution of Boc20 (437 mg, 2.0 mmol) in THF (10 mL), followed by DIEA (300 mL). The mixture was stirred at room temperature overnight and concentrated.Column chromatography on silica gel (EtOAc / hexane 20:80) gave compound 2323 (450 mg, 84%) as a white solid.H NMR (400 MHz , CDCI3) d 7.89 (d, J = 7.5 Hz, 1 H), 7.12 (d, J = 8.2 Hz, 1 H), 5.35 (br s, 1 H), 4.37 (d, J = 5.9 Hz, 2 H) , 1.47 (s, 9H).

Part E: Sodium (4 pills) was dissolved in MeOH (15 ml). The mixture was stirred at room temperature for 10 min., Until all the sodium had reacted. To this solution was added compound 2323 (450 mg, 1.4 mmol) in MeOH (5 mL) by syringe. The reaction mixture was stirred at 60 ° C for 48 h and concentrated. The residue was dissolved in EtOAc and 1 N NH 4 Cl solution, washed with brine, dried over Na 2 SO 4, and concentrated. The column chromatography (S02, EtOAc / hexane 20:80) gave compound 2324 as a white solid (350 mg, 79%). 1 H NMR (400 MHz, CDCl 3) d 7.43 (d, J = 7.3 Hz, 1 H), 6.73 (d, J = 7.5 Hz, 1 H), 5.26 (br s, 1 H), 4.32 (d, J = 5.1 Hz, 2H), 4.02 (s, 3H), 1 .48 (s, 9H). ' Part F: Compound 2325 was prepared according to the same procedure as in Example 52M Part E for Suzuki coupling. HPLC-S t R = 2.35 min. (UV254 nm); mass calculated for the formula Ci9H2iF3N204 398.2, LCMS observed m / z 399.1 (M + H).

Part G: Compound 2325 was deprotected with TFA in CH2Cl2, HPLC-MS tR = 1.12 min. (UV254 nm); mass calculated for the order Ci4Hi3F3 202 298.1, LCMS observed m / z 299.0 (M + H).

EXAMPLE 52Q 0.5 N NaOH, and 1 ml of water. The resulting mixture was stirred vigorously for 2 h and then filtered through Celite. The filtrate was concentrated to give pure 2329 as an oil (0.2 g, 0.6 mmol). i Part C: Alcohol 2329 (0.2 g, 0.6 mmol) and triethylamine (0. 8 g, 1.8 mmol) were dissolved in CH2Cl2 (200 mL) and cooled to 0 ° C. The cold solution was stirred, and CH3SO2CI (as a CH2Cl2 solution, 0.2 g, 1.8 mmol, 5 mL CH2Cl2) was added dropwise, and stirring was continued for 24 h. The reaction mixture was then washed twice with 50 ml of water and twice with 50 ml of brine. The organic and aqueous phases were separated, and the organic phase was dried, and concentrated to give pure product 2330 as an oil (0.21 g).

Part D: Mesylate 2330 was dissolved in DMF (10 mL) and treated with NaN3 (0.23 g, 1.8 mmol), and the mixture was vigorously stirred for 36-72 h. The reaction mixture was then diluted with 100 ml of water and extracted with ethyl acetate (2 x 100 ml). The organic phases were combined, dried and concentrated to give pure azide 2331 (0.19 g, 87%).

Part E: Azide 2331 (0.19 g, 0.6 mmol)) and triphenylphosphine (0.15 g, 0.6 mmol) were dissolved in 5 mL of THF, and then water (0.6 mL, 33.3 mmol) was added. The resulting mixture was stirred vigorously! for 16-24 h. The solvent was removed and the crude amine 2332 was taken for the next step without further purification. j The following compounds were prepared using the EXAMPLE 53 EXAMPLE 53A 14 mmol), methylamine hydrochloride (0.94 g, 14 mmol) and triethylamine (1.95 mL, 14 mmol) in ethanol (15 mL) was stirred at rt overnight. Then sodium borohydride (0.4 g, 10.5 mmol) was added and the resulting mixture was stirred at rt. for 8 h. The reaction mixture was then poured into aqueous ammonium hydroxide (40 ml), the resulting inorganic white precipitate was filtered and washed several times with dichloromethane. The organic layer was separated, and the aqueous phase was extracted with dichloromethane. The combined dichloromethane extracts were washed with brine, concentrated and subjected to chromatography (SiO2, 5% methanol / dichloromethane) to give 2362 (1.03 g, 62%). 1 H NMR (400 Mhz, CDCl 3) d 7.30-7.17 (m, 5H), 4.31 -4.30 (d, 1 H), 3.78-3.62 (m, 2H), 3.57-3.47 (m, 2H), 2.97-2.70 ( m, 3H), 2.43 (s, 3H), 1.27-1.20 (m, 6H).

Part B: Compound 2005 was prepared using procedures described in Example 27. Compound 2363 was prepared using the coupling conditions described in Example 1. HPLC-MS tR = 2.42 min. (UV254 nm) mass calculated for the formula C34H 5FN 06 624.3, LCMS observed m / z 625.2 (M + H).

Part C: Compound 2364 was prepared using the cycling conditions described in Example 29, HPLC-MS tR min (UV254 nm); mass calculated for the formula C30H34FN5O3 531.3, observed m / z 532.2 (M + H). Part D: Compound 2364 was deprotected using procedures described in Example 29. Purification by preparatory LC and conversion to a hydrochloric salt gave 2365 as an off-white solid. HPLC MS C27 Compound 2366 was prepared using procedures described in Waldvogel, E. et al. Helv. Chim. Acta. 1997, 80, 2084-, 2099. Compound 2367 was prepared using the coupling conditions described in Example 1, HPLC-MS tR = 1.88 min. (UV254 nm); mass calculated for the formula C26H35FN4O6 518.2, LCMS observed m / z 519. 2 (M + H). ! Part B: Compound 2368 was prepared using the cycling conditions described in Example 29. HPLC-MS t R = 1.40 min. (UV254 nm); mass calculated for the formula C2 H30FN5O3 455.2, LCMS observed m / z 456.1 (M + H).

Part C:! Compound 2368 was deprotected using procedures Part A: Compound 2370 was prepared using the procedures described above in Example 29. HPLC-MS t = 1.30 min. (UV254 nm); mass calculated for the formula C23H28EN5O3 441.2, LCMS observed m / z 442.1 (M + H). from I know in sa 1 H NMR (400 MHz, CDCl 3) d 7.27-7.24 (m, 1H), 7.22-7.17 (m, 1H), 7.00 (t, 1H, NH), 6.99-6.96 (m, 2H), 4.62-4.57 (dd, 2H), 3.51-3.48 (d, 2H), 3.38-3.24 (m, 2H), 2.80- 2.74 (m, 2H), 1.88-1.84 (d, 2H), 1.79-1.69 (m, 1H), 1.61-1.50 (m, 2H), 1.53 (s, 3H), 1.52 (s, 3H). HIPLC-MS ^ tR = 1.49 min. (UV254 nm); mass calculated for the formula C2oH26FN504419.2 | LCMS observed m / z 420.1 (M + H).

Part B: Compound 2377 (4.5 g, 21.92 mmol) was dissolved in dry DCM (40 mL) and cooled to 0 ° C, then 77% m-CPBA (5.41 g, 24.12 mmol) was added in three portions during 5 min The reaction mixture was allowed to stir overnight at room temperature. It was poured into saturated aqueous NaHCO3 (100 mL) and the product was extracted into DCM. The organic layer was washed with water and brine and dried (Na2SO4). Flash chromatography on silica gel (MeOH / DCM 5:95) gave compound 2378 as a pale yellow solid (3.2 g, 66%). | H NMR (40 I0 MHz, CDCI3) d 8.24 (m, 1 H), 7.96 (d, J = 16.0 Hz, 1 H), 7.51 (m, 1 H), 7.22 (m 1 H), 6.85 (d, J = 16.0 Hz, 1 H), 1.55 ( s, 1 H).

Part C: A 250-ml balloon flask filled with H20 (30 ml) was cooled to 0 ° C in an ice bath. Subsequently, K3 reagents [Fe (CN) 6] (9.88 g, 30 mmol), K2C03 (6.91 g, 50 mmol), and MeSO2NH2 (0.95 g, 10 mmol) were added, followed by K2 [Os02 (OH)] 4] (14.7 mg, 0.04 mmol), (DHQ) PHAL (233.7 mg, 0.3 mmol), compound 2378 (2.21 g, 10 mmol) and--BuOH (20 mL). The reaction mixture was stirred at 0 ° C for 24 h. The solid was filtered and washed with excess EtOAc. The organic layer was separated. The aqueous solution was concentrated until dried, and the resulting solid was extracted with CH2Cl2. The above solutions of EtOAc and CH2Cl2 were combined and concentrated. Instant chromatography on gel silica (MeOH / CH2CI2 10:90) gave compound 2379 as a white solid (2.2 g, 86%). Recrystallization from EtOAc gave analytically pure material (1.51 g, 52% production). 1 H NMR (400 MHz, CDCl 3), d 8.24 (d, J = 6.5 Hz, 1 H), 7.54 (dd, J = 7.7, 2.0 Hz, 1 H), 7.39 (t, J = 7.5 Hz, 1 1 H), 7.30 (m, 1 H), 5.41 (d, J = 2.6 Hz, 1 H), 4.69 (d, J = 2.7 Hz, 1 H), 1.54 (s, 9H) Part D: Compound 2379 (1.0 g, 3.9 mmol) in GH2CI2 (10 mL) was treated with TFA (4 ml). The solution was allowed to stir at room temperature i for 2 h, and then concentrated to give compound 2380 as a solid white (750 mg, 96%). H NMR (400 MHz, DMSO-d6) 8.20 (dd, J = 6.3, 1.2.

Hz, 1 H), 7.54 (dd, J = 6.4, 2.2 Hz, 1 H), 7.37 - 7.32 (m |, 2H), 5.38 (d, J = 2.1 Hz, 1 H), 4.62 (d, J = 2.3 Hz, 1 H).

Part E: Compound 2381 was prepared using the conditions of coupling described in Example 1. The purification by LC preparatory gave 2381 as a white solid (63 mg). HPLC-MS R = 1.30 min.

(UV254 nm); mass calculated for the formula C21H23FN404, 414.2, LCMS observed m / z 415.1 (M + H).

At room temperature, the mixture was diluted with EtOAc and water, filtered through a pad of Celite, washed with water, brine, dried (Na2SO4), and concentrated. Flash column chromatography on silica gel (EtOAc / hexane 15:85) gave compound 2383 as a pale yellow solid (2.32 g, 57%). 1 H NMR (400 MHz, acetone-d 6) d 8.84 (s, 1 H), 8.68 (s, 1 H), 7.61 (d, J = 15.7 Hz, 1 H), 6.92 (d, J = 15.5 Hz, 1 H), 1.55 (s, 9H).

Part B: A 50 ml balloon flask filled with H2O (9 ml) was cooled to 0 ° C in an ice bath. K3 reagents [Fe (CN) 6] (1.29 g, 3.93 mmol), K2CO3 (905 mg, 6.55 mmol), and MeS02NH2 (124.6 mg, 1.31 mmol), followed by K2 [OsO2 (OH)) were added sequentially. 4] (2.0 mg, 0.005 mmol), (DHQ) PHAL (31.0 mg, 0.04 mmol), compound 2383 (315 mg, 1 mmol) and t-BuOH (6 mL). The reaction mixture was stirred at 0 ° C for 36 h. Then EtOAc and H2O were added to dissolve the solid. The organic caps were separated and the aqueous layer was extracted back with EtOAc. The EtOAc Extracts were combined, washed with water and brine, dried (Na2SO4), and concentrated. Flash chromatography on silica gel (EtOAc / hexane 40:60) gave compound 2384 as a white solid (285 mg, 79%). 1 H NMR (400 MHz, CDCl 3) d 8.68 (s, 1 H), 8.54 (s, 1 H), 5.13 (d, J \ = 2.3 Hz, 1 H), 4.55 (d, J = 2.9 Hz, 1 H), 1.55 (s, 9H). HPLC-MS t R = 1.73 min. (UV254 J; mass calculated for the formula CnH15CIN2O4, 274.1, LCMS observed m / z 275.0 (M + H).

Part C: Compound 2384 (285 mg, 1.04 mmol) in dioxane (5 mL) was treated with 4N HCl in dioxane (5 ml). After stirring at room temperature environment for 2 h, the solution was concentrated to give compound 2385 (200 mg, 88%). 1 H NMR (400 MHz, CDCl 3) d 8.70 (s, 'H), 8.66 (s, 1 H), 5.00 (d, J = 2.6 Hz, 1 H), 4.31 (d, J = 2.2 Hz, 1 H), 1.55 (s, 9H) Part D: Compound 2386 was prepared using the conditions of! coupling described in Example 1. The purification by LC preparatory gave 2386 as a white solid (42 mg). HPLC-MS tR = 1.55 min.

(UV254 nm); mass calculated for the formula C20H2- | CIF FN5O3, 433.1, LCMS observed m / z 434.0 Part E: Compound 2386 (20 mg, 0.046 mmol) mixed with 10% Pd / C (20 mg) in EtOAc (10 mL) was stirred at room temperature for 12 h under hydrogen atmosphere (1 atm). The solution was filtered through Celite and concentrated. Purification by preparatory LC gave 2387 as a solid white (15 mg, 81%). HPLC-MS t R = 1.35 min. (UV254 nm); calculated mass for the formula C20H22FN5O3, 399.2, LCMS observed m / z 400.1 LCMS observed m / z 303.0 (M + H). j Part B: To compound 2388 (180 mg, 0.59 mmol) and HATU (269 mg, 0.71) mmol) in DMF (4 mL) was added isoindoline (84 mg, 0.71 mmol). The mixture of The reaction was stirred at room temperature for 12 h, and concentrated. He The residue was dissolved with EtOAc and water, washed with saturated bicarbonate and brine, dried over Na2SO4, and concentrated. The purification by column chromatography on silica gel (60:40 EtOAc / hexane) gave the desired product 2389 as a yellow solid pale (150 mg, 63%). 1 H NMR (400 MHz, CDCl 3) d 8.67 (s, 1 H), 8.51 (s, 1 H), 7. 29 (m, 4H), 6.39 (d, J = 7.1 Hz, 1 H), 5.93 (d, J = 6.7 Hz, 1 H), 5.21 (d, J = 5.4 Hz, 1 H), 5.05 (d, J = 4.1 Hz, 1 H), 4.78 (d, J = 5.6 Hz, 1 l | l), 4.52 (d, J = 4.7 Hz, 1 H), 2.18 (s, 3H), 2.16 (s, 3H). HPLC-MS tR = 1.70 min. (UV254 nm); dough calculated for the formula Ci9H18CIN305 403.1, LCMS observed m / z 404.0 (M + H).

Part C: A 4 ml vial was loaded with Pd2 (dba) 3 (2.3 mg, 0.0025 mmol), tri (t-butyl) phosphonium tetrafluoroborate (1.5 mg, 0.0025 mmol), compound 2389 (20 mg, 0.05 mmol), phenylboronic acid (9.1 mg, 0.075 mmol) and fluoride potassium (13 mg, 0.225 mmol). Under argon, dioxane (1 ml) was added through syringe. The bottle was sealed with a screw cap coated with Teflon and placed in a preheated oil bath at 80 ° C. The reaction mixture is left under stirring at 80 ° C for 12 h. The LC-MS indicated that the reaction. After cooling to room temperature, the mixture of To compound 2389 (50 mg, 0.12 mmol) in NMP (1 mL) was added 4-N-phenylpipicin (29 mg, 0.18 mmol) and DIEA (0.032 mL, 0.18 mmol). Mix of reaction was allowed to stir at 80 ° C for 16 h. After cooling to room temperature, the solution was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated. The resulting oily solid (52 mg) was used for the next step without further purification.

HPLC-MS t R = 1.96 min. (UV254 nm); mass calculated for the formula C 29 H 31 N 5 O 5 529.2, LCMS observed m / z 530.2 (M + H). procedures described in Example 10B part A and part B. Compound 2406: 1 H NMR (400 MHz, CDCl 3) d 7.40-7.30 (m, 5H) 6.1 1 (s, 1 H), 5.36 (m, 1 H), 5.18 (s, 2H), 3.72 (m, 1 H), 3.00 (m, 1 H), 2.33 (m, 1 H), 1.90 - 1.40 (m, 7H). HPLC-MS IR = 1.34 min. (UV254 nm); mass calculated for Ci6H19N3O2S 317.4, LSMS observed m / z 318.1 (M + H).

Part D: Compound 2406 (75 mg, 0.24 mmol) stirred in 30% HBr in acetic acid (2 ml) for 1 hour at room temperature. The solvent was evaporated and the residue dissolved in water and lyophilized to give 2407 (66 mg) as a red solid. The following compounds were prepared using the procedures described above. for 1 h. The reaction mixture was concentrated, partitioned between ethyl acetate and water and extracted with ethyl acetate. The organic extracts combined were washed with saturated sodium bicarbonate solution, brine, dried and evaporated, to give ester 2427 as a solid whitish (0.907 g, 86%). 1 H NMR (400 MHz, CDCl 3) d 7.43-7.28 (m, . 53-5.46 (dd, 1 H), 4.86-4.69 (m, 2H), 3.77-3.75 (d, 3H), 1.54-1.49 (d, 9H).

Part B: Chloroketone 2428 was prepared using described procedures in Example 10. 1 H NMR (400 MHz, CDCl 3) d 7.46-7.30 (m, 4H), 5.65-5.48 (d I of d, 1 H), 4.90-4.71 (m, 2H), 4.42-4.06 ( m, 2H), 1 .57-1.5; 2 (d, 9H).

Part C: Compound 2429 was prepared using described procedures in Example 10. HPLC-MS tR = 1.51 min. (UV254 nm); mass calculated for I formula C17H2i N302S 331 .1, LCMS observed m / z 332.1 '(M + H).

Part D: Compound 2430 was prepared using procedures described in Example 10, HPLC-MS tR = 0.80 min. (UV254 nm); mass calculated for Formula Ci2Hi3N3S 231.1, LCMS observed m / z 232.1 (M + H).

EXAMPLE 55B formula C15H14CINO 259.1, LCMS observed m / z 260.0 | (M + H). ice, was deactivated by the addition of sodium hydroxide solution 2 M was extracted and subjected to sonication with dichloromethane (the residue dissolved). The combined dichloromethane extracts concentrated to a solid residue, which was then triturated with THF. The resulting white solid was filtered and dried to give compound 2433 (1.2 g, 74%). 1 H NMR (400 MHz, DMSO-de) d 7.82-7.67 (m, 6H), 7.58-7.55 (dd, 1 H), 7.4 -7.39 (d, 1 H), 3.98 (t, 2H), 3.23 (t, 2H). HPLC-MS t R = 0.96 min. (UV254"m); mass calculated for Formula C15H12CIN 241.1, LCMS observed m / z 242.1 (+ H).

Part C: According to a modification of a Mach procedure, U. R. et al. (ChemBioChem 2004, 5, 508-518) to a solution of imine 2433 (760 mg, 3.14 mmol) in ethanol (50 ml) was added sodium bofohydride in portions (300 mg, 7.86 mmol) and the resulting mixture was heated to reflux overnight. The reaction mixture was cooled, deactivated with water, concentrated, partitioned between ethyl acetate and water, and extracted with ethyl acetate. ethyl. The combined organic extracts were dried and concentrated to give the amine 2434 (418 mg, 55%). 1H NMR (400 MHz, DMSO-d6) d 7.33-7.04 (m, 7H), 6.62-6.60 (d, 1 H), 5.00 (s, 1 H), 3.36-3.26 (m, 1 H), 3.1 1 -3.06 (m, 1 H), 2. 98-2.73 (m, 2H). HPLC-MS t R = 1.14 min. (UV nm); mass calculated for formula Ci5H14CIN 243.1, LCMS observed m / z 244.1 (M + H).

EXAMPLE 55C 2436 2436 2437 Part A: A mixture of compound 2435 (6 g, 36.5j mmol) and urea (1.95 g, 32. 5 mmol) was heated on a sand bath at 350 ° C for 30 minutes. I The resulting black tar was cooled to 100"C and jaguar was added carefully (25 mi). This mixture was stirred for 1 hour. The solid jse was collected by filtration, dissolved in DMF (40 ml) and shaken with arc (1 g) for 1 hour. hour. The mixture was filtered and water (100 ml) was added to the filtrate to precipitate a brown solid. The solid was collected by filtration and dried with air.

The solid was dissolved in boiling MeOH (120 ml) j with Darco (1 g). The The mixture was filtered and the filtrate was concentrated until dried. The residue is suspended in EtOAc and filtered to give the desired compound 2436 as a solid brown (2.5 g, 43%). ! Part B: Compound 2436 (1 g, 6.2 mmol) was added to a 1 M solution of borane / THF (21 mL, 21 mmol) at 0 ° C and the mixture was heated to room temperature environment and then refluxed for 18 hours. The mixture of The reaction was cooled to room temperature and HCl 6N was added dropwise (50 mi) The reaction mixture was concentrated to remove THF and then cooled to 0 and sodium hydroxide (13 g) pills were carefully added to the reaction mixture. The reaction mixture was extracted with CH2Cl2 (1 x 50 mL, 1 x 20 mL). The organic layer was dried over MgSO4, filtered and concentrated. Purification by column chromatography (SiO2, 3% MeOH (NH3) / CH2Cl2, followed by 5% MeOH (NH3) / CH2Cl2) gave the desired compound 2437 as a tan solid (64 mg, 7.7%). The following compounds were prepared using the procedures described above.

Part A: Compound 2451 (200 mg, 0.52 mmol), compound 3000 (194 mg, 0.68 mmol), HATU (260 mg 0.68 mmol), and DIEA (0.5 mL) in DMF (5 mL) were dissolved. The reaction mixture was stirred overnight at room temperature and then partitioned between ethyl acetate and water. The organic layers were washed with 1 M HCl, bicarbonate} saturated sodium, brine, dried over sodium sulfate, and concentrated. Purification by column chromatography (33% SiO2 ethyl acetate / hexanes to 100% ethyl acetate) gave the desired product (230 mg). HPLC-MS t R = 2.20 min. (UV254 J; mass calculated for the formula C3i H37FN407596.2, LCMS observed m / z 597.2 (M + H) Part B: Compound 2457 (230 mg, 0.386 mmol) was dissolved in methylene chloride (4 mL) and trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated and 2458 (190 mg) was used without further purification. HPLC-MS t R = 1.77 min. (UV254 nm); mass calculated for the formula C27H29FN407 540.2, LCMS observed m / z 541.2 (M + H).

Part C: Compound 2458 (190 mg, 0.32 mmol), HATU (160 mg, 0.416 mmol), pyrrolidine (0.035 mL, 0.416 mmol), and DIEA (0.5 mL) were dissolved in DMF (5 mi). The reaction mixture was stirred overnight at room temperature and then partitioned between ethyl acetate and water. The organic layers were washed with 1 M HCl, saturated sodium bicarbonate, brine, dried over sodium sulfate, and concentrated. Purification by column chromatography (Si02) 25% ethyl acetate / hexanes to 100% ethyl acetate) gave the desired product (200 mg). HPLC-MS tR = 1.92 min. (UV254 nm); mass calculated for the formula C31 H36FN5O6 593.2, LpMS observed m / z 594.2 (M + H).

Part D: Compound 2459 (55 mg, 0.092 mmol) was dissolved in ammonia 7 M in MeOH (0.5 mL) and MeOH (2 mL) and stirred for 30 minutes. The solvent was removed under reduced pressure. The residue was dissolved in MeOH (5 mL) and acetic acid (0.3 mL) and Pd-C (100 mg) was added under an argon atmosphere. The reaction was stirred under a hydrogen atmosphere for 3 hours and then filtered on a pad of Celite. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The combined organic layers were washed with saturated sodium bicarbonate, salted, dried over sodium sulfate and concentrated. The residue was dissolved in ethyl acetate (2 mL) and treated with 4 M HCl in dioxane (0.1 mL). The solids were filtered and washed several times with ethyl acetate to give 2460 as an HCl salt (29 mg). HPLC-MS tR = 1 .15 min. (UV254 nm); mass calculated for the formula C21 H28FN5O3 41 7.2, LCMS observed m / z 418.1 (M + H).

Column chromatography (SiO2, 33% of jetyl acetate / hexanes) gave the desired product (800 mg). H NMR (400 MHz, CDCI3j d 4.60 (d, 1H), 4.30 (m, 4H), 4.15 (d, 1H), 3.50 (s, 3H), 1.35 (t, 6H).

Part B: Compound 2463 was prepared using ur to modification to a procedure found in Tetrahedron 1993, 49, 37, 8381-8396. He diester 2462 (0.837 g, 3.6 mmol) was suspended in pH phosphate buffer 8 (75 ml) and the pH was monitored at 8.33. Pig liver esterase was added (20 mg) to the suspension and the reaction mixture was stirred at room temperature ambient. The pH of the reaction was maintained between 7.9-8.2 by the addition Drip 1 M NaOH (3.27 mL, 3.24 mmol) for 1.5 hours. The reaction mixture was partitioned between diethyl ether and water. The aqueous layer was acidified to pH 2 and extracted with ethyl acetate. The combined layers of ethyl acetate are dried over sodium sulfate and evaporated to give the desired product as a 4.5: 1 mixture of inseparable acids (275 mg). 1 H NMR (400 MHz, CDCl3) d 4.60 (d, 1 H), 4.40 (m, 2H), 4.25 (d, 1 H), 3.50 (s, 3H), 1.35 (t, 3H).

Part C: Compound 2463 (130 mg, 0.65 mmol), HATU i (322 mg, 0.845 mmol), 4-phenylbenzylamine (153 mg, 0.84 p mmol), and DIEA (0.2 ml) were dissolved in DMF (6 ml). The reaction mixture was stirred! overnight at Room temperature and then divided between ethyl acetate and water. The organic layers were washed with 1 M HCl, saturated sodium bicarbonate, brine, dried over sodium sulfate, and concentrated. Recrystallization from ethyl acetate from I gave pure product (50 mg) and product slightly impure (150 mg). HPLC-MS tR = 1.70 min. (UV254 nm); mLsa calculated for Compound 2467 was prepared according to a modified procedure of the literature (Nagashima, N. and Ohno, M., J. Chem. Pharm. Bull., 1991, 39, 1972-1982). L-diethyl tartrate (2461) (6.18 g, 30 mmol) and dibutyltin oxide (7.47 g, 30 mmol) in toluene (100 mL) were heated under reflux for 1 h, removing the water formed as the azotropic mixture. The solution was evaporated until completely dried under vacuum to give a white solid. To this solid was added dry CsF (8.66 g, 59 mmol) and DMF (60 mL). The resulting mixture was cooled to 0 ° C, and benzyl bromide (6 mL, 51 mmol) was added dropwise via syringe. Once the addition is complete, the mixture of reaction was allowed to stir vigorously at room temperature for 12 h. The solvent was removed in vacuo and the residue obtained was dissolved in EtOAc and H20. The organic layer was washed with aqueous NaHCO 3 solution, brine, dried over Na 2 SO 4, and concentrated. Purification by flash column chromatography on silica gel (30:70 EtOAc / hexane) gave compound 2467 as a colorless liquid (8.10 g, 91%). 1 H NMR (400 MHz, CDCl 3) d 7.37-7.25 (m, 5 H), 4.87 (d, J = 12.0 Hz, 1 H), 4.58 (br s, 1 H), 4.02 (d, J = 12.0 Hz, 1 H), 4.34 - 4.25 (m, 3 H), 4.23 -4.21 (m, 1 H), 4.08 -4.03 (m, 1 H), 3.12 (br s, 1 H), 1.35 (t, J = 7.0 Hz, 3H), 1 .1 Ú (t, J = 6.9 Hz, 3H).

Part B: To compound 2467 (2.96 g, 10 mmol) in toluene (10 mL) was added Ag2O (4.63 g, 20 mmol) and allyl bromide (1.31 mL, 15 mmol). The reaction mixture was allowed to stir at 10 ° C for 16 h and cooled to room temperature. After filtering through a bed of Celite, the solution was concentrated. Flash column chromatography on silica gel (EtOAc / hexane 20: 80) gave the desired product 2468 (2.65 g, 79%). 1 H NMR (400 MHz, CDCl 3) d 7.33-7.25 (m, 5H), 4.87 (d, J = 12.0 Hz, 1 H), 5.89-5.79 (m, 1 H), 5.26-5.15 (m, 2H), 4.87 (d, J = 1 1 .4 Hz, 1 H), 4.46 (d, J = 1 1 .7 Hz, 1 H), 4.41 -4.38 (m, 2H), 4.34 - 3.92; (m, 6H), 1.32 (t, J = 7.2 Hz, 3H), 1 .19 (t, J = 7.2 Hz, 3H).

Part C: To a frozen mixture of compound 2468 (1.0 g, 3 mmol) and N-methylmorpholine monohydrate (703 mg, 6 mmol) in THF / H20 3: 1 (20 ml) OsO 4 (2.5% by weight in β-BuOH, 610 mg, 0.06 mmol) was added. After stirring for 30 min, the ice bath was removed and the reaction mixture was stirred at room temperature overnight. Solid NaHSO3 was added (750 mg, 7.2 mmol), and the mixture was stirred for an additional 30 minutes. The The mixture was filtered through a silica pad and the solution was concentrated to the vacuum to give an oil. This material was dissolved in THF / H20 3: 1 (20 ml) and added Nal04 (1.28 g, 6 mmol). The mixture was allowed to stir at room temperature and for 1 h. It was filtered through silica, and the solvent was evaporated. The flash column chromatography over silica gel (EtOAc / hexane 50:50) gave the aldehyde 2469 (760 mg, 75%) as a colorless acetol). 1H NMR (400 MHz, CDCl 3) d 9.72 (s, 1 H), 7.35-7.26 (m, 5H), 4.89 (d, J = 1 1.8 Hz, 1 H), 4. 52-4.48 (m, 2H), 4.45 - 4.04 (m, 7H), .34 (t, J = 7.7 Hz, 3H), 1 .19 (t, J = 7.4 Hz, 3H).

Part D: j Compound 2469 (340 mg, 1 mmol) and amine 916 (187 mg, 1 mmol) in 1,2-dichloroethane (5 ml) were stirred at room temperature for (MeOH / EtOAc 10:90), giving the desired product 2470 (350 mg, 69%) as a colorless oil. HPLC-MS tR = 1.49 min. (UV254 nm); mass calculated for the i i formula C28H35N3O6 509.2, LCMS observed m / z 510.1 (M + H).

Part E: To a solution of compound 2470 (170 mg, 0.33 mmol) in dioxane / water 1: 1 (10 mL) was added LiOH (1 M, 1.32 mL, 1.32 mmol) per drop. The mixture was stirred at room temperature for 2 h after which it was neutralized with 1 M HCl and concentrated. The residue was used for the next step without further purification. HPLC-MS tR = 1.12 min. (UV254 nm); mass calculated for the formula C24H27N306 453.2, LCMS observed m / z 454.1 (M + H).

Part F: The crude compound 2471 was dissolved in DMF (10 mL) and cooled to 0 ° C in an ice bath, added slowly! HATU (304 mg, 0.8 mmol) and the reaction mixture was stirred at 0 ° C for 2 h. LC-MS indicated the disappearance of the diacid and the formation of the cyclized product 2472. HPLC-MS IR = 1.65 min. (UV25 nm); mass calculated for the formula C24H25N3O5 435.2, LCMS observed m / z 436.1 (M + H).

Part G: To the previous solution at 0 ° C was added (48 mg, 0.4 mmol) and the reaction mixture was stirred at room temperature overnight. The DMF was evaporated, the residue was dissolved in EtOAc and water, washed with 1N HCl, saturated NaHCO3 and brine, dried over Na2SO4 and concentrated to give 2437 as an oily solid (85 mg | 47% yield in three). Steps). HPLC-MS t R = 2.00 min. (UV254 nm); mass calculated for the formula C32H32N40 536.1, LCMS observed m / z 537.1 (M + H).

Part H: The crude compound 2473 was dissolved in EtOH (20 mL), and palladium on carbon (10%, 40 mg) was added. The mixture was hydrogenated (atmospheric pressure) at room temperature overnight. The suspension was filtered through Celite and concentrated. The resulting residue was purified by preparative LC to give 2474 as a white solid (9.4 mg). HPLC-MS t R = 3.57 min (10 min method, UV254 nm); mass calculated for the formula C25H26N4O4 446.2, LCMS observed m / z 447.1 (M + H). The following compounds were prepared using the procedures described above.; i Part A: To a solution of Boc20 (6.1 g, 28 mmol) and Et3N (7.8 mL, 56 mmol) in DMF (20 mL) at 0 ° C was added portionwise 3-chlorophenylhydrazine hydrochloride (5.0 g, 28 mmol) in DMF (20 ml). The reaction mixture is left under stirring at room temperature for 2 m and concentrated. The residue was dissolved in EtOAc and H20, washed with 1 N citric acid and saturated NaHCO3, dried over Na2SO4 and concentrated to give 2490 (17.83 g, 97%) as an off-white solid. 1 H NMR (400 MHz, CDCl 3) 6 7.13 (t, J = 8.3 Hz 1 H), 6.86-6.81 (m, 2 H), 6.70-6.66 (m, 1 H), 6.36 (br s, 1 H) 1.48 ( s, 10H).

Part B: 3-Chloropropionyl chloride (0.400 mL, 4.12 mmol) was added dropwise to a solution of compound 2490 (1.0 g, 4.12 mmol) and K2CO3 (1.14 g, 8.24 mmol) in DMF (10 mL). ) at 0 ° C. The reaction mixture was allowed to stir at 80 ° C overnight and was concentrated. The residue dissolved in EtOAc and H20, washed with 1 N citric acid and saturated NaHCO3, dried over Na2SO4, and concentrated. Column chromatography (EtOAc / hexane 25:75) gave compound 2491 (600 mg, 49%) as an off-white solid. 1 H NMR (400 MHz, CDCl 3) d 7.57 (t, J = 2.3 Hz, 1 H), 7.51 -7.48 (m, 1 H), 7.27 (t, J = 8.3 Hz, 1 H), 7.12-7.09 (m , 1 H), 4.16 (t, J = 7.2 Hz, 2H), 2.7¡7 (t, J = 7.3 Hz, 2H), 1.34 (s, 9H).

Part C: Compound 2491 was deprotected with TFA in CH2Cl2. The material was used without further purification.

EXAMPLE 58B 2433 Part A: To a suspension of NaH (60% in mineral oil, 1.56 g, 39 mmol) in benzene (40 ml) at 0 ° C was added 3-chlorophenylhydrazine (2.13 g, 15 g). mmol). The mixture was stirred at 80 ° C for 1 h, after which it was added slowly 1, 3-dibromopropane (2.0 g, 10 mmol) by syringe. He stirred to 80 ° C overnight and deactivated by the addition of water (20 ml). The organic layer was separated, washed with water and brine, dried over Na2SO, and concentrated. Column chromatography (DCM) gave the compound 2493 (850 mg, 47%) as a pale yellow oil. 1H NMR (400 MHz, CDCI3) d 7.12 (t, J = 8.2 Hz, 1 H), 7.04 (t, J = 2.3 H; z, 1 H), 6.84-6.81 (m, 1 H), 6.74-6.71 (m, 1 H), 3.75 (bs, 1 H), 3.35 (t, J = 7.5 Hz |, 2H), 3.00 (t, J = 6.7 Hz, 2H), 2.16-2.1 1 (m, 2H). i The following compounds were prepared using the procedures described above. | EXAMPLE 59 EXAMPLE 59A Part B 471 25Q1 Part A: To compound 471 (100 mg, 0.37 mmol) in EtOH (2 mL) was added chloroacetaldehyde (50% by weight in water, 233 mg, 1.48 mmol). The reaction mixture was allowed to stir at 90 ° C overnight and was concentrated. The residue was dissolved in EtOAc, washed with water and brine, dried (Na2SO4) and concentrated. The crude product 2500 (90 mg, 82%) was used without further purification. HPLC-MS tR = 1.10 min; mass calculated for the formula C14H19N3O2S 293.1, observed m / z 294.1 (M + H).

Part B: Compound 2500 (90 mg) was dissolved in 2 ml of 4 N HCL in dioxane / H 2 O (1: 1). After stirring at room temperature for 1 h, the solution was concentrated to give a brown solid (80 mg, 90%). HPLC-MS tR = 0.22 min; mass calculated for the formula C9HnN3S 193.1, m / z observed 194.1 (M + H); EXAMPLE 59B Part I; 470 2502 2503 Part A: A mixture of chloroketone 471 (200 mg, 0.81 mmol) and 2-aminopyridine (140 mg, 0.81 mmol) in ethanol (5 mL) was heated to reflux and stirred overnight. The reaction mixture was concentrated and purified by preparative HPLC to give 2504 (1 19 mg). HP LC-MS tR = 1 .22 min. (UV254 nm); mass calculated for the formula C19H25 N3O4 359.2, LCMS observed m / z 360.1 (M + H).

Part B: To a solution of imidazopyridine 2504 (1 19 mg, 0.33 mmol) in dioxane (2 mL) was added HCl (4N in dioxane, 4 mL) and water (0.5 mL). The mixture was stirred at room temperature for 1 hour and concentrated. The resulting residue 2505 (83 mg) was dried in vacuo and used in the next step without further purification. HPLC-MS t R = 0.70 min. (UV254 n); mass calculated for the formula Ci4H17N302 259.1, LCMS observed m / z 260.1 (M + H).

The following compounds were prepared using the procedures described above.

Part A: Trifluoroacetic anhydride (16 ml, 15.1 mmol) was dissolved in methylene chloride (60 ml) and cooled in an ice bath. The compound 840 (10.0 g, 82.6 mmol) was added dropwise to methylene chloride (40 ml) and stirred at room temperature for one hour. The solution cooled in a ice bath and iodine (1.1 g, 43.2 mmol) and compound 2509 (9.8 g) were added. g, 22 mmol) and stirred for 12 hours in the dark (cover flask with aluminum paper). Additional compound 2509 (9.5 g, 20 mmol) was added and I continued stirring for 12 hours. The reaction mixture was added to a cooled solution of methylene chloride and 5% sodium bisulfite and He stirred for an hour. The organic layer was washed with sodium carbonate Saturated, filtered through a silica pad and concentrated. The residue is It was suspended in diethyl ether (30 ml) and hexanes (90 ml) and stirred for 30 minutes. The mixture was filtered to give compound 2510 as a solid white (15.5 g). The product was stored in the dark at room temperature. 1 H NMR (400 MHz, CDCl 3) 7.70 (d, 2 H), 7.06 (d, 2 H), 5.10 (m, 1 H), 1.60 (d, 3H). | Part B: Compound 2510 (4.0 g, 1 1 .66 mmol), pyrazole was combined (0.953 g, 14 mmol), copper (I) iodide (444 mg, 2.33 mmol), carbonate cesium (7.6 g, 23.3 mmol), 1, 10-phenanthroline (844 mg, 4.66 mmol) and dimethylacetamide (40 ml) in a 80 ml bottle of screw cap and shaken in Saturated, brine and water, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (2: 1 hexanes / ethyl acetate) to give compound 2511 (2.15 g). 1H NMR (400 MHz, CDCl 3) d 7.90 (d, 1 H), 7.72 (m, 1 H), 7.66 (d, 2 H), 7.40 (d, 2 H), 6.75 (d, 1 H), 6.49 (d, 1 H) , 5.20 (m, 1 H), 4.82-4.75 (dd, 2H), 3.83 j (s, 3H), 1.57 (d, 3H), 1.54 (s, 3H), 1.50 (s, 3H).

Part E: Compound 2511 (2.15 g, 5.76 mmol) was dissolved in THF (20 mL) and 1 N lithium hydroxide and stirred for 2 hours. Diethyl ether was added and the aqueous layer was acidified to pH 2 with 1N HCl and extracted with ethyl acetate. The combined layers of ethyl acetate were dried over sodium sulfate and concentrated to give compound 2512 as a white solid. (1.95 g). 1 H MPN (400 MHz CDCl 3) d 7.9 (d, 1 H), 7.74 (m, 1 H), 7.70 (d, 2 H), 7.42 (d, 2 H), 6.96 (d, 1 H), 6.49 (t , 1 H), 5.2 (m, 1 H), 4.60-4.50 (dd, 2H), 1.64 (d, 3H), 1.54 (d, 3H). j several times with water, brine (1 x 50 ml), dried over Na 2 SO 4 and concentrated to give a light yellow oil. Purification by column chromatography (SiO2, 25% acetate / hexane) gave 2521 (2.66 g, 84%) as a white solid.

Part B: A mixture of 2521 (0.2 g, 0.72 mmol) and hydrazine (0.22 mL, 7.0 mmol) in ethanol (20 mL) was heated at 70 ° C for 5 hours. The solvent was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate, washed with water (2 x 30 ml), brine (1 x 20 ml), dried over Na 2 SO 4 and concentrated to give 2522 (0.18 g). , 86%) as a yellow oil, which was used in the next step without further purification.

Part C: Stirred at t.a. a mixture of 2522 (0. 2 g, 0.72 mmol) and ethyl isocyanate (0.077 g, 1.083 mmol) in DCM (5 mL) for 16 hours. Additional ethyl isocyanate (0.077 g, 1.083 mmol) was added and the reaction was stirred for another two hours. The solvent was removed under reduced pressure to give the crude product as a white gum. It was dissolved in DCM (20 mL) and treated with triethylamine (0.5 mL, 3.6 mmol), DMAP (0.017 g, 0.139 mmol) and p-toluenesulfonyl chloride (0.16 g, 0.83 mmol). The mixture was stirred at room temperature for 64 hours and the solvent was removed. The residue was purified by preparative chromatography using 5% MeOH / CH 2 Cl 2, to give the product which was further purified using ethyl acetate / hexane (3/1) to give intermediate 2523 (0.1 g, 44%) as a light brown solid. .Part D: Intermediary 2523 (0.05 g, 15 mmol) was dissolved in DCM Part C: Compound 2531 (751 mg, 2.83 mmol) was transformed into 2532 (418 mg, 52%) using the procedures described in Example 10 Part A.

HPLC-MS t R = 1.85 min. (MS); mass calculated for the formula C11H16CIF2NO3 283. 1, m / z observed 228.1 (M-55).

Part D: Compound 2532 (418 mg, 1.47 mmol) was cyclized with N-I methylthiourea according to the procedures described in Example 51 B and Part C to give 2533 (200 mg, 42%). HPLC-MS t R = 1.38 min (UV 254 nm); mass calculated for the formula C8H-M F2N3S 319.1, m / z observed 320.1 (M + H).

Part E: Compound 2534 was synthesized in quantitative yield using the procedure described in Example 51 D Part H. 1 H NMR (400 ii MHz, CDCl 3) d 6.89 (s, 1 H), 4.98 (dd, 1 H, J = 7.2, 1 1.7 Hz), 3.89 (m, 1 H), 3.72 i (m, 1 H), 3.13 (s, 3 H), 3.09-2.85 (m, 2 H). í Part B: Compound 2538 (630 mg, 1.49 mmol) in Et20 (20 mL) was cooled to 0 ° C. To this solution was added 2.15 M hydrobromide in Et20 (830 μ ?, 1.79 mmol) per drop. The reaction mixture was stirred for 20 min at 0 ° C and concentrated. The residue was dissolved in EtOAc i, the solution was washed then with saturated bicarbonate solution, brine, dried (Na2S04) and it was concentrated in vacuo to give 2539 (630 mg, 89%) as an off-white solid.

HPLC-MS t R = 2.40 min. (UV254 nm); mass calculated for the formula C26H22BrNO3 475.1, LCMS observed m / z 476.0 (M + H) Part C: Compound 2539 (150 mg, 0.31 mmol) and thiourea (36 mg, 0.47) mmol) in DMF (2 mL) were allowed to stir at room temperature during 3 hr. The solution was concentrated and the residue was dissolved with EtOAc and solution saturated with NaHCO3. The organic phase was washed with H2O, brine, dried Na2SO4, and concentrated. The instantaneous column chromatography on silica (60:40 EtOAc / hexane) gave 2540 (120 mg, 84%) as a solid White. HPLC-MS tR = 1.96 min. (UV254 nm); mass calculated for the formula C27H23N3O2S 453.2, LCMS observed m / z 454.1 (M + H).

Part D: Compound 2540 (150 mg, 0.26 mmol) was treated with 20% piperidine in DMF (10 mL). The solution was stirred at room temperature According to a modification of a procedure of Ortwine, D. F. et al. (J. Med. Chem. 1992, 35, 1345-1370) to a mixture freezing of carbamate 2542 (6.81 g, 29.9 mmol) and acid glacial acetic acid 3: 1 sulfuric acid (64 ml) was added (in two portions) acid monohydrate glyoxyl (3.03 g, 32.9 mmol) and the mixture was stirred at rt overnight. The The reaction mixture was poured onto ice, and extracted with dichloromethane (5 | times). The combined dichloromethane extracts were dried and concentrated to an oily residue which is then t? > in toluene and concentrated (3 times) and dried under vacuum overnight to give the compound 2543 (7.91 g, 93%). 1 H NMR (400 MHz, DMSO-d 6) d 2.9 (s, broad, COOH), 7.50-7.12 (m, 3H), 5.42 (s, 1 H), 4.12-4. D3 (m, 2H), 3.77-3.50 (m, 2H), 2.89-2.79 (m, 2H), 1.24-1.16 (m, 3H). HPLC-MS tR = 1.68 min. (UV254 I nm); mass calculated for the formula C13H-14CINO4 283.1, LCMS observed m / z 284. 0 (M + H).

Part C: Diazoketone 2544 was prepared using the procedures described in Example 62C Part A. 1H NMR (400 MHz, CDCI3) 6 7.23-7.18 (m, 3H), 5.60-5.41 (m, 2H), 4.26-4.22 (m, 2H), 3.90-3.65 (m, 2H), 2.97-2.82 (m, 2H), 1 .36-1 .32 (m, 3H). HPLC-MS t R = 1.8 minutes. (UV nm); calculated mass for the formula C14HUCIN3O3 307.1, LCMS observed m / z 280.1 (M-N2 + H), and i 330.1 (M + Na). ' Part D: Bromoketone 2545 was prepared using the procedures described in Example 62C Part B. H NMR (400 MHz, CDCl 3) 7.31 -7.20 (m, 3H), 5.87-5.81 (m, 1 H), 4.25-4.04 ( m, 4H), 3.90-3.82 (m, 1 H), 3.60-3.51 (m, 1 H), 2.98-2.79 (m, 2H), 1.34-1.31 (m, 3H). HPLC-MS tR = 2.07 min. (UV254 nm); mass calculated for the formula Ci 4Hi5BrCIN03 359.0, LCMS observed m / z 360.0 (M + H).Part E: Thiazole 2546 was prepared using the procedures described in Example 10, HPLC-MS tR = 2.05 min. (UV254 nm); mass calculated for the formula C18H22CIN302S 379.1, LCMS observed m / z 38?!? (M + H).

Part F: To a solution of thiazole 2546 (117 ijng, 0.31 mmol) in chloroform (1.5 mL) was added iodotrimethylsilane (0.32, mL, 2.24 mmol) and the resulting mixture was heated at 50 ° C for 2 h. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate, brine and concentrated to give the amine 2547 as a dark yellow solid (93 mg, 97%). 1 H NMR (400 MHz, CDCl 3) d 7.12-6.97 (m, 3 H), 6.01 (s, 1 H), 5.26 (s, broad, 1 H), 5.15 (s, 1 H), 3.60-3.53 (m, 1 H), 3.18-2.80 (m, 4H), 1. 28-1.26 (d of d, 6H). HPLC-MS t R = 1.24 min. (UV254 | nm); mass calculated for the formula Ci5H18CIN3S 307.1, LCMS observed m / z! 308.2 (M + H). from O ion Freezing of 3-chlorophenethylamine 2431 (1.1 g, 75 mmol) and triethylamine (10.9 mL, 78.7 mmol) in DCM (300 mL) was added dropwise to benzyl chloroformate (1.1 ml, 78.1 mmol), and the The resulting solution was stirred at 0 ° C for 30 min, and then at rt overnight. The reaction mixture was washed with saturated sodium bicarbonate solution, brine, dried and concentrated to give benzyl carbamate 2548 as a colorless oil (21.4 g, 99%). 1 H NMR (400 MHz, CDCl 3) d 7.38-7.30 (m, 5H), 7.23-7.05 (m, 4H), 5.1 (s, 2H), 4.75 (s, broad, NH), 3.46 (q, 2H), 2.82 (t, 2H).

Part B: According to a modification of a procedure of Ortwine, D. F. et al. (J. Med. Chem. 1992, 35, 1345-1370), to a mixture freeze of benzyl carbamate 2548 (8.6 g, 31.4 mmol) and acetic acid glacial sulfuric acid 3: 1 (64 ml) was added (in two portions) monohydrate of glyoxylic acid (3.0 g, 32.6 mmol) and the mixture was stirred at rt during the night. The reaction mixture was poured into ice, and was flushed with dichloromethane (4 times). The aqueous phase was concentrated, diluted with itetrahydrofuran (200 mi), and was treated with 6M NaOH solution (130 ml) until? 12-13, followed by di-tert-butyl dicarbonate (7.94 g, 36.4 mmol), and then stirred at rt for the night. The reaction mixture was concentrated, diluted with water, acidified with 2M HCl solution to pH 2, and extracted with ethyl acetate. The combined organic extracts were concentrated and subjected to chromatography (SiO2, 5% methanol / dichloromethane) to give compound 2549 (0.95 g, 15% based on the reacted starting material). 1H NMR (400 MHz, CDCI3) 5 7.54-7.27 (m, 3H), 5.67-5.50 (d, 1 H), 3.87-3.79 (m, 2H), 3.01 - 2.88 (m, 2H), 1 .61 -1 .57 ( 9H).

Part C: Amine Weinreb 2550 was prepared using the procedures described in Example 51 1, Part A. | H NMR (400 MHz, CDCI3) .5 7.37-7.14 (m, 3H), 6.1-5.88 (d, 1 H), 4.0 (s, 3H), 3.84-3.67 (m, 2H), 3. 21 (s, 3H), 3.17-3.09 (m, 1 H), 2.79-2.72 (m, 1 H), 1.5 (s, 9H). HPLC-MS tR = 2. 15 min. (UV254 nm); mass calculated for the formula JC17H23CIN2O4 354.1, i LCMS observed m / z 255.1 (M-BOC + H). i Part D: Acetylene 2551 was prepared using the procedures described in Example 511. Part B. HPLC-MS tR = 2.22 min. (UV254 nm); mass calculated for the formula Ci7Hi8CIN03 319.1, LCMS observed m / z 264.0 (M- (t-butyl)).

Part E: Pyrazole 2552 was prepared using the procedures described in Example 62G Part A. HPLC-MS t R = 1.97 min. (UV254 nm); mass calculated for the formula C 7H2oCIN302 333.1, LCMS observed m / z 234 (M-BOC + H). ! Part F: Amine 2553 was prepared using a procedure similar to that described in Example 511, Part D. HPLC-MS tR = 0.89 min. (UV254 nm); mass calculated for the formula C12H12CIN3 233.1, LCMS observed m / z 234.1 (M + H). with saturated sodium bicarbonate and stirred for 1 hour. The reaction mixture was filtered through Celite. The aqueous layer was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated. Purification by column chromatography (S1O2, 50% ethyl acetate / hexanes) gave 2555 (1.75 g). | H NMR (400 MHz, CDCl 3) d 7.40-7.30 (m, 5 H), 5.25-5.20 (m, 2 H), 4.90-4.8% (m, 1 H), 4.00-3.80 (m, 2 H), 3.80. -3.60 (m, 3H), 3.00 (m, 1 H), 2.60 (m, 1 H).

Part B: Compound 2556 was prepared according to the procedure Bioorg. Med. Chem. 2002, 10, 5, 1 197-1206. H NMR (400 MHz, CDCl 3) .6 8. 25 (s, 1 H), 7.4-7.3 (m, 5 H), 5.3-5.15 (m, 3H), 4.7-4.55 (m, 2H), 4.3-4.2 (m, 2H), 1 .3 (t , 3H).

Part C: Compound 2557 was prepared from compound 2556 according to the procedure described in Example 1 B Part B. 1 H NMR (400 MHz, CDCl 3) d 8.00 (m, 1 H), 7.60-7.40 (m, 5H), 5.30-5.20 (m, 2H), 5.10 (m, 2H), 4.80-4.60 (m, 1 H).

Part D: Compound 2558 was prepared as described in Example 51 B Part C of compound 2557. 1 H NMR (400 MHz, CDCl 3) d 8.00 (s, 1 H), 7.40-7.20 (m, 5H), 6.20 ( s, 1 H), 5.30-5.00 (m, 3H), 4.70 (m, 2H), 3.25 (m, 2H), 1.30 (m, 3H).

Part E: Compound 2558 (80 mg, 0.202 mmol) was dissolved in 30% HBr in acetic acid (3 mL) and stirred for 2 hours. The solvent was removed and the residue dissolved in water and washed with ethyl acetate. The aqueous layer was lyophilized to give 2559 as a red solid (1000 mg). HPLC-MS tR = 0.41 4 min. (UV25 nm); mass calculated for the formula CnHi4N6S 262.1, LCMS observed m / z 263.1 (M + H). by column chromatography (SiO2, 15% ethyl acetate / hexanes) gave 2561 (350 mg). H NMR (400 MHz, CDCl 3) d 7.35 (s, 1 H), 5.00-4.80 (m, 1 H), 4.40 (m, 1 H), 3.60-3.40 (m, 2H), 2.30-2.20 (m, 1 H), 2.10-2.00 (m, 1 H), 2. 00-1.80 (m, 2H), 1.40 (m, 9H), 1.20 (s, 6H).

Part C: Compound 2561 (86 mg, 0.238 mmol) was dissolved in 4M HCl Part A: I To 471 (81 mg, 0.30 mmol) and DIEA (0.156 mL, 0.90 mmol) in i dichloromethane (5 mL) was slowly added acetyl chloride (0.052 mL, 0.72 mmol) at 0 ° C. The reaction mixture was allowed to stir at room temperature environment for 2 hr and concentrated. The residue was then dissolved in EtOAc and EtOAc, washed with water, 1N citric acid, NaHCO3, and brine, dried over Na2SO4 and concentrated to give 2564 (120 mg, 94%) as an oily solid. HPLC-MS tR = 1.96 min. (UV254 nm); mass calculated for the formula Ci4H23N304S2 361.1, LCMS observed m / z 362.0 (M + H).

Part A: To a stirred solution of dimethyl ester of L-tartrate (1) (29.8 g, 136 mmol) in methanol (60 ml) at 0 ° C (ice bath) was added a solution of potassium hydroxide (6.9 g, 123 g). mmol) in water (20 ml) for 30 minutes.

The reaction mixture was stirred at room temperature for 3 hours. The volatile I was removed in vacuo, water (40 ml) was added and the basic solution was washed with diethyl ether (30 ml x3). The basic solution was acidified to pH 2.0 with 6N HCl, saturated with solid sodium chloride and the product extracted into diethyl ether (40 ml x4). Drying over magnesium sulfate] and the concentration afforded compound 2 (22.2 g, 79% yield) and child The The LC-MS analysis of the reaction indicated that the reaction was complete. The volatiles were removed in vacuo, ethyl acetate was added, and the organic solution was subsequently washed with saturated NaHCO3 (x1), water (x1), brine (x1), dried over magnesium sulfate and concentrated. Purification by flash column chromatography (S1O2, 20% ethyl acetate in hexanes) provided compound 3 (60-80% yield).

Part C: A mixture of compound 3 (850 mg, 3.9 mmol) and LiOH (1 M, 5.85 mL, 5.85 mmol) in THF (30 mL) and water (10 mL) was stirred at room temperature for 5 hours. The LC-MS analysis of the reaction indicated that the reaction was complete. The volatiles were removed in vacuo, water was added and the aqueous phase acidified to pH 4.0 with HC1 1 | N. The acid solution was saturated with solid sodium chloride, the product was extracted into ethyl acetate (x2), dried over magnesium sulfate and concentrated to give compound 4-7 (60-70% yield). The following structures were synthesized using this procedure: ADDITIONAL EXAMPLE 2 ADDITIONAL EXAMPLE 2A Ethyl acetate (5 ml) was added, and the precipitates were removed by passing them through a plug of Celite. The filtrate was concentrated, and the crude was purified by flash column chromatography (Si02) 6% ethyl acetate in hexanes) to give compound 9 as a brown solid (321 mg, 82% yield). HPLC-MS t R = 1.88 min (UV25i nm); mass calculated for the formula Ci H N 193.1, LCMS observed m / z 194.1 (M + H). (10) using the Sonogashira Coupling conditions described in the Example ); calculated mass (M + H).

To a mixture of 3-bromo-N-methylbenzylamine (12) (400 mg, 2 mmol), copper iodide (15.2 mg, 0.08 mmol) and dichlorobis (triphenylphosphine) palladium (II) (28 mg, 0.04 mmol) in DMF (3 mL) was added phenylacetyrene (244.8 mg, 2.4 mmol) and triethylamine (556 uL, 4 mmol) - The reaction vessel was flushed with argon, and the reaction mixture was heated in the microwave oven for 5 minutes to i1. 10 ° C. The volatiles calculated for the formula Ci 4 H N 193.1, LCMS observed m / z 194.1 (M + H). ADDITIONAL EXAMPLE 2E Part A Part A: Compound 17 was prepared from 3-iodoaniline (16) using the Sonogashira coupling conditions described in Additional Example 2A, Part A. HPLC-MS t R = 1.94 min (U 254 nm); mass calculated for the formula C14HnN 193.1, LCMS observed m / z 194.1 (M + H). 0. 4 mmol) and diisopropylethylamine (209 uL, 1.2 mmol). The reaction mixture was heated at 55 ° C for 16 hours. Ethyl acetate (50 mL) was added, and the organic solution was washed successively with saturated NaHCO3 (x1), brine (x1), 0.5N HCl (x1), dried over magnesium sulfate and concentrated. Purification by flash column chromatography (S1O2, 20% ethyl acetate in hexanes) gave compound 19 as a white solid. HPLC-MS t R = 2.52 min (UV254 nm); mass calculated for the formula C27H34N204, 450.3, LCMS observed m / z 339.1 (M- (2x t-Bu) + H).

Part A: Compound 22 was prepared from Boc-L-Thr (t-Bu) -OH (21) and compound 9, using the coupling conditions described in the additional example 2F, Part A. HPLC-MS tR = 2.62 min (UV254 nm); mass calculated for the formula C27H34N2O4, 450.3, LCMS observed m / z 339.1 (M- (2x t-Bu) + H).

Part B: They were removed in vacuo, ethyl acetate was added, and the organic solution was washed successively with saturated NaHCO3 (x1), water (x1), brine (x1), dried over magnesium sulfate and concentrated. Purification by preparatory LC provided compound 24 (80-90% yield).

I t i I i | ? ? i I I Part D: j Compound 106 (1.0 g) was dissolved in dry and cooled THF to -40 ° C and kept under a nitrogen atmosphere. Two equivalents of BH3 in THF solution (2. M) were added dropwise and the solution was added. stirring at -40 ° C for one hour followed by letting it, reaction mixture I was warmed to room temperature and stirring continued during the night. The solvent was evaporated and extracted with ethyl acetate (200 m). The organic layer was washed with water, brine, and dried over MgSO 4. anhydrous. It was filtered and concentrated to dryness to afford the product C27H36 2O4, 452.27, LCMS observed m / z 453.1 (M + H) Part G: Compound 109 (1 10 mg, 0.25 mmol) and 4-bromoisocyanate (0.3 mmol, 60 mg, 1.2 equivalents) were dissolved in dichloromethane and the solution it was stirred at room temperature overnight. The analysis showed the termination of the reaction. The reaction mixture was added with 100 ml of dichloromethane and washed with water, brine and the DCM layer was dried over MgSO 4 anhydrous, filtered and evaporated in vacuo to give compound 1 10, which it was purified on a column of silica gel using the hexane-ethyl acetate eluants. HPLC-MS t R = 3.25 min (UV254 nm); mass calculated for formula C34H4oN305Br, 649.22, LCMS observed m / z 650.0 (M + H).

Part H: Compound 1 10 (25 mg) was dissolved in dichloromethane (2 ml) and 90% aqueous trifluoroacetic acid was added and stirred at room temperature environment for 45 minutes. The solvent was evaporated under vacuum and the material The resulting product was purified on preparative HPLC to provide the product 1 1 1 HPLC-MS t R = 1.80 min (UV254 nm); mass calculated for the formula i I C27H28N305Br, 553.12, LCMS observed m / z 554.1 (M + H).

Additional example 1 (parts a, b, c) j Part D: j i Compound 106 (2 mmol, 610 mg) was dissolved in THF (50 ml) and it was cooled to 0 ° C and kept under a nitrogen atmosphere. To the solution aforementioned, with agitation, a solution of?,? carbonyldiimidazole (2.2 mmol, 356 mg) in THf and stirring continued for the night. Removal of the solvent gave the activated ester with yield quantitative and is used in the next step without purification.

HPLC-MS t R = 3.25 min (UV254 nm); mass calculated for formula C19H2iN305, 371.15, LCMS observed m / z 372.10 (M + H).

Part E: Compound 13 generated in situ, [addition of dibutylmagnesium to ethyl malonate hydrogen in THF at -78 ° C stirred at -78 ° C for 1 hr] was added to a solution containing compound 12 in THF and it was stirred at room temperature for 24 hours. The solvent was evaporated and ethyl acetate (100 ml) was added. The organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered and evaporated to give a gummy material, purified on a silica gel column to give compound 14.

HPLC-MS t R = 1.95 min (?? 254 nm); mass calculated for the formula C20H25NO6, 375.17, LCMS observed m / z 376.10 (M + H).

Part F: To Compound 114 (0.2 mmol, 75 in ethanol (5 mL) was added 3-hydroxybenzylhydrazide dihydrochloride (0 .. mmol, 50 mg) and triethylamine (140 uL, 1 mmol, 5 equivalents) and was refluxed. overnight LCMS analysis showed product formation Ethanol was evaporated and the compound was purified by preparative HPLC to give product 1 15. HPLC-MS tR = 1.50 min (UV25 nm) mass calculated for the formula C25H27N3O5, 449.17, LCMS observed m / z 450.10 (M + H).

Part G: Compound 1 16 was prepared using the procedure described in Additional Example 3 Part B. HPLC-MS R = 1.40 min (UV25 nm) mass m / z 410.10 similar to the additional 6 the for Part A: Compound 106 was prepared as described in example 6.

Compound 106 (305 mg, 1 mmol) was dissolved in dimethylformamide and HATU (408 mg, 1.1 mmol) were added, diisopropylethylamine amine (525 uL, 3 mmol) stirred at temperature ambient. After ten minutes, 4-bromo or phenylene diamine was added to the reaction mixture and stirring was continued overnight. The LCMS analysis showed the completion of the reaction. The mixture was diluted reaction. I ADDITIONAL EXAMPLE 9 Compound 121 Compound 120 Dissolve 3-quinolin-2-yl-acrylic acid (^ 00 mg, 2 mmol) in i dimethylformamide and HATU (800 mg, 2.2 mmol) and add diisopropylethylamine. (1.2 ml, 6 mmol) and stirred at room temperature. To this solution, you added 4-methylsulfonylbenzylamine hydrochloride and agitation continued During 4 hours. The reaction mixture was diluted with ethyl acetate and washed with water, brine and dried over anhydrous MgSO 4: filtered and evaporated i organic solvent to provide the product 120.

Compound 121 Compound 120 (185 mg, 0.5 mmol) was dissolved in dichloromethane and osmium tetroxide (254 mg, 1 mmol) was added and the mixture was stirred overnight. The LC analysis indicated the formation of the product. Evaporation of the solvent and purification of the product by passing it through the column of silica gel followed by HPL < high school, resulted in the product 121.

EXAMPLE 10 The compounds mentioned in the table below can be prepared from the procedures described in experiments 2A or 2C, using Sonogashira coupling followed by coupling with compound 5 or 7 with HATU and hydrolysis as described in example 3 A and B.

Those skilled in the art will appreciate that changes could be made to the embodiments described above, without departing from its broad inventive concept. Therefore, it is understood that this invention is not limited to the particular embodiments described, but is intended to cover the modifications that are within the spirit and competence of the invention, as defined by the appended claims. Each and every one of the documents referred to in this patent application are incorporated as a reference to this document in its entirety, for all purposes.

Claims (39)

NOVELTY OF THE INVENTION CLAIMS 1. A compound selected from the group consisting of: twenty twenty twenty twenty twenty twenty twenty or a pharmaceutically acceptable salt, solvate or ester thereof. 2. The compound according to claim 1, further characterized in that said compound is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or ester thereof. 3. A pharmaceutical composition comprising as an active ingredient at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof. . The pharmaceutical composition according to claim 3, further characterized in that it additionally comprises at least one pharmaceutically acceptable carrier. 5. The use of at least one compound in accordance with the claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for treating disorders associated with the tumor necrosis factor alpha (TACE) conversion enzyme, aggrecanase, aggrecan degradation metalloprotease (ADMP) , UDP-3-0- (R-3-hydroxymyristoyl) -N-acetylglucosamine deacetylase (LpxC), tumor necrosis factor-alpha (TNF-a), matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAM's) or a combination of them in a patient. 6. A method for preparing a pharmaceutical composition useful for treating disorders associated with TACE, LpxC, aggrecanase, ADMP, TNF-a, MMP's, ADAM's or any combination thereof, said method comprising intimately contacting at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, and at least one pharmaceutically acceptable carrier . 7. A pharmaceutical composition useful for treating disorders associated with TACE, aggrecanase, ADMP, TNF-α, MMP, ADAM or any combination thereof in a subject, comprising a therapeutically effective amount of at least one compound in accordance with claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof. 8. A compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, in the form purified. The use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for treating a condition or disease mediated by TACE, LpxC, MMP's, ADMP, TNF-a, aggrecanase, or any combination thereof, in a subject. 10. The use as claimed in claim 9, wherein the aggrecanase is aggrecanase 1, aggrecanase 2, aggrecanase 3, or aggrecanase 4. The use of at least one compound according to claim 1 or a salt, solvate or pharmaceutically acceptable ester thereof, for the manufacture of a medicament useful for treating a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastasis, glaucoma neovascular disease, inflammatory bowel disease, multiple sclerosis and psoriasis in a subject. The use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for treating a condition or disease selected from the group consisting of fever, conditions cardiovascular, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease and HIV infection in a subject. 13. The use of at least one compound in accordance with the
1. Claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for treating a condition or disease selected from the group consisting of septic shock, hemodynamic shock, sepsis syndrome, post-ischemic reperfusion injury , malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, inflammatory skin diseases, inflammatory bowel diseases such as Crohn's disease and colitis, osteoarthritis and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Behcehe's disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, syndrome of pain complex regional r, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, noninsulin-dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, infarction myocardial infarction, cerebral infarction, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing alveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible airway obstruction, adult respiratory distress syndrome, asthma , chronic obstructive pulmonary disease (COPD) and bronchitis, in a subject. 14. The use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof for the manufacture of a medicament useful for treating a condition or disease associated with COPD in a subject. The use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for treating a condition or disease associated with rheumatoid arthritis in a subject. 16. The use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for treating a condition or disease associated with Crohn's disease in a subject. The use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for treating a condition or disease associated with psoriasis in a subject. 18. The use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for treating a condition or disease associated with ankylosing spondylitis in a subject. 19. The use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for treating a condition or disease associated with sciatica in a subject. The use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for treating a condition or disease associated with complex regional pain syndrome, in a subject. The use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for treating a condition or disease associated with psoriatic arthritis in a subject. 22. The use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof., for the manufacture of a medicament useful for treating a condition or disease associated with multiple sclerosis in a subject, wherein said medicament is adapted to be administrable in combination with a compound selected from the group consisting of Avonex®, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis. 23. The use as claimed in claim 1, wherein the medicament is also adapted to be administrable with at least one medicament selected from the group consisting of disease modifying antirheumatic drugs (DMARDS), NSAIDs, COX inhibitors. -2, COX inhibitors-, immunosuppressants, biological response modifiers (BRM's), anti-inflammatory agents and H1 antagonists. 24. The use as claimed in claim 12, wherein the medicament is also adapted to be administrable with at least one medicament selected from the group consisting of DMARDS, NSAID's, COX-2 inhibitors, COX-1 inhibitors, immunosuppressants, BRM's, anti-inflammatory agents and H1 antagonists. 25. The use as claimed in claim 13, wherein the medicament is also adapted to be administrable with at least one medicament selected from the group consisting of DMARDS, NSAID's, COX-2 inhibitors, COX-1 inhibitors, immunosuppressants, BRM's, anti-inflammatory agents and H1 antagonists. 26. The use of a compound according to claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, for the manufacture of a medicament useful for the treatment of a microbial infection in a mammal. 27. The use as claimed in claim 26, wherein said infection is a gram negative infection. 28. The use as claimed in claim 26, wherein said infection is a gram positive infection. 29. The use as claimed in claim 26, wherein the medicament is also adapted to be administrable with one or more additional antibacterial agents. 30. The use as claimed in claim 29, wherein said antibacterial agent is active against gram negative bacteria. 31 The use as claimed in claim 29, wherein said antibacterial agent is active against gram positive bacteria. 32. The use as claimed in claim 26, wherein said microbial infection is caused by at least one organism selected from the group consisting of Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Acinetobacter hydrophila, Actinobacillus actinomycetemcomitans, Aeromonas hydrophila, Alcaligenes xylosoxidans, Bacteroides distasonis, Bactera roldes fragilis, Bacteroides melaninogenicus, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bartonella henselae, Bordetella pertussis, Branhamella catarrhalis, Brucella melitensis, Brucella abortus, Brucella canis, Burkholderia cepacia, Burkholderia mallei, Burkholderia pseudomallei, Campylobacter coli, Campylobacter fetus, Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Citrobacter koseri, Coxiella burnetli, Edwarsiella tarda, Ehrlichia chafeenis, Eikenella corrondens, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Escherich ia coli, Flavobacterium meningosepticum, Francisella tularensis, Fusobacterium spp., Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Helicobacter pylori, Kingella kingae, Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella pneumoniae, Klebsiella rhinoscleromatis, Legionella pneumophila, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitides, Pasteurella multocida, Plesiomonas shigelloides, Porphyromonas asaccharolytica, Porphyromonas gingivalis, Prevotella bivia, Prevotella buccae, Prevotella corporis, Prevotella endodontalis, Prevotella intermedia, Prevotella melaninogenica, Prevotella oralis, Proteus mirabilis, Proteus myxofaciens, Proteus penner, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuarfii, Pseudomonas aeruginosa, Pseudomonas fluorescens, Ricketsia prowozekii, Enteric Salmonella, Serratia marcescens, Shigella boydii, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Stenotrophomonas maltophilia, Streptobacillus moniliformis, Vibrio alginolyticus, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vuluificus , Yersinia enterocolitica, Yersinia pestis, and Yersinia pseudotuberculosis. 33. The use as claimed in claim 26, wherein the organism is selected from the group consisting of Acinetobacter baumannii., Acinetobacter spp., Aeromonas hydrophila, Bacteroides fragilis, Bacteroides spp., Bordetella pertussis, Campyiobacter jejuni, Campyiobacter spp., Citrobacter freundii, Citrobacter spp., Enterobacter cloacae, Enterobacter spp., Escherichia coli, Fusobacterium spp., Haemophilus influenzae, Haemophilus parainfluenzae, Helicobacter pylori, Klebsiella pneumoniae, Klebsiella spp., Legionella pneumophila, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitides, Pasteurella multocida, Prevotella spp., Proteus mirabilis, Proteus spp., Providencia stuartii, Pseudomonas aeruginosa, Pseudomonas spp. ., Enteric Salmonella, Salmonella typhi, Serratia marcescens, Shigella spp., Stenotrophomonas maltophilia, Vibrio cholerae, Vibrio spp., And Yersinia spp. 34. The use as claimed in claim 26, wherein said microbial infection is a fungal infection. 35. The use of at least one compound of the formula (I): Formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: A is selected from the group consisting of: and -C02R1; d is 0 to 4; J is selected from the group consisting of O, S, and NR5; E is selected from the group consisting of: O, S, and NR5; T is O u S; R and R2 are the same or different, each is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl, and heteroaryl; or alternatively R1 and R2, taken together with the N to which R and R2 are shown attached, said heterocyclic ring having 4-8 members having 1 -3 heteroatoms including N, said heterocyclic ring being optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl, heteroaryl and 4-8 membered heterocyclic ring may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group of R70 portions below; R10 is selected from the group consisting of H, alkyl, and fluoroalkyl; R20 is selected from the group consisting of H, alkyl, and fluoroalkyl; R30 is H or alkyl, or alternatively R30 and R40, taken together with the N to which R40 is shown attached in Formula I, join to form a 4-7 membered heterocyclic ring, wherein said heterocyclic ring is unsubstituted or optionally substituted independently with one or more portions that may be the same or different, each portion being independently selected from the group of portions R70 below; R40 is H or alkyl; R50 is H or alkyl; W is - (CR 32) n-, where n is from 0 to 5 or a covalent bond, or alternatively two R 13 groups can be fused to form a 3-8 membered cycloalkyl, wherein said 3-8 membered cycloalkyl can be substituted or optionally substituted independently with one or more portions which may be the same or different, each portion is independently selected from the group of portions R6 shown below; X is absent or present, and if X is present, it is selected from the group consisting of a covalent bond, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group of portions R70 shown below; And it is absent or present, and if Y is present, it is selected from the group consisting of a covalent bond, - [C (R6) 2] n- where n is 1 to 2, -O-, -S-, - NR1-, -SOv- where v is 1 to 2, -SOn (CR62) p- where n is 1 or 2 and p is 1 to 4, -0 (CR62) q- or - (CR62) qO- where q is 1 a 4, -N (R7) S (0) n- or -S (0) nN (R7) - where n is 1 or 2, and -N (R7) C (O) - or -C (0) N (R7) -; Z is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, said cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally fused with aryl, heterocyclyl, heteroaryl or cycloalkyl; wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group of portions R70 that appears below; R5 is selected from the group consisting of hydrogen, alkyl, and alkylaryl; each R6 is the same or different and is independently selected from the group consisting of hydrogen, halogen, -SR1 5, -S (0) qR1 where q is 1 to 2, alkyl, cycloalkyl, heterocyclyl, alkoxy, hydroxy, nitro, cyano, amino, alkenyl, alkynyl, arylalkyl, aminocarbonyl, alkylcarbonyl, and alkoxycarbonyl; each R7 is the same or different and is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, alkenyl, alkynyl, arylalkyl, alkylcarbonyl, and alkoxycarbonyl, wherein each of the aryl, heteroaryl and heterocyclyl can be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group of portions R70 shown below; R13 is the same or different and is independently selected from the group consisting of hydrogen, halogen, -OH, -OR14, alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylaryl, alkylamino, and alkylcarbonyl; R14 is alkyl; each R70 is a substituent for H where indicated, and is the same or different and is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN , -CF3, -OCF3, -OR15, -C (O) R15, -C (O) OR15, -C (0) N (R15) (R16) > -SR15j. S (O) qN (R 5) (Rl6) where q is 1 to 2, -C (= NOR15) R16, -N (R15) (R16) I _A | QU¡ |. N (R 5) (R 6), -N (R 5) C (O) R 16, -CH 2 -N (R 5) C (O) R 16 -N (R 15) S (0) R 6, - N (R15) S (O) 2R16, -CH2-N (R5) S (O) R1 6, -N (R17) S (O) 2N (R16) (R15)). eXRl S), -N (Rl 7) C (0) N (Rl 6) (Rl 5) f -CH2- N (R17) C (0) N (R 6) (R 5), -N (R 5) C (O) OR 16 -CH 2 -N (R 5) C (O) OR 6, and - S (0) qR15 where q is from 1 to 2; and where each of the alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl are independently unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, -CF3, -CN, -OR1 5, -N (R 5) (R 6), -C (0) OR 15, -0 (0) 1 ^ 15) ^ 16), and -N (R15) S (0) R16; and every R15, 16 17 R and R are independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or alternatively R15 and Re taken together with the N to which they are shown attached, join to form a 4-8 membered heterocyclic ring, wherein said 4-8 membered cycloalkyl may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion is selected independently from the group consisting of R75 portions that appear below; each R75 is selected independently from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl, and wherein each of alkyl, cycloalkyl, heterocyclyl, aryl, Arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl is independently unsubstituted or substituted with 1 to 5 selected groups independently from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, -CF3, -CN, -OR19, -N (R19) 2, -C (O) OR19, -C (0) N (R19) 2, and -N (R19) S ( O) R19; and each R19 is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, for the manufacture of a medicament useful for treating a disorder associated with UDP-3-0 (R-3-hydroxymyristoyl) -N-acetylglucosamine deacetylase ( LpxC) in a subject. 36. The use as claimed in claim 35, wherein the disorder is a microbial infection. 37. The use as claimed in claim 36, wherein said microbial infection is a bacterial or fungal infection. 38. The use as claimed in claim 37, wherein said bacterial infection is a gram negative infection. 39. The use as claimed in claim 37, wherein said bacterial infection is a gram positive infection.