MX2007000521A - Iap binding compounds - Google Patents

Abstract

IAP binding molecules and compositions including these are disclosed. The IAP binding molecules interact with IAPs (inhibitor of apoptosis proteins) in cells and may be used to modify apoptosis in cells treated with such molecules. Embodiments of these compounds have a Kd of less that 0.1 micromolar. Methods of using these IAP binding molecules for therapeutic, diagnostic, and assay purposes are also disclosed.

Description

IAP LINK COMPOUNDS CROSS REFERENCE TO RELATED REQUESTS This application claims the benefit of the provisional US patent application. Serial No. 60 / 588,050, filed July 15, 2004, which is hereby incorporated by reference in its entirety. BACKGROUND Apoptosis, programmed cell death, plays a central role in the development and homeostasis of all multi-cellular organisms. Alterations in apoptotic pathways have been implicated in many types of human pathologies, including developmental disorders, cancer, autoimmune diseases, as well as neurodegenerative disorders. The routes of programmed cell death have become objective or targets for the development of therapeutic agents. In some cases, because it is easier to kill dead cells than to support them, anti-cancer therapies using pro-apoptotic agents such as conventional radiation and chemo-therapy have been used to trigger the activation of mitochondrial-mediated apoptotic pathways. However, these therapies lack molecular specificity and more specific molecular targets are required.

Apoptosis is primarily performed by activated caspases, a family of cysteine proteases with aspartate specificity in their substrates. Caspases are produced in cells as catalytically inactive zymogens and must be processed proteolytically to become active proteases during apoptosis. In normal surviving cells that have not received an apoptotic stimulus, most caspases remain inactive. Even if some caspases are aberrantly activated, their proteolytic activity can be totally inhibited by a family of evolutionarily conserved proteins, called inhibitors of apoptosis proteins (IAPs = inhibitors of apoptosis proteins) (Deveraux &Reed, Genes Dev. 13: 239-252, 1999). Each of the IAPs contains 1-3 copies of the so-called baculoviral IAP repeat domain (BIR = Baculoviral IAP Repeat) and interacts directly with and inhibits the enzymatic activity of mature caspases. Several IAPs from different mammals including XIAP, survivin and LIVIN / ML-IAP, (Kasof and Gomes, J. Biol. Chem. 276: 3238-3246, 2001; Vucic et al., Curr. Biol. 10: 1359-1366, 2000 Ashhab et al., FEBS Lett 495: 56-60, 2001), have been identified and exhibit anti-apoptotic activity in cell culture (Deveraux &Reed, 1999, supra). Since IAPs are expressed in most cancer cells, they can directly contribute to tumor progression and subsequent resistance to drug treatment. In normal cells designated for apoptosis, however, the inhibitory effect mediated by IAP must be removed, a process performed at least in part by a mitochondrial protein called Smac, the second mitochondrial caspase activator; (Du et al., Cell 102: 33-42,2000) or DIABLO (direct IAP binding protein with low pH, Verhagen et al., Cell 102: 43-53,2000). Smac / DIABLO, synthesized in the cytoplasm, targets the inter-membrane space of mitochondria. Upon apoptotic stimulation, Smac is released from mitochondria back into the cytosol, along with cytochrome c. While cytochrome c induces multimerization of Apaf-l to activate procaspase-9 and procaspase-3, Smac eliminates the inhibitory effect of multiple IAPs. Smac interacts with all the IAPs that have been examined to date, including XIAP, c-IAPl, c-IAP2, ML-IAP, and survivin. Smac seems to be a regulator of apoptosis in mammals. In addition to the inhibition of caspases, over-expressed IAPs can function to bind Smac and prevent it from binding to XIAP and releasing caspases (Vucic et al., Biochem.

J. 385 (Pt 1): 11-20, 2005). Smac is synthesized as a precursor molecule of 239 amino acids; the 55 N-terminal residues serve as the mitochondrial target sequence that is removed after import. The mature form of Smac contains 184 amino acids and behaves like an oligomer in solution. Smac and various fragments thereof have been proposed to be used as targets for the identification of therapeutic agents. The biological activity of Smac is considered to be related to binding its four N-terminal residues to a surface groove characterized in a portion of XIAP referred to as the BIR3 domain. This link prevents XIAP from exerting its suppressive function of apoptosis in the cell. The N-terminal tetrapeptides of IAP-binding proteins of the pro-apoptotic protein of Drosophila Hid, Grim and Reaper, are considered to work in the same way. The co-pending common property international application, No. PCT / US02 / 17342, filed on May 31, 2002 and incorporated herein by reference in its entirety, describes assays for use in high-performance monitoring of agents binding to a BIR domain of an IAP, thereby alleviating IAP-mediated suppression of apoptosis. The assays utilize a labeled peptide or peptidomimetic binding peptide that binds to a BIR domain of an IAP, wherein at least one measurable characteristic of the tag changes as a function of the IAP binding compound that is bound to LAP or free in solution. The BIR domain of an IAP is contacted with the labeled LAP peptide or peptidomimetic, to form a complex, and the complex is exposed to a compound to be tested for BIR binding. Displacement of the labeled or peptidomimetic IAP peptide from the complex, if any, by the test compound is measured. Disadvantages in the use of peptides for in vivo administration as diagnostic or therapeutic agents, may include their short half-life due to proteolytic degradation of the peptide in the body, low absorption through the intestinal walls, potential immunogenic reactions, as well as the expense involved in the synthesis of peptide. It would be beneficial to prepare non-peptide IAP binding compounds that have comparable biological activity of bioactive peptides, but have improved pharmacological properties and are easier or less expensive to synthesize. In connection with the Smac tetrapeptides would it be a significant advance in the technique, to develop binding compounds ??? which can be used to promote apoptosis, while having the improved properties associated with non-peptide compounds. These compounds can be used as diagnostic and therapeutic agents in the treatment of conditions related to apoptosis. COMPENDIUM OF THE INVENTION One embodiment of the present invention is a compound, or composition comprising a compound of the general formula (2): where: ?? and A2 are independently hydrogen, alkyl, aryl or alkylaryl group, Rla is H or a methyl group; Rib is an alkyl or aryl group; ? is a group -0-, -S-, -CH2-, or -NH- and J is a group -CH-, or -N-, provided that when J is -N-, ?? is the group -CH2-, or -NH-; Y is H, or an alkyl group; Z is a group -OH, aryloxy, alkoxy, benzylloxy, benzyloxy, amino, arylamino, alkylamino, benzylamino; R2 is a detectable label or is: M is an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene group, G is chosen from a bond, -0-; -N (R2d) - wherein R2d is H, alkyl, cycloalkyl or aryl; or -S (0) m- where m is 0, 1, or 2; and R10 is cycloalkyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl; n independently is the integer 0, 1, 2, 3, 4, or 5. Another embodiment of the present invention is a compound or composition that includes a compound of the general formula (3): wherein Ai is H, lower alkyl group, or optionally substituted lower alkyl; Ria and Rib are separately H, lower alkyl group, optionally substituted lower alkyl, lower alkylene, optionally substituted lower alkenylene; or Ai together with either Ria or Rlb, form an optionally-substituted heterocycloalkyl group with 3 to 6 atoms; Y is H, an alkyl group, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, aryl, heteroaryl, arylalkyl, optionally-substituted versions of these groups, substituted hydroxy versions of these groups, or Y together with Z, M, G, or Rio form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Y is linked to Z, M, G or Ri0; Z is H, an alkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, cycloalkyloxy, aryl, heteroaryl, aryloxy or heteroaryloxy group; or Z together with Y, M, G or Rio form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Z is linked to Y, M, G or Ri0; is an optionally substituted alkyl, alkenyl, or alkynyl group; an alkyl, alkenyl or alkynyl group optionally substituted with 1 to 5 carbon atoms; an optionally substituted alkylene, alkenylene or alkynylene group; or an optionally substituted alkylene, alkenylene or alkynylene group with 1 to 5 carbon atoms; G is a bond, a heteroatom, ~ (C = 0) ~; -S (0) t ~ where t = 0, 1, or 2; -NRis-; -NCOR18-; or -NS (0) xR18- wherein x = 0, 1, or 2, and Ris is lower alkyl, optionally substituted lower alkyl or cycloalkyl or Ri8 is contained within a carbocyclic or heterocyclic ring containing 1 to 5 heteroatoms, where Laugh is linked to Z, M, or RÍO; R10 is an aryl, heteroaryl, a fused aryl, a fused heteroaryl group; or R; LO is any of structures (4a), (4b), (4c) or (4d): (4a) (4b) (4c) (4d) wherein X2 is a heteroatom and independently groups R'iir ¾2Í any of R13-17, or any of R14-17 is H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently Rn, R'n, R12, any of R13-17, or any of R1 -17 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or optionally substituted heteroaryloxy; or independently Rn, R'n, R12, any of R13-17, or any of R14-17 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups Rn, R'n, R12, any of ¾3- ?? or any of R14-17 is contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups in the Y, Z, M, G, Rn, R'n, Ri2 position, any of Ri3-i7, or any of Ri4_i7. Another embodiment is a compound, or a composition comprising a compound of the general formula (5) (5) where ? is H, or lower alkyl; Rla is H; Rib is lower alkyl group; Y is an alkyl group, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of these groups, substituted hydroxy versions of these groups; Zla and Zlb are independently an H, hydroxy, alkoxy, aryloxy, or heteroaryloxy group; M is an optionally substituted alkyl group or an optionally substituted alkylene group of 1 to 5 carbon atoms; G is a bond, a heteroatom, or -NCORi8- and Ris is lower alkyl, optionally substituted lower alkyl group; Rio is any of the structures (4a), (4b), (4c) or (4d): wherein X2 is a heteroatom independently of the groups ¾i, R'n, R12, any of Ri3 ~ i7, or any of R14-17 are H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether , amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently Riir R'11; Ri2; any of Ri3_i7, or any of R14-1-7 are H, alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or optionally substituted heteroaryloxy; independently Rn, R'n, R12, any of Ri3-i7, or any of Ri4-i7 are acyl or acetyl group, carboxylate, sulfonate, sulfone, imine or oxime groups; or groups U, R '[p], R12, any of RI3-17A or any of R14-1-? are contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups in the position Y, Zia, Zn,, M, G, Ru, R'u, R12, any of ¾3- ? 7 / · or any of R14-17. In a preferred embodiment, the present invention is a compound, or a composition comprising a compound of the general formula (5) (5) where ?? is H, or lower alkyl; Ria is H; Rib is lower alkyl group; Y is an alkyl group, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of these groups, hydroxy substituted versions of these groups; Zia and Zib are independently an H, hydroxy, alkoxy, aryloxy or heteroaryloxy group; M is an optionally substituted alkyl group or an optionally substituted alkylene group of 1 to 5 carbon atoms; G is a bond, a heteroatom, or -NCORis- and Ris is a lower alkyl group, optionally substituted lower alkyl; R10 is any of structures (4a), (4b), (4c) or (4d): where X2 is a heteroatom and independently groups ¾.! / · R'u; ¾2A any of Ri3-i7, or any of Ri -i7 are H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently ¾i, R'n, R12 any of R13-17, or any of Ri -i7 are H, alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or heteroaryloxy; optionally substituted; independently Rn, R'n, R12, any of Ri3-i7, or any of Ri4-i7 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine or oxime groups; or groups Ru, R'u, Ri2r any of R13-17, or any of Ri _i are contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups in the Y, Zia Zlb position , M, G, Ru, R'ii, R12, any of R13-17, or either of R1 -17. Even more preferable, X2 is nitrogen. Additional embodiments of the present invention include molecules and compositions that may be useful for modifying or regulating apoptosis in cells. These IAP binding molecules can bind to a variety of Apoptosis Protein Inhibitors (IAP's = Inhibitor of Apoptosis Proteins). These molecules can be monomers or dimers and can also include a detectable label or therapeutic portion and can be formulated as pharmaceutical or diagnostic compositions containing these molecules. Methods for using these compounds as therapeutic and diagnostic agents are also described. The IAP binding molecules of the present invention, which can also be referred to as IAP binding charge molecules, can permeate, be transfected or otherwise transported in cells in an active or passive manner and can be used to displace IAPs from other proteins such as caspases or Smac in cells. At least a portion of the LAP charge-binding molecule binds to a BIR domain of an LAP. The IAP linkage loading molecule can provide a therapeutic effect for a cell proliferation disorder and can include additional therapeutic, diagnostic or other substituents in the molecule. Modes of LAP binding molecules include pyrrolidine derivatives that bind to a BLR domain of an LAP. Modalities of the present invention include LAP binding charge molecules and their pharmaceutically acceptable salts having the general structure of formula (2): where: ? and A2 can independently be hydrogen, an alkyl, aryl or alkylaryl group, Rla can be H or a methyl group; Rib can be an alkyl or aryl group, in some embodiments Rn, is a methyl, ethyl, n-propyl, isopropyl, or ethenyl group; ?? can be a group -0-, -S-, -CH2-, or -NH-, and J can be a group -CH-, or -N-, provided that when J is -N-, ?? is -CH2-, or a group -NH-; And it can be H, or an alkyl group; Z can be H, a group -OH,. aryloxy, alkoxy, benzyloxy, amino, arylamino, alkylamino, benzylamino, in some embodiments Z is a group -OH, aryloxy, alkoxy, benzyloxy, benzyloxy, amino, arylamino, alkylamino, benzylamino; R2 can include a detectable label or it can be: wherein R2a can be an optionally substituted aryl, cycloalkyl, aralkyl, or cycloalkyl group; R2 can be H or an alkyl group, R2c can be an optionally substituted aryl, cycloalkyl, aralkyl or cycloalkylalkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl or cycloalkylaryl group. In some embodiments R2c is substituted tetrahydronaphthyl or tetrahydronaphthyl group, more preferably R2c is Or chiral carbons (i *) for (i * = 3 to 8) can independently have a configuration. { R) or (S); M can be an alkylene, alkenylene, alkylene, heteroalkylene, heteroalkenylene, heteroalkylene group, in some embodiments M is: In some modes G may be selected from a link (ie, G is absent), -0-; - N (R2d) - wherein R2d can be H, alkyl, cycloalkyl or aryl; or -S (0) m- where m is 0, 1, or 2; Rio may be cycloalkyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl; In some modalities Rio is: wherein R3, R'3, R4, R5, R'5, R6, R7, R8 and R9 can each independently be H, methyl, ethyl, n-propyl, isopropyl, halo, cyano, - (CH2) PC ( = 0) OH, - (CH2) PC (= 0) 0-alkyl, - (CH2) PC (= 0) NH2; n and p are integers and preferably n is independently the integer 0, 1, 2, 3, 4, or 5 and p is independently the integer 0, 1, 2, or 3; preferably at least one R3, R'3, R4, and R'5, R5 or at least two of R6, R, R¾ and 9 each independently are H, methyl, ethyl, n-propyl, isopropyl, halo, or cyano; provided that when one or more of R3, R'3, R'5, and R5 is isopropyl, R is different from isopropyl; provided that when R4 is isopropyl, R3, R'3, R'5, and R5, each independently are different from isopropyl; provided that when R8 is isopropyl, R9 is different from isopropyl; and provided that in a therapeutic composition, (2) is not the structure where R2 is where ?? is H, A2 is methyl, Rla is H, Rn, is methyl, ?? is -NH-, J is -CH-, Y is t-butyl, Z is (-OC6H5) and (3 *) has a configuration (S), (4 *) has a configuration (S), (5 *) has a configuration (S) or. { R), (6 *) has a configuration (S) or (i?), And (7 *) has a configuration (R). Some embodiments of compounds of structure (2) have a d as determined by the methods described, for example, in Example 1 less than 100 micromolar, preferably 1 micromolar, and even more preferably less than 0.1 micromolar. Some embodiments of the LAP binding compounds or LAP binding charge molecules of structure (2), wherein A2 is H, Xi is -NH-, J is -CH-, and n is 0 for I, can be illustrated with the structure (3): In some embodiments of the compounds of structure (3), i may be H, lower alkyl, or optionally substituted lower alkyl group; Rla and Rib can separately be H, lower alkyl group, optionally substituted lower alkyl, lower alkylene, optionally substituted lower alkylene; or Ai together with either Ria or Rlb can form an optionally substituted heterocycloalkyl group of 3 to 6 atoms; Y can be H, an alkyl group, an alkyl group of 1 to 10 carbon atoms, a branched alkyl group of 1 to 10 carbon atoms, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, an aryl group , heteroalkynyl, heteroaryl or arylalkyl; optionally substituted versions of the aforementioned groups; hydroxy substituted versions of the aforementioned groups; or Y together with Z, M, G, or Rio forms an optionally substituted carbocyclic ring, or an optionally substituted heterocyclic ring containing 1 to 5 heteroatoms, wherein Y is linked to Z, M, G, or Ri0; preferably Y is linked to M, G, or Ri0 by any amount atoms to about 20 atoms. Z can be H, alkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, cycloalkyloxy, aryl, heteroaryl, aryloxy, or heteroaryloxy group; or Z together with Y, M, G, or Rio form an optionally substituted carbocyclic ring, or an optionally substituted heterocyclic ring containing 1 to 5 heteroatoms, wherein Z is linked to Y, M, G, or Rio; preferably Z is linked to Y, M, G, or R10 by any number of atoms up to about 20 atoms. M can be an optionally substituted alkyl, alkenyl, or alkynyl group; an optionally substituted alkyl, alkenyl or alkynyl group of 1 to 5 carbon atoms; an optionally substituted alkylene, alkenylene, or alkynylene group; or an alkylene, alkenylene or alkynylene group optionally substituted by 1 to 5 carbon atoms. G may be absent (a link), or a heteroatom including -0-; -NH-; - (C = 0) -; -S (0) t- where t is the integer 0, 1, or 2; -NR ^ -; -NCORis-; or -NS (0) xRi8- wherein x is the integer 0, 1, or 2, and R18 may be lower alkyl, optionally substituted, or cycloalkyl or Ri8 is contained within an optionally substituted carbocyclic ring, or optionally substituted heterocyclic ring containing 1 to 5 heteroatoms, wherein R is linked to Z, M, or Rio, preferably Ri8 is linked to Z, M, or Rio, by any number of atoms up to about 20 atoms. Rio can be an aryl group, a heteroaryl, a fused aryl group, a fused heteroaryl group or optionally substituted versions of these groups; or Rio can be any of structures (4a), (4b), (4c), or (4d): (4b) (4c) (4d) wherein X2 is a heteroatom in structures (4a) or (4b), or X2 is a carbon-carbon bond as illustrated in structures (4c) or (4d), and the groups independently ¾i, R'11, R12 , or any of R13-17, or any of Ri-i7 can be H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or heteroaryloxy; or independently ¾i, R'n, Ri2r any of R13-17, or any of Ri-i7 may be H, optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl , aryloxy, or heteroaryloxy; or independently Rn, R'n, Ri2c any of R13-17, or any of Ri4-i7 can be acyl or acetyl, carboxylate, sulfonate, sulfone, imine, or oxime groups; or the groups Rn, R'n; Rn, any of R13-17, or any of Ri4 ~ i7 may be contained within an optionally substituted carbocyclic ring, or an optionally substituted heterocyclic ring containing 1 to 5 heteroatoms, and may be linked to groups in the Y, Z position , M, G, Rn, R'n, R12, any of Ri3-i7 / - or any of R14-17, preferably these groups are linked by any number of atoms up to about 20 atoms. Some embodiments of compounds of structure (3) have a ¾ as determined by the methods described, for example in Example 1 of less than 100 micro-molar, preferably less than 1 micro-molar, and even more preferably less than 0.1 micro-molar . Some embodiments include compounds of structure (5) wherein: ?? it can be H, or lower alkyl, or Ai and Rn, together they form a ring of 3 to 5 atoms; Ría can be H; Rib can be a lower alkyl group, or together with Ai ring forms of 3 to 5 atoms; And it can be an alkyl group, an alkyl group of 1 to 10 carbon atoms, a branched alkyl group with 1 to 10 carbon atoms, an alkynyl group, heteroalkynyl, a cycloalkyl group with 3 to 7 carbon atoms, optionally substituted versions of the aforementioned groups, substituted hydroxy versions of the aforementioned groups, or Y together with Zia, Zn, or Rio forms an optionally substituted carbocyclic ring, or an optionally substituted heterocyclic ring containing 1 to 5 heteroatoms, wherein Y may be linked to Zia, Zn, or Ri0; preferably Y is linked to Zia, Zib, or Rio by any number of atoms up to about 20 atoms. Zia and Zib can independently be H, a hydroxy, amino, alkylamino, dialkylamino, alkoxy, aryloxy or heteroaryloxy group; or Zia, ib together with Y or Rio forms a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Zia or Zib, is linked to Y or Ri0; preferably Zia or ib, is linked to Y or Rio by any number of atoms up to about 20 atoms. M can be an optionally substituted alkyl group or an optionally substituted alkylene group of 1 to 5 carbon atoms. G may be absent (a link), or a heteroatom including -0-; -NH-; - (O = 0) -; -NR18-; -NCORis-; or -NS (0) xR18- wherein x = 0, 1, or 2, and R18 may be a lower alkyl group, an optionally substituted lower alkyl group. Rio can be aryl, a heteroaryl group or R10 can be any of the structures (4a), (4b), (4c), or (4d): wherein X2 can be a heteroatom in structures (4a) or 4 (b) or X2 is a carbon-carbon bond as illustrated in structures (4c) or (4d), and independently groups Rn, R'n, R12 any of R13-17, or any of Ri _i7 may be H, optionally substituted alkyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; or independently Ru, R ', R12, any of Ri3-i7, or any of Ri4-i7 can be H, optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl , aryloxy, or heteroaryloxy; or independently Rn, R'u, R12, any of Ri3-i7, or any of R14-17 can be acyl or acetyl, carboxylate, sulfonate, sulfone, imine, or oxime groups; or Rile R'iic Ri2r groups any of Ri3-i7, or any of Ri -i7 may be contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups in the Y, Zia position, Zibf M, G, Rn, R'u, Rn any of Ri3-i7, or any of Ri4-i, preferably these groups are linked by any number of atoms up to about 20 atoms. Some embodiments of the compounds of structure (5) have a ¾ as determined by the methods described, for example, in Example 1 with less than 100 micromolar, preferably less than 1 micromolar, and even more preferably less than 0.1 micromolar.Some embodiments include compounds of structure (5) wherein: (5) ?? it can be H, methyl, ethyl, or i and Rib together form a ring of 3-5 atoms. Ría can be H; Rib can be a methyl or ethyl group, or together with Ai form a ring of 3 to 5 atoms. And it may be an alkyl group, an alkyl group of 1 to 10 carbon atoms, a branched alkyl group of 1 to 10 carbon atoms, an alkynyl group, heteroalkynyl, a cycloalkyl group of 3 to 7"carbon atoms, optionally substituted of the aforementioned groups, hydroxy substituted versions of the aforementioned groups, or Y together with Zia, Zib, or Ri0 form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Y is linked to Zia , Zbi or Rio, preferably Y is linked to Zla, Zlhr or Rw by any number of atoms up to about 20. Zia and Zib can independently be H, a hydroxy, amino, alkylamino, dialkylamino, alkoxy, aryloxy, or heteroaryloxy group; or 3, Zl together with α or R10 form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Zia or Zib are linked to Y or Rio, preferably Zia or Zib, is linked to Y or Rio which any number of atoms up to about 20 atoms. M can be an optionally substituted alkyl group or optionally substituted alkylene of 1 to 5 carbon atoms. G may be absent (a link), or a heteroatom including -0-; -NH-; - (C = 0) -; - Ri8 ~; -NCORi8 ~; or -NS (0) xRi8- wherein x may be the integer 0, 1, or 2, and Ris may be lower alkyl group, optionally substituted lower alkyl group. Rio can be a fused aryl, a fused heteroaryl group, or preferably Rio is any of structures (4a), (4b), (4c), or (4d): (4a) (4b) (4c) (4d) wherein X2 may be a heteroatom (4a) or (4b), or X2 may be a carbon-carbon (4c) or (4d) bond, and independently Rn, 'ii / R12 / any of RI3-I7A or any of R 14-17 can be H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; or independently Ru, R'u, Ri2r any of R13-17, or any of Ri4_i7 may be H, optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or heteroaryloxy; or independently Ru, R'u R12, any of R13-17 / or any of R14-17 can be acyl or acetyl, carboxylate, sulfonate, sulfone, imine or oxime groups; or groups Ru, R'u, R12, any of R13-17, or any of R14-17, may be contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups in the position Y, Zla, Zib, M, G, Rn, R '[TT], R12, either of i3-i7 / or any of R1 -17 / preferably these groups are linked by any number of atoms to about 20 atoms. Some embodiments include compounds of structure (5) wherein: wherein Ai can be H, or a methyl group; Rla is H; Rlb can be a methyl or ethyl group. In structure (5) Y can be an alkyl group, an alkyl group of 1 to 10 carbon atoms, a branched alkyl group of 1 to 10 carbon atoms, an alkynyl group, heteroalkynyl, a cycloalkyl group of 3 to 7 atoms carbon, optionally substituted versions of the aforementioned groups, substituted hydroxy versions of the aforementioned groups, or Y together with Rio forms a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Y is linked to R10; preferably Y is linked to Rio by any number of atoms up to about 20. Zia and Zib can independently be H, a hydroxy, alkoxy or aryloxy group. M can be methylene, an optionally substituted alkyl group or an optionally substituted alkylene group of 1 to 5 carbon atoms. G may be absent (a link), or a heteroatom including -0-; or -NH-, Rio can be an aryl group, heteroaryl, or in some embodiments Rio can be a structure of the formula (4a): where . X2 is a heteroatom and independently groups ¾.? / R12, or any of R14-17 may be H, optional substituents including halogen, alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; or independently Rn, R12, or any of Ri4-i7 can be H, optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or heteroaryloxy; or independently Rn, R12 / or any of Ri4-i7 can be acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine or oxime groups; or groups Rn, R12, or any of R14-17 can be contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups at the position Y, Zia, ib,, G, Rn, ? 2, or any of i -i7, preferably these groups are linked by any number of atoms to about 20 atoms. IAP binding compounds or IAP binding charge molecules in various embodiments of formula (2), (3), or (5) can be used in the manufacture of a medicament for therapeutic and / or prophylactic treatment of a cell proliferation condition (including developmental disorders, cancer, autoimmune diseases, as well as neurodegenerative disorders). The IAP binding compounds or LAP binding charge molecules in various embodiments of the formula (2), (3), or (5) can be used in the preparation of a drug for treating cancer or a condition of cell proliferation disorder in form ready for use. The drug can be administered to a patient to treat or prevent cancer or a cell proliferation disorder. In ready-to-use form, it refers to the compounds that are presented for sale and may include the compounds in a tablet, liquid or other form for administration, convenient packaging, instructions and other items. One embodiment of the invention is a method for treating cells or tissue which may include administering to cells having a proliferative disorder, for example HeLa cells which is known to over-express IAP (other cells may include but are not limited to those with disorders of development, cancer, autoimmune diseases, as well as neurodegenerative disorders), an amount of LAP binding compounds or LAP binding cargo molecules in various embodiments of formula (2), (3), or (5) which is effective to reduce or eliminate the cell proliferation disorder in the cell or tissue sample. A further embodiment of the present invention is a method for treating disorders associated with cell proliferation, including but not limited to disorders and proliferative diseases. These methods include administration of the compounds of the present invention, alone or in combination with other active agents, including pharmaceuticals and chemotherapeutic agents. For example, the dimers of LAP binding compounds of the present invention can be administered alone or in combination with chemotherapeutic agents as described in the co-pending U.S. patent application. Common Property Serial No. 60 / 692,111, which is incorporated herein by reference in its entirety. The above IAP linking compounds, as well as their pharmaceutically acceptable salts and solvates can be formulated as pharmaceutical compositions or as diagnostic agents or both. These pharmaceutical compositions and diagnostic agents can be used for treatment and detection of cell proliferative disorders, as well as in monitoring assays to discover and develop additional diagnostic and therapeutic agents to modify cell proliferation and detect proliferative disorders. The present invention includes an assay for use in monitoring or design of high performance rational drug of LAP binding compounds that can, such as the tetrapeptide Smac or its homologs in other species, bind to a BLR domain of an LAP in this manner by modifying and preferably alleviating the IAP-mediated suppression of apoptosis. The binding of the test compounds can be used in the design of IAP binding compounds and IAP binding charge molecules for identification, prevention and treatment of diseases related to cell proliferation. The LAP binding cargo molecule or compounds in embodiments of the present invention can bind proteins such as through the BIR domain of an LAP. In some embodiments, the LAP binding molecule interacts with the BUG domain of the XLAP protein or BLR2 domain of DIAPl. The LAP binding molecule can interact with the protein through a specific binding slot of the BLR domain. The assay includes the step of providing a labeled LAP binding compound or an LAP charge-binding molecule of structure (2), (3), or (5), which binds to the appropriate BLR domain of the LAP, where preferably at least one characteristic to be measured of the tagged LAP binding compound changes as a function of the labeled LAP binding compound that is ligated to the LAP or free in solution. The assay may further include contacting the BLR domain of an LAP with the tagged LAP binding compound under conditions that allow binding of the tagged LAP binding compound to the BLR domain, thereby forming a complex of LAP binding compound bound to labeled BLR. which has the measurable characteristic. The complex of LAP binding compounds linked to labeled BLR can be contacted with other peptides, LAP binding compounds, or developed test compounds, to measure the binding of the peptides, LAP binding compounds, or test compound for the BLR domain to the to measure the displacement of LAP binding compound labeled from the LAP binding compound complex bound to labeled BLR. Displacement of the labeled LAP binding compound from the LAP binding complex bound to BLR labeled by the peptides, LAP binding compounds, or test compound, can be determined by measuring the change in the measurable characteristic of the labeled LAP binding compound, in this way determining whether the test compound is capable of binding to the BLR domain of the LAP and the strength of the interaction. The present invention relates to the treatment of cell proliferation conditions and diseases and more specifically conditions wherein the activity of LAP in cells, tissues or an individual is abnormal. The invention characterizes molecules which are LAP binding compounds of structure (2), (3), or (5), which bind to IAPs such as but not limited to XIAP, c-IAPl, C-IAP2, ML-IAP and which they survive in cells. The mimetic molecules optionally include an integral or linked loading portion which may include therapeutic or diagnostic functionality. The LAP binding compound molecules can be administered to cells, a tissue, or a patient that requires the treatment or detection of a cell proliferation condition or disease. The need for treatment can be identified by contacting cells or a tissue, preferably the patient, with an IAP binding molecule having a detectable label or charge that changes when the molecule binds to an IAP in the tissue or cells. The binding of the IAP binding compound molecule to the IAP in the cells can be used to modify a cell proliferation condition or disease or can be combined with other therapeutic treatments such as radiation therapy. The activity of IAP in the cells of or the progress of the course of treatment for a cell proliferation condition or disease can be measured with an IAP binding loading molecule having a detectable label. In accordance with one aspect of the invention, there is provided a method for selectively identifying neoplastic or cancer cells in a mixed population of cells. The method includes contacting the mixed cell population with an IAP-binding molecule permeable to cells of the structure (2), (3), or (5), under conditions that allow the IAP binding cargo molecule to bind a protein such as an IAP within neoplastic cells, thereby selectively identifying neoplastic cells by a detectable property of the charge molecule IAP binding, and in some embodiments, a change in a detectable property of the LAP binding cargo molecule by complexing with LAP in the neoplastic cells. The cells may be cultured cells or primary cells of a patient (human or animal). Alternatively, the cells may be present in the patient and contact is achieved by introducing the IAP binding loading molecule into the patient. In one embodiment of the IAP linkage loading molecule, the loading portion of the molecule comprises a dye label. In other modalities, the loading portion of. the molecule can be but is not limited to an active NMR core or an MRI contrast agent. The selective identification of tissues or cells that have LAP is carried out through magnetic resonance imaging (MRI) or magnetic resonance imaging. Alternatively, the labeled IAP binding loading molecule comprises a radioisotope and selective identification is performed by positron mission tomography. Another aspect of the invention features a method for selective damage or induction of apoptosis in neoplastic cells to kill some or all of the neoplastic cells in a mixed population of cells. The method includes contacting a sample of the mixed cell population with an IAP linkage loading molecule of the formula (2), or (3), or (5). The LAP binding portion of the molecule or the loading portion of the molecule can include a portion or substituent that is directly or indirectly toxic to the cells, such as but not limited to a radioisotope or a photosensitizing agent. The LAP binding portion of the molecule binds to a protein such as an LAP within the neoplastic cell, where the toxic portion of the IAP binding loading molecule directly or indirectly exerts its toxic effect, thereby damaging or killing the less a portion of the neoplastic cells in a mixed population of cells. Another embodiment of the present invention is a composition that includes cells and an LAP binding cargo molecule. The LAP binding cargo molecule binds to an LAP protein, such as XLAP, C-LAP1, C-IAP2, ML-LAP, or survivin, preferably linked to a BLR surface groove of an LAP protein. In some embodiments, the LAP binding molecule binds to the BLR3 surface groove of a XIAP protein. The LAP binding loading molecule of structure (2), (3), or (5), can permeate or transfect cells and can for example be used to displace one or more LAP caspase proteins in cells or displace a protein as Smac kidnapped by LAPs. The LAP binding cargo molecule may have a detectable property that is modified by chemical, physical or a combination thereof of the LAP binding molecule with the LAP protein in the cells. This composition is useful as a control to monitor the presence of LAP in the cells undergoing treatment or for. use as a standard in the detection of abnormal levels of LAP in a sample of cells. The detectable property may be the emission of light by the loading portion of the molecule that changes when the LAP binding portion of the molecule binds to an LAP protein. The LAP binding compounds or the LAP binding charge molecules of structure (2), (3), or (5) in embodiments of the invention can be characterized as having a link constant LAP Kd. In some embodiments Kd is less than about 10 μM, in other embodiments Kd is less than about 1 μ, and still in other embodiments Kd is less than about 0.1 μ? as determined by the methods described in Example 1 or equivalents of these methods known to those skilled in the art. Molecules of the formula (2), (3), or (5) that have a Kd less than about 10? they can be used in an in vitro binding assay with the BLR domain of an LAP and in some embodiments the BLR.3 domain of XLAP. The LAP binding charge molecule, and preferably the loading portion of the molecule includes but is not limited to a fluorogenic group, a radioisotope or other chromogenic group. In additional embodiments, the LAP binding cargo molecule may include another peptide or peptidomimic unit (eg, dimer). The LAP binding cargo molecule can include an active NMR core or an MRI contrast agent and the selective identification of the loading portion of the molecule made through nuclear magnetic resonance or magnetic resonance imaging. The one or more cells in the composition may include but are not limited to cells from a body fluid, tissue, tumor, fibroid, neoplastic cells, stem cells, nervous system cells or any combination thereof of an animal, a mammal, or human. Cells in the composition can be taken from tissues suspected of exhibiting an abnormal level of LAP based on physical examination, motor skill tests, or palpation of a mass in a part of the body. The composition may include one or more pharmaceutically acceptable excipients. Another embodiment of the present invention is a method for identifying LAPs in cells that include monitoring a mixture of one or more LAP charge-binding molecules comprising structure (2), (3), or (5), or their dimers, with one or more sample cells for the presence of detectable label from a loading molecule, link ??? or a change in a detectable property of one or more LAP link molecules in the mixture. Preferably, the detectable property of the LAP binding loading molecule changes upon formation of a complex between the LAP binding loading molecule and the BLR domain of an LAP protein, LAPs may include but are not limited to, XLAP, C -LAP1, C-IAP2, L-LAP, or survivin in the sample cells. In the sample, LAP can be linked to a caspase, other Smac-like proteins, or combinations of these within the cell. Supervision can be performed on cells and an LAP binding cargo molecule in a fluid sample, a flowing flow, or fluids after purification. This invention can be used to detect abnormal expression on or under expression of LAP in cells and the indication of abnormal expression used to start a course of treatment of the cells. Preferably, the LAP binding loading molecule is used to detect over expression of LAPs in cells. The method may further include the act of comparing a change in a detectable property of one or more LAP binding charge molecules, in admixture with one or more control cells to the detectable change in property of one or more binding charge molecules. LAP, in mixture with one or more sample cells. The comparison can be related to the amount or activity of LAP in the sample cells. The method may include the act of combining one or more LAP binding cargo molecules with one or more cells including but not limited to sample cells, control cells or various combinations of these cells. Supervision can employ the absorption or emission of radiant energy by the mixture of LAP binding cargo molecules and cells, including but not limited to, MRI, fluorescence, chemiluminesence, magnetic resonance imaging and positron emission tomography. . Preferably, the change in detectable property of one or more of the LAP binding charge molecules in the mixture chemically and / or physically binding to the LAP in the cells is a change in the fluorescent emission intensity of the LAP binding molecule. . In some embodiments, a change occurs in fluorescent emission of one or more IAP-binding charge molecules capable of displacing IAP caspases or Smac from IAPs in the sample cells. A method for treating cells of the present invention, includes identifying the expression of IAP in cells and administering an amount of a permeable cell-loading IAP-binding molecule or other therapeutic to the cells to modify the activity of IAP in the cells. The LAP binding cargo molecule can be formulated with a pharmaceutically acceptable excipient. For example, after identification of abnormal levels of LAP in a cell sample, (optionally by comparison with a control sample of cells), purified Smac, an LAP binding compound or an: LAP binding charge molecule, may be added to cells to induce apoptosis. This invention can be used to identify cells that require treatment, treat cells and monitor the progress of treatment of cells having abnormal LAP levels. The act of identifying cells that have abnormal IAP expression includes monitoring a mixture of one or more LAP binding charge molecules, with one or more sample cells by a change in a detectable property of one or more of the binding charge molecules LAP. The detectable property changes upon formation of a complex between the LAP binding molecule and LAP in the sample cells. Another embodiment of the present invention is an article or equipment that includes packaging material containing a composition of an LAP binding compound or an LAP binding loading molecule of the formula (2), (3), or (5) or its dimer The packaging material has a label indicating how the LAP binding charge composition can be employed for treatment or detection levels of LAP in a cell sample. The label may also indicate how the LAP binding cargo molecule or other LAP binding loading molecule included in the pharmaceutical composition can be used to treat cells wherein an abnormal level of LAP expression is determined. One embodiment of the present invention is a method for selectively identifying neoplastic cells in a mixed population of cells. In the method a sample of the population of mixed cells is contacted with one or more LAP binding charge molecules of the formula (2), (3), or (5) or their dimers, under conditions that allow the molecule to LAP binding load bind LAP inside the neoplastic cells and in this way selectively identify the neoplastic cells. The cells may include but are not limited to, cultured cells, cells that are removed from a subject by biopsy, or cells of a fluid. Contact can be made by introducing the labeled LAP binding loading molecule into a tissue sample or a tissue in a living subject that possesses or is suspected to possess the neoplastic cells. The LAP binding charge molecule may have a loading-labeling dye portion and preferably the dye is a fluorogenic dye. The labeled IAP binding loading molecule may have an active NMR core or contrast agent and the selective indication made through nuclear magnetic resonance or magnetic resonance imaging. The labeled IAP load-binding molecule can have a loading portion of the molecule that is a radioisotope and where the selective identification made through positron emission tomography. The IAP linkage loading molecule can be formulated with pharmaceutically acceptable excipients and optionally other therapeutic agents to modify apoptosis in the cell sample. Another embodiment of the present invention is a method for selectively damaging or terminating neoplastic cells in a mixed population of normal and neoplastic cells. The method includes contacting a sample of the mixed cell population with an IAP-charge-binding molecule permeable cell of the formula (2), (3), or (5) or its dimers including an agent that is directly or indirectly toxic to cells, preferably, the loading portion of the molecule is an agent that is directly or indirectly toxic to cells. Under conditions that allow the molecule to charge bond - ??? ligate LAP into neoplastic cells, the agent directly or indirectly exerts its toxic effect, thus damaging or exterminating at least a portion of the neoplastic cells. The method can employ a toxic agent that is a radioisotope. The method can use a photosensitizing toxic agent and selective damage or extermination is performed by exposing the cell population to light. DETAILED DESCRIPTION OF THE INVENTION Before the present compositions and methods are described, it will be understood that this invention is not limited to the particular molecules, compositions, methodologies or protocols described, since these may vary. It is also understood that the terminology used in the description is for the purpose of describing only the particular versions or embodiments, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. It should also be noted that as used herein, and in the appended claims, the singular forms "a / a", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example reference to a "cell" is a reference to one or more cells and their equivalents known to those skilled in the art and so forth. Unless defined otherwise, all technical and scientific terms employed herein have the same meanings commonly understood by a person of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the methods, devices and materials of the embodiments are now described. All the publications mentioned here are incorporated here by reference. Nothing here shall be considered as an admission that the invention has no right to assign a prior date of said description by virtue of prior invention. "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases in which the event occurs and cases in which it does not. The LAP binding molecule of the present invention and pharmaceutical compositions containing these compounds, can bind to the apoptosis protein inhibitor (IAP's = Inhibitor of Apoptosis Proteins) such as but not limited to XIAP, c-IAPl, C-IAP2, survin , and LIVIN / ML-IAP. These compounds can include substituents or diagnostic or therapeutic portions, as part of the binding portion of the molecule or linked to the binding portion of the molecule. The IAP link loading molecules can be arbitrarily divided to include an IAP binding portion and a loading portion. The IAP binding portion of the molecule interacts as an IAP protein, preferably the BIR domain of an IAP protein and can be a monomer or dimer. In some embodiments, the IAP linkage portion of the molecule interacts with the BIR3 surface groove of XIAP. The loading portion of the molecule can be part of the main structure or the IAP binding portion of the molecule in the loading portion can be chemically bound to the IAP binding portion of the molecule. The loading portion of the molecule may include but is not limited to structures, portions and substituents for imaging, therapeutic agents, probes, labels or markers. The loading portion and LAP binding portion of the molecule can be connected by a chemical linkage to the LAP binding portion, including but not limited to amide, ester, or disulfide, chelation or linkage groups such as diaminobutane or ethylene. glycol and its oligomers where it is convenient to separate the LAP binding portion of the molecule from the loading portion of the molecule. One or more atoms in any portion of the LAP binding cargo molecule can be a radioisotope and used for detection or treatment. In other modalities, the charge portion can constitute a second monomer, thereby forming a dimer molecule, by a linking group. The binding portion of the LAP binding compound confers specificity of IAP target protein to the molecule and the loading portion can provide a functional group to the molecule to monitor or evaluate the location of the molecule or provide a therapeutic to that site within a molecule. cell sample or a tissue in a mammal. The LAP binding compounds can be used to displace sequestered proteins in cells, for example caspase-3,7 or 9 or Smac which interacts with an IAP, such that the released protein can be used to promote apoptosis within the cells. When the loading portion of the molecule binds to the LAP binding portion, the loading portion can be chemically linked or bound to any portion of the LAP binding portion of the molecule, such that it does not adversely affect the LAP binding, permeation of cells or transfection in cells. While the chemical interaction between the LAP binding portion and the loading portion of the molecule can occur, the molecule is engineered in such a way that the permeation of the cell to the molecule, its LAP binding property and function of the portion of load are not adversely affected by their combination. The suitability of any LAP binding cargo molecule made by the method described can be tested against labeled peptide [AbuRPF-K (5-Fam) -N¾] in cells such as but not limited to renal cell carcinoma, non-small cell lung cancer, HeLa cells or others that are known to express LAP or other cells that have a disorder of proliferation. The LAP binding molecules of the present invention are capable of permeating cells of interest, by binding to LAP in the cells and optionally supplying the load to the cells. Modalities of compounds of the structure (2), (3), (5) include 2-substituted pyrrolidine-1-carbonyls or 2, 4-independently substituted pyrrolidine-1-carbonyls, having a Kd as determined by the methods described, for example, in Example 1 under 100 micro-molar, preferably, less than 1 micro-molar, and even more preferably, less than 0.1 micro-molar. The pharmaceutically active compounds of the invention are sometimes referred to herein as drugs, to highlight their therapeutic utility in promoting apoptosis by binding to LAPs. However, another embodiment of the invention uses the compounds as diagnostic agents, for detection of LAP in vitxo, in situ or in vivo, or for IAP binding assays. In these embodiments, the compounds of the invention are detectably labeled, for example, with a fluorophore. Another embodiment of the invention uses the compounds as targeting agents, ie when incorporating antitumor or other tumor cell killing agents such as radionuclide into their structure. Accordingly, drugs refer to pharmaceutical / biologically active compounds (ie, LAP binding) for use as therapeutic, prophylactic or diagnostic agents. The term "heteroatom" refers to nitrogen, oxygen, sulfur or other atoms or groups in which the nitrogen, sulfur and other atoms may optionally be oxidized and the nitrogen may be optionally quaternized. Any hetero atoms with unfilled valences are considered to have enough hydrogen atoms to satisfy the valences. In some embodiments, for example where the hetero atom is nitrogen and includes a hydrogen or other group to satisfy the valence of the nitrogen atom, the replacement of nitrogen in a similar structure by another hetero atom, for example by oxygen, will result in the hydrogen or group previously bound to nitrogen is absent. The term hetero atom may include but is not limited to, for example, -0-, -S-, -S (0) -, - S (0) 2 ~ r -N -, - N (H) -, and -N (Ci-C6 alkyl). The term "alkyl" refers to a saturated, straight, branched or cyclic hydrocarbon having from about 1 to about 30 carbon atoms (and all combinations and subcombinations of specific ranges and numbers of carbon atoms therein). "Lower alkyl group" refers to saturated, straight, branched or cyclic hydrocarbon having a group of 1 to 10 carbon atoms, more preferably 1 to 5 carbon atoms and all combinations and subcombinations of specific ranges and numbers of carbon atoms therein . Alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, cyclopropyl, methylcyclopropyl, cyclopentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclohexyl, cyclooctyl, adamantyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The term "substituted alkyl" refers to a straight, branched or cyclic saturated hydrocarbon having from about 1 to about 30 carbon atoms (and all combinations and sub-combinations of specific ranges and numbers of carbon atoms therein) having 1 to 3 carbon atoms. to 5 substituents. Substituted lower alkyl group refers to a straight, branched or cyclic saturated hydrocarbon with 1 to 10 carbon atoms, more preferably 1 to 5 carbon atoms (and all combinations and sub-combinations of ranges and specific numbers of carbon atoms therein) ) which has from 1 to 5 substituents. Substituted alkyl radicals and substituted lower alkyl groups may have from 1 to 5 substituents, including but not limited to alkoxy, substituted alkoxy, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, amidal alkyl (such as -CH2C (= 0) NH2 or -CH2CH2C (= 0) NH2), thioamidino, acylalkylamino, cyano, halogen atoms (F, Cl, Br, I) to give halogenated or partially halogenated alkyl groups including but not limited to -CF3, -FC2CF3, -CH2CF2CI and the like, hydroxy, nitro, carboxyl, carboxylalkyl, carboxylheterocyclic, heterocyclic substituted with carboxyl , cycloalkyl, guanidino, heteroaryl, aryl, heterocyclic, alkylamino, dialkylamino, or optionally substituted versions of any of the aforementioned groups. The term "alkylene radical" as used herein, includes reference to a branched or unbranched saturated branched hydrocarbon radical containing from 1 to 30 carbon atoms, and includes for example methylene (-CH2-), ethylene (-CH2CH2-) , propylene (-CH2CH2CH2-), 2-methylpropylene (-CH2CH (CH3) CH2-), hexylene (- (CH2) 6-) t and the like. Lower alkylene includes an alkylene group of 1 to 10, more preferably 1 to 5, carbon atoms. Substituted alkylene radicals include reference to a saturated, branched or unbranched alkylene radical or group having 1-30 carbon atoms and having from 1 to 5 substituents. Lower substituted alkylene radicals refer to a substituted alkylene radical group having 1-10 carbon atoms, preferably having 1-5 carbon atoms, and having 1 to 5 substituents. Substituents may include but are not limited to those for alkyl groups. The term "alkenyl radical" as used herein, includes reference to a branched cyclic hydrocarbon or unbranched hydrocarbon radical with 2 to 30 carbon atoms containing at least one carbon-carbon double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, t-butenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl and the like. The term "lower alkenyl" includes an alkenyl group having 2 to 10 carbon atoms, preferably 2 to 5 carbon atoms, containing at least one carbon-carbon double bond. The one or more carbon-carbon double bonds can independently have a cis or trans configuration. A substituted alkenyl radical. refers to an alkenyl radical or lower alkenyl group having 1 to 5 substituents which may include but are not limited to those for the alkyl groups. The term "alkenylene radical" refers to a branched or unbranched difunctional hydrocarbon radical group containing from 2 to 30 carbon atoms and at least one carbon-carbon double bond. "Lower alkenylene" includes an alkenylene group with 2 to 10, more preferably 2 to 5 carbon atoms, containing a carbon-carbon double bond. "Substituted alkenylene radical" refers to an alkenylene radical or lower alkenyl group having 1 to 5 substituents which may include but are not limited to those for the alkyl groups. The term radical or alkynyl group refers to straight or branched chain hydrocarbon radical having 2 to 12 carbon atoms and at least one triple bond, some embodiments include alkynyl groups of 2 to 6 carbon atoms having a triple bond. A substituted alkynyl will contain one, two or three substituents as defined for substituted alkyl groups. Alkynylene includes reference to a difunctional branched or unbranched hydrocarbon chain containing from 2 to 12 carbon atoms and at least one carbon-carbon triple bond; some embodiments include alkynylene groups of 2 to 6 carbon atoms with a triple bond. A substituted alkynylene will contain one, two or three substituents as defined for substituted alkyl groups. As used herein, "halo" or halogen refers to any halogen, such as I, Br, Cl or F. As used herein, "cyano" refers to the group -C = N. The term radical or aryl group is refers to optionally substituted mono or bicyclic aromatic ring radicals having from about 5 to about 14 carbon atoms (and all combinations and sub-combinations of specific ranges and numbers of carbon atoms therein), with from about 6 to about 10 carbon atoms preferred. Non-limiting examples of aryl groups include, for example, phenyl and naphthyl. A substituted aryl group will contain one or more substituents as defined for substituted alkyl groups. "Radical aralkyl" refers to alkyl radicals containing an aryl substituent and have from about 6 to about 20 carbon atoms (and all combinations and sub-combinations of specific ranges and numbers of carbon atoms there), with from about 6 to about 12 preferred carbon atoms. Aralkyl groups may be optionally substituted. Non-limiting examples include, for example, benzyl, naphthylmethyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. A substituted arylalkyl group will contain one or more substituents on the aryl or alkyl group as defined for substituted alkyl groups. Radical or cycloalkylaryl group refers to a cycloalkyl radical fused to an aryl group, including all combinations of independently substituted alkyl cycloalkylaryls, the cycloalkyl and aryl group have two atoms in common. Examples of fused cycloalkylaryl groups used in compounds of the present invention may include 1-indanyl, 2-indanyl, 1- (1, 2, 3, 4-tetrahydronaphthyl), and the like. Tetrahydronaphthyl more specifically refers to those radicals or univalent groups derived from fused polycyclic hydrocarbons including all combinations of independently substituted alkyl tetrahydronaphthyl. These radicals may have a connection point in (Ci) or equivalently (C4) in the structure (11), or position labeled (C2) and in equivalent form (C3) in structure (Ha). The Ci_4 chiral carbon atoms in tetrahydronaphthylene and their alkyl substituted derivatives may already have a (R) or (S) configuration.

Radical or cycloalkyl group more specifically includes reference to a monovalent saturated carbocyclic alkyl radical, which consists of one or more rings in its structures and having from about 3 to about 14 carbon atoms (and all combinations and sub-combinations of ranges and specific numbers of carbon atoms there), with from about 3 to about 7 preferred carbon atoms. Multiple-ring structures can be bridged or fused ring structures. The rings may be optionally substituted with one or more of the substituents for the alkyl groups. Examples of cycloalkyl groups include but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and adamantyl. A substituted cycloalkyl group will contain one or more substituents as defined for substituted alkyl groups. Radical cycloalkylalkyl refers more specifically to alkyl radicals containing a cycloalkyl substituent and having from about 4 to about 20 carbon atoms (and all combinations and sub-combinations of specific ranges and numbers of carbon atoms), with about 6 carbon atoms. to about 12 preferred carbon atoms and may include but are not limited to methyl-cyclopropyl, methylcyclohexyl, isopropylcyclohexyl and butyl-cyclohexyl groups. Radical or cycloalkylalkyl group may be optionally substituted with one or more substituents for alkyl groups including but not limited to hydroxy, cyano, alkyl, alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, nitro, amino, alkylamino and dialkylamino. The term "acyl" refers to an alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group as defined above linked through one or more carbonyl groups -C (= 0) - to provide a group of the formula -C (= 0) R wherein R is the substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group. When the term acyl is used in conjunction with another group, as in acylamino, this refers to the carbonyl group. { -C (= 0)} linked with the second named group. Thus, acylamino or carbamoyl refers to -C (= 0) NH2, acylalkylamino can refer to groups such as -C (= 0) NR'R "wherein R 'and R" can be H or alkyl. Amidalkyl refers to groups such as -CH2C (0) NH2, -CH2CH2C (= 0) NH2) and more generally - (CH2) PC (-0) NH2. Carboxi refers to the radical or group -C (= 0) OH, carboxyalkyl refers to groups such as - (CH2) PC (= 0) OH, alkyl carboxyalkyl refers to groups such as (~ C (= 0) 0 - (alkyl)), and alkoxycarbonyl or acylalkoxy refers to a group (-C (= 0) 0- (alkyl)), wherein alkyl was previously defined. As used herein, aryloyl or acylaryl refers to a group (-C (= 0) (aryl)), where aryl is as previously defined. Exemplary aroyl groups include benzoyl and naphthoyl. Acetyl refers to the group CH3C (= 0) - and can be abbreviated by the term "Ac" as in Table 5. Formyl refers to the radical or group HC (= 0) -. In the above-mentioned group p can be independently of the integer 0, 1, 2, or 3. Radical aryloxy refers to optionally substituted mono or bicyclic aromatic radical having from about 5 to about 14 carbon atoms and a radical group (aryl-O) -) where aryl is as previously defined. These aryloxy radicals include but are not limited to those illustrated by the radical of formula (12). Optional substituents on the aryl ring on the aryloxy radical may include but are not limited to hydrogen, alkyl, halogen, hydroxy, alkoxy, alkoxycarbonyl or other substituents. Modes of IAP-binding compounds of the present invention may include an optionally substituted aryloxy group such as the phenoxy radical linked to the pyrrolidine ring as illustrated but not limited to compounds in Table 5. Some embodiment of IAP-linking compounds include a phenoxy radical in where the Kd as determined by the methods described, for example in Example 1 is less than about 0.1 micromolar. The terms "alkoxy" and "alkoxy" refer to optionally substituted radical or group (alkyl-O) wherein alkyl is as previously defined. Exemplary alkoxy radicals or groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, cyclopropyl-methoxy and heptoxy. Alkoxy radicals may also include optionally substituted alkyl in the alkyl-O- group. Alkoxy may include optionally substituted aryl groups as previously defined and illustrated by the non-limiting radical of formula (13). A "lower alkoxy" group refers to an optionally substituted alkoxy group containing one to five carbon atoms. "Polyether" refers to a compound or portion that possesses multiple ether linkages, such as but not limited to, polyethylene glycols or polypropylene glycols. "Polyalkyl ethers" refer to alkyls interconnected by or otherwise possessing multiple ether linkages as illustrated by the non-limiting structure of formula (85) in Scheme VIII of Example 16. "Arylalkyloxy" means an arylalkyl-O- group wherein the arylalkyl group is as previously described. Exemplary arylalkyloxy groups include benzyloxy radical (C6H5CH20-) (BnO-), or 1- or 2-naphthalenemethoxy radical. Optional substituents on the aryl ring of the benzyloxy radical may include but are not limited to hydrogen, alkyl, halogen, hydroxy, alkoxy and alkoxycarbonyl or other substituents as defined for the alkyl group.

"Arylamino radical" refers to an optionally substituted mono or bicyclic aromatic radical having from about 5 to about 14 carbon atoms and a group or radical (-NH (aryl)) wherein aryl may be optionally substituted as previously defined for alkyl. Optional substituents on the aryl ring in the arylamino radical may include but are not limited to hydrogen, alkyl, halogen, hydroxy, alkoxy and alkoxycarbonyl. An example of an arylamino group is the radical or anilino group. Amino refers to a group -N¾ and alkylamino refers to a group or radical (-NHR ') wherein R 1 is H, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or optionally substituted versions thereof, as previously defined. Groups or alkylamino radicals include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino and eptylamino. The benzylamino radical refers to the arylamino group NOTE: C6H5CH2NH-, the aryl group may have optional substituents including but not limited to hydrogen, alkyl, halogen, hydroxy, alkoxy and alkoxycarbonyl or other substituents. Dialkylamino includes reference to a radical (-NR'R "), wherein R 'and R" can each independently be H, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or optionally substituted versions thereof, as previously defined. Examples of dialkylamino radicals include, but are not limited to, dimethylamino, methylethylamino, diethylamino, di (1-methylethyl) amino, and the like. Heteroaryl includes reference to a monovalent radical or aromatic group having one or more rings incorporating one, two or three heteroatoms within the ring (selected from nitrogen, oxygen or sulfur). These heteroaryls may optionally have hydrogen atoms substituted with one or more other substituents. Examples of these heteroaryl radicals include optionally substituted benzofurans, benzo [b] thiophene 1-oxide, indoles, 2- or 3-thienyls or thiophenyls, thiazoyl, pyrazines, pyridines or structures of (4a) or (4b). For example, the structure of formula (E10) with derivatives cited in Table 9, may include a ring fused ¾.0 with a hetero atom X2 (N, 0, or other) and substituents such as Ru or R'n including but not limited to hydrogen, halogens, optionally substituted heteroaryls such as pyridine, benzofuran, indoles, thiazoyl, pyrazine, an alkoxyheteroaryl such as methoxy pyridine or other groups.

The terms heteroalkyl, heteroalkylene, heteroalkenyl, heteroalkenylene, heteroalkynyl and heteroalkynylene include reference to radicals or alkyl, alkylene, alkenyl, alkenylene, alkynyl and alkynylene groups, wherein one or more of the carbon atoms have been replaced or substituted with atoms such as but not limited to atoms of nitrogen, sulfur, simple or multiple bonding oxygen or these atoms have one or more hydrogens to meet the valence requirements of the atom. These substitutions can be used to form molecules that have functional groups including but not limited to amines, ethers and sulfides. A non-limiting example of a heteroalkynyl group is illustrated by the group -CH (Me) OCH2C = CH. Radical heterocycloalkyl includes reference to a radical or monovalent saturated carbocyclic group consisting of one or more rings, which incorporates one, two or three heteroatoms (selected from nitrogen, oxygen or sulfur), which may optionally be substituted with one or more substituents. Heterocycloalkenyl includes reference to a monovalent mono-saturated carbocyclic radical, which consists of one or more rings containing one or more carbon-carbon double bonds, wherein carbon atoms are replaced or substituted by one, two or three heteroatoms within one or more rings , the heteroatoms are chosen from nitrogen, oxygen, or sulfur, the heterocycloalkenyl optionally can be substituted with one or more substituents. Various groups employed in the molecules of the present invention may have one or more hydrogen atoms substituted by chemical moieties or other substituents. Substituents may include but are not limited to halo or halogen (e.g., F, Cl, Br, I), haloalkyls such as -CF3, -FC2CF3, -CH2CF3 and the like, thioalkyl, nitro, optionally substituted alkyl, cycloalkyl, aralkyl, aryl, heteroaryls such as benzofurans, indoles, thienyls, thiophenyls, thiazoles, pyrazines, pyridines, alkoxy pyridine, hydroxy (-OH), alkoxy (-OR), aryloxy, alkoxyheteroaryl, cyano (-CN), carbonyl -C (= 0) -, carboxy (-C00H) and carboxylate salts; - (CH2) C (= 0) OH, groups or radicals - (CH2) PC (= 0) 0 (alkyl), and - (CH2) PC (= 0) NH2 where p independently is the integer 0, 1, 2 or 3; sulfonates such as but not limited to tosyl, brosyl or mesyl; sulfone, imine, or oxime groups, groups such as - (C = 0) Oalkyl, aminocarbonyl or carbamoyl - (C = 0) NH2), -N-substituted aminocarbonyl- (C = 0) NHR ", amino, alkylamino (-NHR1 ) and dialkylamino (-NH ^ R "). In relation to the aforementioned and related amino groups, each portion R 1 or R "can be, independently includes H, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl. When one or more Hydrogen atoms are substituted by chemical moieties or other substituents, the substituents may be selected such that IAP linking compounds of the formula (2), (3), or (5) containing them have a Kd as measured by the described methods, for example in Example 1 with less than about 100 micro-molar, in some embodiments it has a Kd less than 1 micro-molar, and in other embodiments it has a d less than 0.1 micro-molar.In modes where one or more atoms of hydrogen are substituted by chemical moieties or other substituents, the substituents may be selected such that the IAP linking compounds of the formula (2), (3), or (5) which contain them, have an EC50 as measured by methods described, for example, in Example 2 less than about 0.5 micro-molar, in some embodiments they have an EC50 less than about 0.06 micro-molar. In embodiments wherein one or more hydrogen atoms are substituted by chemical moieties or other substituents, the substituents may be selected such that the LAP binding compounds of the formula (2), (3), or (5) contain them, have a Kd link constant of less than about 1 micro-molar, preferably less than 0.1 micro-molar and an EC5o less than about 1 micro-molar, preferably less than about 0.5 micro-molar, and in some embodiments an EC50 less than about 0.06 micro molar. Amino acids can be employed in the IAP binding compounds of this invention and can include the 20 naturally occurring amino acids, known artificial amino acids such as beta or gamma amino acids, and amino acids that contain unnatural side chains, and / or other similar monomers such as hydroxy acids . Preferably, the amino acids used in the LAP binding compounds of the present invention are the 20 amino acids of natural origin. The amino acids or artificial amino acids are chosen with the effect that the corresponding LAP binding compound binds IAPs, and preferably binds the BLR domain of an LAP, and the resulting LAP binding compound is permeable to the cell. A non-limiting example of this amino acid includes the use of Abu (2-aminobutyric acid) as an amino acid in the LAP binding cargo molecule. When the molecule of structure (2), (3), or (5) includes amino acids, it is preferred that the N-terminal amino acid that Ala or Abu. When one or more chiral centers exist in an amino acid, artificial amino acid, or atom of an LAP binding compound of structure (2), (3), or (5), any of the enantiomers, D or L and more generally of R or S configuration, or diastereoisomers may be optionally employed in the LAP binding compound. When any variable occurs more than once in any constituent or in any formula, its definition in each occurrence is independent of its definition in any other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. It is considered that the formulas and chemical names used here correctly and accurately reflect the underlying chemical compounds. However, the nature and value of the present invention do not depend on the theoretical correctness of these formulas, totally or partially. In this way it is understood that the formulas employed herein, as well as the chemical names attributed to the correspondingly indicated compounds, are not intended to limit the invention in any way, including restricting it to any specific tautomeric form or to any other specific optics.; or geometric isomer, except when said stereochemistry is clearly defined. In embodiments of compounds of structure (2), (3), or (5) substituents such as Ai, A2, Ria, and Rib / - ¾ / · Xi ^? / · Z, M, G, or Rio, may independently selected, such that compounds of structure (2), (3), or (5) are not a tripeptide or a tetrapeptide of amino acids, for example AVPI or AVP. Some embodiments of the compounds of structure (2), wherein A2 is H, Xi is -NH-, J is -CU-, and n is 0 for R2, can be illustrated by structure (3): In some embodiments of the compounds of structure (3), Ai is H, lower alkyl, or optionally substituted lower alkyl group, an N-acyl derivative such as acylamino or acylalkylamino, t-butoxycarbonyl, acetyl, sheath, carbamoyl, alkylene, or other; Ria and Rib separately are H, lower alkyl, optionally substituted lower alkyl, lower alkylene, optionally substituted lower alkylene group; or Ai together with either Ria or Rib form an optionally substituted heterocycloalkyl group of 3 to 6 atoms, as illustrated by some of the non-limiting embodiments of the compounds in Table 5. In the IAP linking compounds of the structure (3 ), And can be H, an alkyl group, an alkyl group with 1 to 10 carbon atoms, a branched alkyl group with 1 to 10 carbon atoms, an alkynyl group, heteroalkynyl, a cycloalkyl group with 3 to 7 carbon atoms , aryl, heteroaryl, arylalkyl; optionally substituted versions of the aforementioned groups such as an optionally substituted alkyl group, alkyl group optionally substituted with 1 to 10 carbon atoms, a branched alkyl group optionally substituted with 1 to 10 carbon atoms, an optionally substituted alkenyl group, a group optionally substituted alkynyl, an optionally substituted heteroalkynyl group, an optionally substituted cycloalkyl group of 3 to 7 carbon atoms, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group; in some embodiments the substituted substituent or portion for the above-mentioned group includes one or more hydroxy groups; or Y together with Z, M, G, or R10 can be an optionally substituted carbocyclic ring, or an optionally substituted heterocyclic ring containing 1 to 5 heteroatoms, wherein Y is linked to Z, M, G, or Ri0; preferably Y is linked to Y, M, G, or R10 by any number of atoms up to about 20 atoms. A non-limiting example of this heterocyclic ring is illustrated by the 1AP linkage molecule having the structure of the formula (E12-2) in Example 12. In IAP linking compounds of the structure (3), Z can be H, alkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, cycloalkyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy; optionally substituted versions of these groups; optionally substituted versions of these groups including one or more hydroxyl groups; or Z together with Y, M, G, or R10 can form an optionally substituted carbocyclic ring, or an optionally substituted heterocyclic ring containing 1 to 5 heteroatoms, wherein Z is linked to Y,, G, or Rio; preferably Z is linked to Y, M, G, or R10 by any number of atoms up to about 20 atoms. In some embodiments, Z is an alkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, cycloalkyloxy, aryl, heteroaryl, aryloxy, or heteroaryloxy group. The stereochemistry of the substituent or group Z may be indicated using a wedge link with bold letters, to show a group Z that leaves the plane of the page or a wedge link with dotted lines, to show a group Z after the plane of the page, in modalities of (3), the IAP link molecule may have a structure where the Z group is directed away from the plane of the page, the LAP link molecule may have a structure where the Z group is directed after the page plane, or the link molecule LAP may include a mixture wherein the group Z is a combination of these. In IAP link compounds of structure (3),? it may be an optionally substituted alkyl, alkenyl, or alkynyl group; it may be an alkyl, alkenyl, or alkynyl group optionally substituted with 1 to 5 carbon atoms; M can be an optionally substituted alkylene, alkenylene, or alkynylene group; or an optionally substituted alkylene, alkenylene, or alkynylene group of 1 to 5 carbon atoms. In some embodiments, for example but not limited to IAP link compounds of structure (E6) or (E14), M is a diradical alkylene as the methylene group end-linked to the methylene group in the 2-position of the pyrrolidine ring and the other end of the methylene group to an aryl group, a heteroaryl group, or an optionally substituted heteroaryl group such as a benzofuran or indole group, or optionally substituted versions of the group of the structure (4a-d). In IAP bonding compounds of the structure (3), G may be absent (a link) as in the non-limiting examples of structure compounds (E6) or (E14), or G can be a heteroatom that includes but is not limited to -0-; -NH-; - (C = 0) -; -S (0) t- where t can be the integer 0, 1, or 2; -NRi8 ~; -NCOR18-; or -NS (0) xRi8- wherein x may be the integer 0, 1, or 2, and Ri8 may be lower alkyl, optionally substituted lower alkyl, or cycloalkyl or Ris may be contained within an optionally substituted carbocyclic, or ring optionally substituted heterocyclic containing 1 to 5 heteroatoms, wherein Ris is linked to Z, M, or Rio, preferably Ri8 is linked to Z, M, or R10, by any number of atoms up to about 20 atoms. In IAP linking compounds of structure (3), Rio can be an aryl group, a heteroaryl, a fused aryl group, or a fused heteroaryl group. In some embodiments, for example, but not limited to compounds in Table 5, Rio can be a substituted aryl group, a substituted heteroaryl group, a substituted fused aryl group, or a substituted fused heteroaryl. In some modalities Ri0 can be any of structures (4a), (4b), (4c), or (4d): (4a) (4b) (4c) (4d) where X2 is a heteroatom in structures (4a) or (4b) or X2 is a carbon-carbon bond in structures (4c) or (4d), and independently groups Ru, R'u, R12, any of Ri3 -i7, or any of Ri4-i7 can be H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy, heteroaryloxy, other substituents or optionally replaced of these groups. In embodiments wherein Ru or R'u is a heteroaryl group, it may be a 2- or 3-thienyl group SC4Hn- (thiophenyl), pyridine, pyrazine or the optionally substituted versions thereof. In some embodiments Ri2 may be an aryl or a heteroaryl group, such as but not limited to benzofuran, indole, benzo [a] thiophene-1-oxide or benzo [b] thiophene-1,1-dioxide or optionally substituted versions of these . When X2 is any of -O- or -S (0) k-, for the integer k which can independently be 0, 1, or 2, R12 is absent. Independently R, R'iif Ri2 / - any of Ri3-i7, or any of Ri-i7 may be H, optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, carboxyalkyl, alkyl carboxyalkyl, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy. Independently Ru, R'u, R12, any of R13-17, or any of Ri-i7 can be acyl or acetyl groups, carboxylate, sulfonate, sulfunium, imine, or oxime groups; or groups Rn, R'n; R12, any of R13-17, or any of Ri4-i7 may be contained within the carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups in the Y, Z, M, G, Rn position, R'n, R12, any of R13-17, or any of R14-17, preferably these groups are linked by any number of atoms to about 20 atoms. In some embodiments, R10 may be cycloalkyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, or optionally substituted modalities thereof. In some modalities Rio can be the group: wherein R3, R '3, R4, R5, R'5, may each independently be substituents such as H, alkyl, cycloalkyl, alkylene, aryl, heteroaryl, optionally substituted alkoxy, alkyl, cycloalkyl, alkylene, aryl, heteroaryl, halo, cyano, - (CH2) PC (= 0) OH, - (C¾) PC (= 0) O-alkyl, - (CH2) pC (= 0) NH2, p is independently the integer 0, 1, 2, or 3 For example, in IAP linking compounds of structure (E4) wherein M is alkenylene, G is a heteroatom as -0-, RiQ can be an optionally substituted aryl group having substituents for example but not limited to hydrogen, chlorine, bromine, alkyl, alkylene, alkoxy, or combinations thereof. Some embodiments of LAP binding compounds of the formula (3) include compounds of structure (5) wherein: Ai is H, or lower alkyl, or Ax and Rn, together form a ring of 3-5 atoms. In these embodiments, Ria is H and Rib may be a lower alkyl group, or together with Ai forms a ring of 3 to 5 atoms. In embodiments of IAP linking compounds of structure (5), Y can be an alkyl group, an alkyl group of 1 to 10 carbon atoms, a branched alkyl group with 1 to 10 carbon atoms, an alkynyl group, heteroalkynyl, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of the aforementioned groups, and / or hydroxy-substituted versions of the aforementioned groups, or Y together with Zla, Zab, or R10 forms a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Y is linked to Zia, Zlb or R10; preferably Y is linked to Zib, Zib, or Rio, by any number of atoms up to about 20 atoms. In embodiments of LAP binding compounds of structure (5), Zia and Zib can independently be H, hydroxy, amino, alkylamino, dialkylamino, alkoxy, aryloxy, or heteroaryloxy group; or Zia, or Zib, together with Y or Rxo form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Zia or Zlb, is linked to Y or Rio; preferably Zla or Zlb, is linked to Y or Rio by any number of atoms up to about 20 atoms. In embodiments of LAP binding compounds of structure (5), M can be an optionally substituted alkyl group or optionally substituted alkylene with 1 to 5 carbon atoms. In these structures, G may be absent (a bond), or a heteroatom including -0-; -NH-; - (C = 0) -; -NR18-; -NCORis-; or -NS (0) xRi8- wherein x = 0, 1, or 2, and R18 is lower alkyl, optionally substituted lower alkyl group. The IAP linking compounds or molecules of structure (2), (3), or (5) can be prepared by various processes, which are described by the non-limiting schemes in the Examples and which also form part of the subject matter of the present invention. invention. These IAP binding molecules can be prepared from molecules of structure (6a) or (6b): wherein Y, M, Z, G, R2 and Rio are previously described and wherein R 'and R "can be H, or a protecting group The stereochemistry of the substituent or group Z or M can be indicated using a wedge bond with bold, to show either the group leaves the page plane or a wedge link with dotted lines to show a group Z or M after the page plane.In terms of structure (6a) or (6b), the linkage molecule IAP can have a structure in which the group Z or M is directed out of the plane of the page, the link molecule LAP can have a structure in which the group Z or M is directed after the plane of the page, or the IAP binding molecule may include a mixture wherein the group Z or M includes a combination of these Structures of formula (6a) or (6b) may be prepared from compounds such as but not limited to pyrrolidines such as ) in Scheme I or (29) in Scheme IVa using the similar procedure or procedures is here described. The structure of formula (6a) or (6b) can further be reacted to give IAP-binding molecules of structure (2), (3), or (5), by treatment with an N-Boc-ami or acid or other convenient amine-containing portion that includes Ai, A2, Rj.a, or Rlb or combinations thereof as described herein. Certain acidic or basic compounds of the present invention may exist as zwitterions. All forms of the compounds, including free acid, free base and zwitterions, are contemplated within the scope of the present invention. It is well known in the art that compounds containing both amino and carboxyl groups often exist in equilibrium with their zwitterionic forms. In this way, any of the compounds described herein containing, for example, both amino and carboxyl groups, also include reference to their corresponding zwitterions. In any of the previous teachings, an IAP binding loading molecule or other IAP binding compound of the invention may already be a compound of one of the formulas described herein, or a stereoisomer, prodrug, salt, hydrate, solvate, acid salt hydrate or crystalline form isomorphically pharmaceutically acceptable thereof. "Pharmaceutically acceptable salt" refers to those salts of the LAP binding charge molecules and LAP binding compounds of structure (2), (3), or (5) or their dimers, which retain the biological effectiveness and properties of the free bases or free acids, cell permeation and LAP binding, which are not biological or otherwise undesirable. If the compound exists as a free base, the desired salt can be prepared by methods known to those of ordinary skill in the art, such as treatment of the compound with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid. and similar; or with organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid , ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. If the compound exists as a free acid, the desired salt can also be prepared by methods known to those of ordinary skill in the art, such as the treatment of the compound with an inorganic base or an organic base. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including substituted amines of natural origin, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine. , tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-Ethylpiperidine, polyamine resins and similar before. LAP binding cargo molecules or their pharmaceutically acceptable salts may include pharmaceutically acceptable solvent molecules within their crystal lattice. When the solvent is water, the compounds can form hydrates, in the case of other solvents and in particular organic solvents such as but not limited to ethanol, the compounds can form solvates. The IAP binding charge molecules or IAP binding compounds of structure (2), (3), or (5) and their homologs can be formulated, isolated or purified as solvates. The compounds used in the methods of the present invention can exist in the form of prodrug. The prodrug includes any covalently linked carriers that release the active precursor drug, for example according to formula (2) or other formulas or compounds employed in the methods of the present invention in vivo when this prodrug is administered to a mammalian subject. Since the prodrugs are known to improve numerous desirable qualities of pharmaceutical products (eg, solubility, bioavailability, manufacture, etc.), the compounds employed in the present methods can, if desired, be delivered in prodrug form. In this way, the present invention contemplates methods for delivering prodrugs. Prodrugs of the compounds employed in the present invention, for example formula (2) can be prepared by modifying functional groups present in the compound such that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Accordingly, prodrugs include for example compounds described herein in which a hydroxy, amino or carboxy group is attached to any group which, when the prodrug is administered to a mammalian subject, is cleaved to form a free hydroxyl, free amino or acid. carboxylic respectively. Examples include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups; and alkyl, carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl and phenethyl esters and the like.

The compounds employed in the methods of the present invention can be prepared in a number of ways well known to those skilled in the art. The compounds can be synthesized for example, by the methods described in the specification and example, or their variations as appreciated by the person skilled in the art. Processes described in association with the present invention are contemplated to be practiced on any scale, including scale of micrograms, milligrams, grams, multi-grams, kilogram, multi-kilograms or industrial commercial scale. IAP link compounds of the structure (2), (3), or (5) can be mixed or combined with pharmaceutically acceptable excipients or treated by lyophilization. These pharmaceutical compositions can be administered topically, locally or systematically to a cell sample, a tissue, or a patient. Topical or local administration may allow greater application control of the pharmaceutical composition. The molecules or IAP binding compounds include structure (2), (3), or (5) in simple form or in combination, can be mixed with an appropriate pharmaceutical carrier prior to administration. Examples of pharmaceutical carriers and additives generally employed that can be used to form pharmaceutical, diagnostic or therapeutic compositions of the IAP binding molecules can include but are not limited to conventional diluents, binders, lubricants, coloring agents, disintegrating agents, buffering agents, isotonifying agents, preservatives, anesthetics and the like. Pharmaceutical carriers that may be used include but are not limited to water, saline, ethanol, dextran, sucrose, lactose, maltose, xylose, trehalose, mannitol, xylitol, sorbitol, inositol, albumin, serum, gelatin, creatinine, polyethylene glycol, non-ionic surfactants (for example polyoxyethylene sorbitan fatty acid esters, hardened castor oils with polyoxyethylene, esters of fatty acid sucrose, polyoxyethylene polyoxypropylene glycol) and similar compounds. Pharmaceutical carriers and excipients as well as IAP binding molecules can also be used in combination. Steroisomers are compounds that have different molecular formulas and nature or binding sequence but differ in the arrangement of their atoms in space and include optical and geometric isomers. Compounds of the present invention, or their pharmaceutically acceptable salts, may have one or more asymmetric carbon atoms or other asymmetric atoms in their structure, and therefore there may exist as stereoisomers, enantiomers, diaesteroisomers, simple racemates and mixtures of enantiomers or diastereomers . These compounds may also include geometric isomers. All of these stereoisomers, racemates and their mixtures of the LAP binding compounds and IAP binding charge molecules of the present invention are intended to be within the scope of this invention, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare and isolate these optimally active forms. For example, mixtures of stereoisomers can be separated by standard techniques including, but not limited to, resolution of racemic, normal, reverse phase and chiral chromatography forms, preferably salt formation, recrystallization and the like, or by chiral synthesis of either materials starting chiral or by deliberate systems of target chiral centers. Link molecule LAPs of structures (2), (3), or (5) that contain chiral centers and the molecules may be in the form of a single enantiomer or as a racemic mixture of enantiomers. In some cases that is, without regard to the structure of certain specific LAPs binding molecules, the chirality (ie, relative stereochemistry) of substituents or groups is indicated in the structure using a wedge bond with bold to indicate a substituent exiting of the page plane and a wedge joint with dotted lines, to indicate a substituent that is projected after the plane of the page. In other cases, the stereochemistry is not indicated and these structures are intended to encompass both the enantiomerically pure or purified forms of the compound shown, as well as a racemic mixture of enantiomers. As will be readily understood, present functional groups may contain protecting groups during the course of synthesis. Protective groups are chemical functional groups that can be selectively added to and removed from functionalities, such as amine, hydroxyl or carboxyl groups. These groups are present in a chemical compound to render this functionality inert to chemistry reaction conditions to which the compound is exposed. Any of a variety of protecting groups can be employed with the present invention. Protective groups include the benzyloxycarbonyl group and the tert-butyloxycarbonyl group. The term "protecting group" or "blocking group" refers to any group that when attached to one or more hydroxyl, amino, carboxyl or other groups of the compounds (including their intermediates such as aminolactams, aminolactones, etc.), prevents reactions from occurring in these groups and whose protective group can optionally be removed by conventional chemical or enzymatic steps, to reestablish the hydroxyl, amino, carboxyl group, for use in an IAP binding compound. The blocking group for removing particular employee is not critical and preferred hydroxyl or amine blocking groups for removing include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl, t-butyl carbamate, benzyl carbamate and any other group that can be chemically introduced into a hydroxyl, amine or other functionality and subsequently selectively removed either by chemical or enzymatic methods, under light conditions compatible with the nature of the product. The loading portion of the molecule can be part of the main structure or binding portion of the IAP molecule or the loading portion can be chemically bound or bound to the LAP binding portion of the molecule. For example, the loading portion can be another unit of formula (2), (3) or (5), linked by a linking group to the first unit, thereby forming a dimer and further comprising a portion of additional charge The loading portion can also be any of the substituents Ai, A2, Ria, RibA? / · &2r or Z in molecules of formula la (2), preferably the charge portion binds to Y, R2, or Z in molecules of the formula (2). In molecules of the formula (3), or (5), the loading portion can be any of the substituents Ai, Ria, Rib, R10, Y, M, G, or Z (includes Zia and ib) r preferably, the filler portion includes a Y, Z linked substituent (includes Zia and Zib), or Rio. The loading portion of the molecule may include but is not limited to structures, portions and substituents to image, therapeutic, detectable groups , probes, labels or markers. The load portion and link portion ??? of the molecule can be connected by a chemical bond to the IAP binding portion including but not limited to amide, ester, or disulfide, chelation, or a linking group such as diaminobutane or ethylene glycol and their oligomers where it is convenient to separating the IAP binding portion of the molecule from the loading portion of the molecule. One or more atoms in any portion of the IAP binding charge molecule can be a radioisotope and used for detection or treatment. The ability for rapid assay of small molecules for their effectiveness in breaking protein-protein interactions can be used in the development of viable drug candidates, one aspect of the present invention comprises an assay that can be used to test the binding affinity of a library of IAP binding compounds for their ability to bind to the BIR domain of an apoptosis protein inhibitor (IAP), for example the BIR3 domain of mammalian XIAP. The assay may be based on a detectable label, which may be a fluorogenic dye molecule which is the loading portion of an IAP binding charge molecule. The detectable label can be any of the substituents on the molecules of formula (2), (3), or (5). For example, the detectable label can be linked to the substituent] ¾, or linked to substituents ¾a-c above in molecules having the structure of formula (2) Similarly, the detectable label can be linked to substituents such as Y, Z, M, G, Rio, or other substituents or molecules having the structure of formula (3), or (5) and their pharmaceutically acceptable salts. A detectable label included in a molecule of formula (2), (3), or (5) may be a dye such as a fluorogenic dye whose emission is sensitive to the environment of the dye. However, the detectable label portion of an I7AP binding loading molecule can also be an NMR active nucleus or a contrast agent, and selective identification is performed through nuclear magnetic resonance or magnetic resonance imaging. The detectable label in an IAP linkage loading molecule can also be a radioisotope and when selective identification is performed through positron emission tomography. The loading portion of the molecule can also be used to destroy cells through a toxic effect of the loading portion of the molecule. Without wishing to be bound by theory, it is considered that the structure molecule (2), (3), or (5) Pack in the BIR domain of an IAP. When the molecule of structure (2), (3), or (5) has a fluorogenic dye as a charge substituent, preferably, the packaging of the structure molecule (2), (3), or (5) in the BIR slot of a ??? causes a large shift in the maximum emission and intensity of the dye, when the environment of the LAP binding charge molecule changes from water to the hydrophobic cavity or binds in or near the IAP slot. If a molecule (e.g., the native Smac protein or a test IAP binding compound) shifts the IAP linkage loading molecule of formula (2), (3), or (5) with the fluorogenic dye of IAP, then the emission will change back to the spectrum observed for the LAP binding charge molecule with the fluorogenic dye in water. Since the emission intensity is related to the binding of a test peptide, or LAP binding compound to the LAP, the intensity can be used to estimate the equilibrium constant, Ka, for displacement of the molecule of formula (2), (3), or (5) by the LAP binding compound; Ka refers to an equilibrium constant for association that is inversely related to the dissociation Kd = 1 / Ka. The greater the equilibrium constant Ka, the greater the affinity of the LAP binding compound it has for BIR or BIR3. This allows the most promising inhibitors to be quickly detected and structural information regarding effective inhibitors, can be incorporated into the design of candidates for the next round of testing. An LAP binding loading molecule of formula (2) having a detectable label can be completed to an LAP and used to monitor other IAP binding compounds. It will be understood by those skilled in the art that, although the LAP binding charge molecule of formula (2), (3), or (5) described above is exemplified and preferred for the practice of the invention, various combinations of IAP binding compounds, BLR binding domains of different IAPs, and detectable labels can be used interchangeably to create variations of the assay described above. The IAP linkage loading molecule of structure (2), (3), or (5) or its dimers, can comprise any therapeutically detectable or therapeutically detectable molecule., such as but not limited to a fluorophore, radioisotope or active NMR core, such that the binding of the binding molecule binds ??? to the BIR domain of an LAP, and preferably the BIR3 slot of XIAP, is not adversely affected by the presence of the detectable or therapeutic label in the IAP link loading molecule. Preferably, the molecule is permeable to cells. A non-limiting example of a detectable label that can be coupled to the LAP binding compounds and LAP binding charge molecules of structure (2), (3), or (5) is the organic fluo dye 6-bromoacetyl-2- dimethylaminonaphthalene(badán) Badán is a fluorogenic dye whose sensitivity to environmental changes was previously used to probe protein-binding interactions. The LAP binding charge molecules of structure (2), (3), or (5) can be used in a test compound assay that can bind to the BLR domain of an LAP. These molecules can be used, for example, to alleviate the suppression of apoptosis or to release sequestered proteins such as Smac from LAPs in cells. A high-throughput cell-free assay for the compounds of structure (2), (3), or (5) can also be prepared using a peptide labeled in fluorescent form as (AbuRPF-K (5-Fam) -NH2) . A wide variety of LAP binding compounds can be monitored or assayed for their ability to bind to the BLR domain of IAPs. LAP binding molecules with greater binding ability than Smac of natural origin, or LAP binding molecules that can release abducted Smac from LAP in cells, can be identified by said assay. These compounds can be developed as therapeutic agents, pharmaceutical compositions for modification and preferably the promotion of apoptosis in the treatment of diseases or pathological conditions in which cell proliferation plays a role. These identified compounds can be used as prophylactics and can also be modified to include detectable labels or toxic agents. The assay can also be used in high performance monitoring of large panels of compounds generated by combination chemistry and other avenues of rational drug design. The fluorescence assay can be used to test linkage of a library of LAP linkage molecules modeled at the Smac link and their homologs, and preferably the N-terminal linkage of Smac, to the surface cavity of the BLR3 region of? ??? . The results of this monitoring make it possible to synthetically analyze the contribution of each portion in the structure of the LAP binding cargo molecule to the total binding of the interaction. For example, when comparing bond, Kd of the molecules (5-54) and (5-55) in Table 5 for alkyl groups of different size for Rib, the contribution of the methylene group to the Kd of LAP bond, can be used to make additional modifications to the molecules. The present invention characterizes LAP binding compounds and methods for their use in binding to Apoptosis Protein Inhibitor (IAPs), including but not limited to ????, C-IAP1, C-LAP2, survivin, ML-LAP or their combinations One function of IAPs is to suppress programmed cell death, whereas Smac, or LAP binding compounds of structure (2), (3), or (5) can be used to alleviate this suppression. Mammalian LAP binding protein Smac depends on binding of its four N-terminal residues to a surface groove characterized in a portion of XIAP referred to as the BLR3 domain. This link prevents XIAP from exerting its function of suppression of apoptosis with caspases in the cell. An LAP binding cargo molecule, such as those of formula (2), (3), or (5), can be employed to alleviate apoptosis mediated by XIAP or other LAP mediated mammalian cells and can optionally provide a functional group that has a detectable property or a therapeutic function for the cells. LAP binding charge molecules, such as those of formulas (2), (3), or (5), may be employed or to release sequestered proteins such as Smac from LAPs in cells. One embodiment of the invention is a method for using versions of LAP binding compounds of the formula (2), (3), or (5) which may include administration to abnormal cells or tissues, which may be known to over- express LAP as well as other cell lines related to developmental disorders, cancer, autoimmune diseases, as well as neurodegenerative disorders such as but not limited to for example SK-OV-3 cells, HeLa cells or other cells, an amount of LAP binding compounds or LAP binding charge molecules in various embodiments of formula (2), (3), or (5) that is effective to reduce, eliminate or otherwise way to treat the sample of the cells. An amount of LAP binding compounds or LAP binding charge molecules in various embodiments of formula (2), (3), or (5) can be administered to normal cells or tissues as a control. The amount of the compound of the formula (2), (3), or (5), combinations or combinations thereof that include other therapeutic compounds that are effective in reducing the proliferation condition, can be determined from changes in the optical density of treated cells and tissue samples or control and treated cells. The compound administered of structure (2), (3), or (5), in some embodiments it includes those with an EC50 as measured using the method described for example, in Example 1 for LAP binding compounds with less than about 1 micromolar, in other embodiments an EC50 with less than about 0.5 micromolar and still in other embodiments, the EC50 for the administered IAP binding compounds of structure (2), (3), or (5) may be less than about 0.06 micromolar. The term "IAP-binding compound" refers to a molecule that provides activity or tertiary linkage with functional domain of BIR-containing protein (e.g., binding motif or active site) of LAP. These LAP binding compounds can be non-peptide agents such as small molecule drugs of the structure (2), (3), or (5) or that include molecules of structure (2), (3), or (5). Knowing the structural characteristics and binding of naturally occurring IAP binding charge molecules such as Smac and its homologs, it is advantageous to make LAP binding compounds having similar or improved linkages compared to the N-terminal tetrapeptides of Smac and IAP binding. their counterparts Aggregate advantages of LAP binding charge molecules of structure (2), (3), or (5) in various embodiments of the invention, are that compounds of this size and structure can be prepared by synthesis on a large scale, can be modified chemically to have improved solubility in aqueous solution, they have improved cell permeation and provide ease of delivery to select sites or targets, in vivo. IAP link loading molecules of the invention may include amino acids as well as molecules wherein the amino acids are modified to produce LAP binding compounds by removal, replacement or modification of one or more naturally occurring side chains of the genetically encoded amino acids. The replacement may include exchange of one or more of the L amino acids with D amino acids. When the side chains of natural origin of the amino acids are replaced, groups such as alkyl, lower alkyl, 4-, 5-, 6- to 7-membered alkyl, cyclic, amide, lower alkyl amide, di (lower alkyl) amide , lower alkoxy, hydroxy, carboxy and its lower ester derivatives, and with 4-, 5-, 6- to 7-membered heterocyclics can be used. For example, proline analogues can be made where the ring size of the proline residue is changed from 5 members to 4, 6, or 7 members or substituents are added at various positions (2, 3, 4, or 5) in the ring . For example, in the structure of formula (2), the substituents can be an ester group R2, or an aryloxy group Z. Cyclic groups can be saturated or unsaturated and, if not saturated, can be aromatic or non-aromatic. Heterocyclic groups can be used as a side group in R2 in the molecules of formula (2), (3) or (5). The heterocyclics may contain one or more heteroatoms of nitrogen, oxygen and / or sulfur. Examples of these heterocyclic groups include furazanyl, furyl, imidazolidinyl, imidazolyl, imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl (for example morpholino), oxazolyl, piperazinyl (for example 1-piperazinyl), piperidyl (for example 1-piperidyl, piperidino), pyranyl , pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl (e.g. 1-pyrrolidinyl), pyrrolinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, thiomorpholinyl (for example thiomorpholino) and triazolyl. These heterocyclic groups may be substituted or unsubstituted. When a group is substituted, the substituent may be alkyl, alkoxy, halogen, oxygen or substituted or unsubstituted phenyl. The binding compounds ??? they may also have amino acid residues that have been chemically modified by phosphorylation, sulfonation, biotinylation or the addition or removal of other portions. A variety of synthetic techniques known to those of skill in the art are available to construct IAP binding compounds with the same or similar desired biological activity as the corresponding native peptide but with more favorable activity than the peptide with respect to solubility., stability, cellular permeability, immunogenicity and / or susceptibility to hydrolysis or proteolysis. These LAP binding cargo molecules are synthetic compounds having a three-dimensional structure (ie a "peptide" motif) based on the three-dimensional structure of a select Smac peptide or homolog. The peptide motif provides the IAP binding compound with the desired biological activity, i.e. LAP-linkage, wherein the binding activity of the LAP binding compound is not substantially reduced and is often the same as or greater than the activity of the native peptide. wherein the LAP binding compound is modeled. LAP binding cargo molecules of the present invention may have additional beneficial characteristics that improve their therapeutic application, such as decreased cost for synthesis, increased cellular permeability, improved stability to radiological elements, greater affinity and / or avidity for target LAPs and life prolonged biological mean. In a class of LAP binding compounds, the main structure can include various chemical bonds such as ester, thioester, thioamide, retroamide, reduced carbonyl, dimethylene and ketomethylene, to modify LAP bond in the LAP binding charge compound. Because caspases are cytosolic enzymes, LAP binding cargo molecules of diagnosis, imaging, prophylactic and therapeutic that chemically bind with LAP proteins, preferably cross cell membranes. The cell membrane permeant LAP binding complexes of the present invention are preferably those that can confer the desired intracellular translocation and LAP binding properties to the LAP binding cargo molecules. Preferably, these LAP binding cargo molecules are characterized by their ability to confer transmembrane translocation and internalization of a complex LAP binding cargo molecule of structure (2), (3), or (5) when administered to the outer surface of an intact tissue or organ cell. The ability of the IAP binding charge molecules of the present invention to permeate the cell and be localized within the cytoplasmic and / or nuclear compartments can be demonstrated by a variety of detection methods such as, for example, fluorescence microscopy, confocal microscopy, electron microscopy, autoradiography or immunohistochemistry. Without wishing to be bound by theory, the IAP linkage molecule of structure (2), (3), or (5) can be linked to IAPs in cells and can, although is not limited to competitively displacing IAPs bound to caspases in the cells or release Smac sequestered with IAPs in the cells. The IAP-binding molecule binds chemically, physically, or by a combination of these, with an IAP protein and can displace it from a mature caspase or Smac protein in a cell. The physical interaction between the LAP binding portion of the LAP binding cargo molecule and an LAP protein can be used to modify apoptosis in cells. LAP binding molecules or charge molecules of formula (2), (3), or (5) may have an LAP binding moiety that may for example displace a molecule or polypeptide such as a mature caspase or labeled peptide in fluorescent form (AbuRPF-K (5-Fam) -NH2) of the BLR domain of an IAP. When an increase in apoptosis in the cells is convenient, LAP binding molecules of the formula (2), (3), or (5) having a Kd binding constant as measured by the methods described for example in Example 1 for the displacement of (AbuRPF-K (5-Fam) -NH2) of the BLR domain of an LAP can be less than about 10 [μ], in some embodiments Kd can be less than about 1 [μ] M, and yet in other embodiments Kd may be less than 0.1 micromolar under the test conditions described in the examples. The labeled IAP binding loading molecule of the structure (2), (3), or (5) may include any convenient detectable label, including fluorophores, chromophores, fluorescent nanoparticles, and other isotope dyes, radioisotopes, metals, small molecules, and the like. When the tag binds or binds to the LAP binding portion of the molecule, the tag of preference does not substantially interfere with the permeance of the cell or linkage of the molecule to LAP and allows its use in diagnostic or therapeutic applications. To select a tag, preferably a detectable property of the tag changes with the binding of the LAP binding cargo molecule with the BLR domain of an LAP protein. The detectable property of the tag may change due to the interaction of the tag with changes in the cellular environment when the molecule binds to LAP, thereby improving or decreasing property. IAP link loading molecules can also find utility as therapeutic agents. In one case, the binding of the IAP binding molecule to LAP in cells can be used to modify apoptosis in cells that require treatment. In another case, an LAP binding cargo molecule in which the loading portion is radio labeled, can be used for radiation therapy. Through the use of these charge molecules, radioactive atoms can be administered to a tumor, tissue or other population of cancer cells that over-express LAP protein. The LAP in the tumor binds to the LAP binding cargo molecule with the nucleonuclei. Similarly, IAP link loading molecules can be designed to incorporate a dye that is active in photodynamic therapy. Other of these therapeutic use utilities will be apparent to those skilled in the art. Cells were evaluated to detect abnormal levels of IAP where the cells can be mixed and optionally incubated with an LAP binding cargo molecule in a fluid sample in a vessel or wells, a circulating fluid or fluids after purification. These samples can be monitored for changes in a detectable property of the LAP link loading molecule. For example, flow cytometry is a method to analyze cells labeled with a fluorescent probe molecule in a flow cytometer. In a flow cytometer the cells pass in a single row through a focused laser beam where they emit fluorescence from the probe in the cell that can be detected by the photomultiplier tubes of the cytometer. Cells with abnormal, high or low expression of IAP can be contacted and optionally incubated with LAP binding loading molecule of structure (2), (3), or (5) having a fluorescent probe loading-portion. The binding of the LAP binding cargo molecule to the LAP protein in the cells can be detected by the flow cytometer. The fluorescence vision intensity can be measured, digitized and stored on a computer disk for analysis and comparison with the fluorescent emission of control cells, samples of treated cells or other samples whose IAP expression is to be determined. A method for monitoring LAP proteins in cells, with a molecule that binds the BLR domain in an LAP protein, is provided. The method includes combining an LAP binding cargo molecule of formula (2), (3), or (5) and cell LAP proteins, under conditions e where the LAP binding cargo molecule and the LAP protein can be combined . It may include the step of incubating a sample of cells with an LAP binding cargo molecule. The LAP linkage by the molecule, an indication of the presence of LAP in the cells, can be determined by monitoring a detectable linkage property of the LAP binding cargo molecule. A change in the detectable property of the LAP binding molecule can be used to determine the expression of LAP in the cells. Where does Protein ??? If it is over expressed in cells, the IAP binding charge molecule can be used to ligate the IAP and alleviate IAP-mediated inhibition of caspase activity in the cells. In alternate form, where an IAP protein sequesters a protein such as Smac or another protein involved in apoptosis, the LAP binding cargo molecule of structure (2), (3), or (5) can be used to release the sequestered Smac or other protein of LAP and modify apoptosis within cells. When convenient or necessary in the course of treatment, other LAP binding cargo molecules can be administered to the cells. These additional LAP binding charge molecules may have different binding affinity for the LAP and may optionally include a loading moiety that is a therapeutic agent such as a radioisotope. The IAP linkage cargo molecules for example those of the formula (2), can be used in various assays to monitor and identify compounds capable of acting as agonists or antagonists of the caspase-LAP protein or LAP-Smac interactions within the cells. For example, LAP binding cargo molecules that can break the IAP-caspase interaction, antagonists of this interaction, are expected to be useful as pro-apoptotic drugs for the treatment of proliferative cell diseases such as cancer. Agonists of this interaction may be useful as anti-apoptotic drugs for the treatment of diseases where the inhibition of apoptosis is required, for example degenerative diseases such as Alzheimer's disease. A living system can include plants, animals, single and multiple cell organisms and insects. The term mammal includes humans and all domestic and wild animals including without limitation cattle, horses, pigs, sheep, goats, dogs, cats and the like. An "effective amount" refers to that amount of an LAP binding charge molecule of formula (2), (3), or (5) of the present invention, which, when administered to a sample of one or more cells including a tissue or a living system such as an animal, preferably a mammal that requires it, is sufficient to effect the detection of LAP in tissue or cells, prophylaxis of tissues or cells or therapeutic treatment of IAP in the cells or tissue, preferably those in a living system. For disease states alleviated by the inhibition of LAP activity, the amount of a compound in the present invention constitutes a therapeutically effective amount that modifies or promotes apoptosis in one or more cells including a tissue or a subject, will vary depending on the compound, the condition of disease and its severity, and the mammal to be treated, but can be routinely determined by a person with ordinary skill in the art taking into consideration their own knowledge and this description. An effective amount for diagnosis is an amount of a LAP binding charge molecule sufficient to allow detection of LAP in cells or tissue and for example may vary depending on the location of the cell or tissue and the stability of the binding charge molecule ??? . A prophylactically effective amount is an amount of an IAP binding charge molecule that prevents the occurrence of a disease state and can be determined for example by prophylactic administration of IAP binding load molecules to cells, tissue or test animals with controls and then exposing these to known conditions that induce abnormal cell proliferation and then determining the prophylactically effective amount of the IAP linkage loading molecule. Treating or treating a disease state in a sample of cells, a tissue, a mammal and particularly in a human, can include detecting the presence of disease in the cells using compounds of structure (2), (3), or ( 5) of the present invention and when a disease is detected, optionally followed by administration of compounds of the present invention, one or more cells, to an animal or tissue including human subjects, to modify and preferably promote apoptosis. The disease state in the case of over expression of IAP proteins in cells, can be alleviated by the inhibition of IAP-caspase interaction or IAP-Smac interaction by administering IAP-binding cargo molecules of the present invention to the cells, thereby causing regression of the disease state. Treatment may also include: preventing the disease state from occurring in a mammal. For example, in a mammal that is predisposed to a disease state characterized by inhibition of apoptosis, but the mammal has not yet been diagnosed as having the disease; An effective amount of the IAP-binding compounds of the present invention can be administered to cells or to the patient to inhibit the disease state or slow down its development. In one embodiment, molecules of structure (2), (3), of (5) can be administered as a composition to provide systemic distribution of IAP-binding molecules such as by oral, buccal or parenteral administration in the mammalian or human. The administration can be included in a method for treating mammals, especially humans, suffering from a proliferation disorder or at risk of a proliferation disorder. "At risk" refers to mammals as people whose genotype, family history or other risk factors indicate a higher than normal probability that the person suffers from a proliferation disorder if left untreated. The expression of IAP in cells can be detected in patients without need for surgery. Accordingly, the present invention encompasses compounds and methods for detecting intracellular biochemical activities in living systems such as whole animals, tissues or cells, by administering IAP binding cargo molecules of this invention that translocate into cells, and which are detectable. in living cells at distances removed from the cells by the presence of intermediate tissue. The methods and compositions can be used to identify cells or tissue that have an abnormal expression of IAP in a combination of one or more cells or tissues; and administering an effective amount of an IAP-binding charge molecule to bind with IAP in the sample cells and modifying the activity of IAP in the cells or tissue. Examples of tissues to which the methods and compositions of the present invention can be applied include, for example, cancer cells, in particular, tumors of the central nervous system, breast cancer, liver cancer, lung, head and neck cancer, lympholas , leukemias, multiple myeloma, bladder cancer, ovarian cancer, prostate cancer, kidney tumors, sarcomas, colon and other gastrointestinal cancer, metastasis and melanomas. Other examples of disease conditions or disorders wherein modification of apoptosis or abnormal LAP activity are involved, of which the methods and compositions of the present invention may be applied, include but are not limited to infection, inflammation, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. A proliferation disorder may include disorder wherein LAP activity inhibits apoptosis in cells that receive an apoptotic stimulus. Apoptosis can be promoted in a cell sample by administering to the cells an amount of LAP binding cargo molecule effective to stimulate apoptosis in the cells. The cells can be cultured cells, cells within a tissue and the tissue is preferably located within a living organism, preferably an animal, more preferably a mammal and more preferably a human. These latter modalities are carried out in formulating the IAP binding loading molecules of the invention in a therapeutically effective amount as a pharmaceutical preparation for administration to a mammalian subject. This pharmaceutical preparation constitutes another aspect of the present invention. The ability of a pharmaceutical agent to simulate or inhibit apoptosis can be tested in a target cell-free activity assay current under LAP. In the absence of an IAP binding cargo molecule, LAP itself may for example interact with Smac or inhibit caspase activity, thereby slowing down apoptosis. These assays include but are not limited to direct caspase-9 activity assays and caspase activation assays (procaspase cleavage). In these assays, an IAP binding loading molecule of the invention, having a predetermined level of activity in these assays, is used as a positive control and optionally a corresponding molecule that is known to be non-active in the assay, is used as a negative control. Assays can be performed using these controls and cells undergoing treatment are evaluated to alleviate inhibition of Smac or caspase activity by IAP in the presence of an IAP binding molecule in the structure (2), (3) or (5). Cells that undergo apoptosis can be differentiated from normal cells by different morphological changes or by molecular markers, such as chromosome cleavage in nucleosome ladders (detected by nuclear DNA staining). LAP biologically active or pharmaceutically active link loading molecules of the invention are those that bind LAP (apoptosis protein inhibitor), specifically, the BLR domain of LAP, more specifically the BLR3 linkage slot of XIAP. This activity can be measured with respect to any LAP, including but not limited to XIAP, c-IAPl, c-LAP2, survivin, ML-IAP, and DLAP. Various aspects of the present invention will be illustrated with reference to the following non-limiting examples. EXAMPLE 1 Linking constants (Kd) were measured using fluorescence polarization as described by Zaneta Nikolovska Coleska, Renxiao Wang, Xueliang Fang, Hongguang Pan, York Tomita, Peng Li, Peter P. Roller, Krzysztof Krajewski, Naoyuki Salto, Jeanne Stuckey and Shaomeng Wang, in "Development and Optimization of a Binding Assay for the XIAP BLR3 Domain üsing Fluorescence Polarization", Analytical Biochemistry 2004, 332, 261-273). Briefly, test LAP binding compounds at various concentrations for binding measurements were mixed with fluorescently labeled peptide 5 nM (AbuRPF- (5-Fam) -NH2) and 40 nM of XIAP-BLR3 for 15 minutes at room temperature in 100 μM 0.1 M potassium phosphate buffer, pH 7.5 containing 100 μg / ml bovine ^ -globulin. After incubation, polarization values (mP) were measured in a ViCtOr2V using a 485 nM filter filter and a 520 nM emission filter. IC50 values were determined from the trace using non-linear least squares analysis using GraphPad Prism. The Kd values of competitive inhibitors were calculated using the equation described by Zaneta Nikolovska Coleska et al. based on the measured IC 50 values, the Kd value of the probe and the XLAP BLR3 complex, and the protein and probe concentrations in the competition assay. In various LAP link examples or ranges for LAP link loading molecules for Kd values: Group A: Kd < 0.1 μ ?; Group B: Kd = 0.1 - 1 μ ?; Group C: Kd = 1 - 10 μ ?; Group D: Kd > 10 μ. EXAMPLE 2 This example illustrates the use of compounds of embodiments of the present invention that can be used in a method of treating cells. The method that these LAP binding compounds use may include administering to abnormal cells, of which it can be known that they overexpress LAP as well as other cell lines related to developmental disorders, cancer, autoimmune diseases, as well as neurodegenerative disorders such as, but not limited to for example SK OV 3 cells, HeLa cells or other cells, an amount of the LAP binding compounds or LAP binding charge molecules in various embodiments of the formula (2), (3), or (5) that they are effective in reducing, eliminating or otherwise treating the cell sample. The MTT assay is an example of an assay that has been used to measure cell growth as previously described (Hansen, MB, Nielsen, SE, and Berg, KJ Immunol. Methods 1989, 119, 203 210) and incorporated herein by reference in its entirety Briefly, SK OV 3 cells were seeded in 96-well plates in McCoy medium containing 10% fetal bovine serum albumin (20,000 per well) and incubated overnight at 37 degrees C. The next day, the test compounds added at various concentrations, typically from about 10 to about 0.0001 μ? and the plates were incubated 37 degrees C for an additional 72 hours. This incubation time was optimal to measure inhibitory effects of different analogues. 50 microliters of 5 mg / mL of MTT reagent are added to each well and the plates are incubated at 37 degrees C for 3 hours. At the end of the incubation period, 50 microliters of DMSO are added to each well to dissolve cells and the optical density (OD = optical density) of the wells is measured with a microplate reader (Víctor2 1420, Wallac, Finland) at 535 nm. Cell survival (CS) is calculated by the following equation: CS = (treated well OD / average control well OD) x 100% EC50, defined as the drug concentration resulting in 50% CS is derived at calculate the den point where the dose-response curve crosses the 50% point of CS using GraphPad Prism. Representative results for IAP binding compounds are: Table 1.

EXAMPLE 3 This example illustrates the preparation of pyrrolidine derivatives of Table 2. Examples include molecules of the formula (E3) which may include heteroalkynyl substituents. Scheme I Preparing hydrochloride AmUiO 2S-N- [2-methyl-LS- (4-phenoxy-phenoxymethyl 2S-pyrrolidin-1-carbonyl) -propyl] -propionamide (7): The tert-butyl ester (45) Phenoxy- (2, S) -phenoxymethyl-pyrrolidine-l-carboxylic acid (2): To a solution of alcohol 1 (0.53 g, 1.8 ramol) in anhydrous DC (10 mL) is added phenol (0.21 g, 2.3 mmol), Ph3P (0.52 g, 2.0 mmol), and 1, r- (azodicarbonyl) -dipiperidine (ADDP, 0.50 g, 1.9 mmol) in sequential order. After 2 hours at room temperature, the heterogeneous reaction mixture is filtered. The white solid is washed with DSM and the clarified filtrate is washed with 2M NaOH, water, brine, dried with Na 2 SO 4, filtered and concentrated. The crude aryl ether is purified by flash silica gel chromatography (3: 1 hexane / EtOAc) to give 0.36 g (54%) of 2 as a colorless oil. 1 H NMR (CDC13, 300 MHz) d 7.29-7.24 (m, 4H), 6.94-6.82 (m, 6H), 4.91 (t, J = 5.1 Hz, 1H), 4.37-4.28 (m, 2H), 4.12- 4.05 (m, 1H) 5 3.79-3.64 (m, 2H), 2.48 (app d, J = 13.8 Hz, 1H), 2.32-2.25 (m, 1H), 1.48 (s, 9H) ppm. B. Acid (4, S) -Fenoxy- (2, S) -phenoxymethyl pyrrolidine (3): Trifluoroacetic (2 mL) is added at room temperature to a solution of 2 (0.36 g, 0.98 mmol) in DCM (10 mL) ). After 1.5 h, the solution is concentrated to dryness and the crude product is dissolved in EtOAc. The organic solution is washed with aqueous aHC03, brine, dried over anhydrous Na2SO, filtered and concentrated. The crude pyrrolidine is purified by flash silica gel chromatography (10% MeOH / DCM) to result in 0.23 g (88%) of 3 as a brown-orange oil. 1 H NMR (CDC13, 300 Hz) d 7.32 7.26 (m, 4H), 6.98 6.87 (m, 6H), 4.90 4.87 (m, 1H), 4.07 4.01 (m, 2H), 3.63 3.57 (m, 1H), 3.35 (app d, J = 12.3 Hz, 1H), 3.17 (app q, J = 5.4 Hz, 1H), 2.77 (br s, 1H), 2.45 2.35 (m, 1H), 1.93 1.86 (m, 1H) ppm. C. [2-Methyl-1- (45'-phenoxy-251-phenoxymethyl-pyrrolidine-1-carbonyl) propylcarbamic acid tert-butyl ester (4): O- (7-Azabenzotriazol-1-yl) -N , N, N 1, N 1 -tetramethyluronium PF 6 (HATU, 0.38 g, 1.0 mmol) is added to a solution of iV Boc Val (0.28 g, 1.3 mmol) in anhydrous NMP (5 mL) at room temperature. N Methylmorpholine (0.1 mL) is added to the reaction mixture. After 10 min, pyrrolidine 3 (0.23 g, 0.86 mmol) in NMP (5 mL) is added. After 2 h, the reaction mixture is diluted with EtOAc and washed with dilute aqueous NaHCO3, 1 N HC1, water and brine. The organic phase is dried over anhydrous a2SO4, filtered and concentrated. The crude amide is purified by flash silica gel chromatography (3: 1 hexane / EtOAc) to give 0.36 g (90%) of 4 as a colorless oil. ½ RN (CDC13, 300 Hz) d 7.34-7.26 (m, 4H), 7.03-6.82 (m, 6H), 5.30 (d, J = 9.3 Hz, 1H), 5.01-4.99 (m, 1H), 4.69- 4.65 (m, 1H), 4.38-4.34 (m, 1H), 4.27-4.07 (m, 3H), 3.83-3.78 (m, 1H), 2.53-2.48 (m, 1H), 2.38-2.31 (m, 1H) ), 2.00-1.94 (m, 1H), 1.48 (s, 9H), 0.97 (d, J = 7.2 Hz, 3H), 0.93 (d, J = 7.2 Hz, 3H) ppm. D. 2-7Amino-3-methyl-1- (45 '~ phenoxy-2. S' -phenoxymethyl-pyrrolidin-1-yl) utan-1-one (5): trifluoroacetic acid (2 mL) is added at room temperature environment to a solution of 4 (0.36 g, 0.79 mmol) in DCM (10 mL). After 1.5 h, the solution is concentrated to dryness and the crude product is dissolved in EtOAc. The organic solution is washed with NaHCC > 3 Acute, dry brine on anhydrous Na2SO4 filtered and concentrated. The crude mine is purified by flash silica gel chromatography (5% MeOH / DC) to result in 0.27 g (96%) of 5 as a light yellow oil. XH NMR (CDC13, 300 MHz) d 7.32-7.01. (m, 4H), 7.01-6.82 (m, 6H), 4.99 (m, 1H), 4.67-4.48 (m, 1H), 4.38-4.27 (m, 1H), 4.16-4.05 (m, 1H), 3.99 (app q, J = 5.1 Hz, 1H), 3.78-3.72 (m, 1H), 2.50-2.28 (m, 2H), 1.86 (br s, 2H), 0.97 (d, J = 7.2 Hz, 3H), 0.91 (d, J = 7.2 Hz, 3H) ppm. E. ter-butyl ester of. { 1S- [2-Methyl-lS- (S-phenoxy-2S-phenoxymethyl-pyrrolidine-1-carbonyl) propylcarbamoyl] -ethyl} -carbamic (6): 0- (7- Azabenzotriazol-l-il) -?,?,? ' , N'-tetramethyluronium PF6 (HATU, 0.23 g, 0.61 mmol) is added to a solution of N Boc Ala (0.14 g, 0.74 mmol) in anhydrous N P (3 mL) at room temperature. W-Methylmorpholine (0.1 mL) is added to the reaction mixture. After 10 min, pyrrolidine 5 (0.17 g, 0.48 mmol) in NMP (5 mL) is added. After 16 h, the reaction mixture is diluted with EtOAc and washed with dilute aqueous NaHCO 3, 1 N HCl, water and brine. The organic phase is dried over Na 2 SO 4, filtered and concentrated. The crude amide is purified by flash silica gel chromatography (1: 1 hexane / EtOAc) to give 0.23 g (92%) of 6 as a colorless oil. XH NMR (CDC13, 300 MHz) d 7.33-7.23 (m, 4H), 7.02-6.87 (m, 6H), 5.02-4.99 (m, 2H), 4.68-4.48 (m, 2H), 4.33 (dd, J = 3.9, 9.3 Hz, 1H), 4.23-4.09 (m, 4H), 3.83-3.78 (m, 1H), 2.52-2.47 (m, 1H), 2.38-2.28 (m, 1H), 2.08-1.99 (m , 1H), 1.80 (br s, 1H), 1.45 (s, 9H), 1.36 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H) ppm. F. 25 'Hydrochloride -Amino-iV- [2-methyl-11Sr- (41S 1 -phenoxy-25'-phenoxymethyl-pyrrolidine-1-carbonyl) -propyl] -propionamide (7): trifluoroacetic acid (2 mL) it is added at room temperature to a solution of 6 (0.23 g, 0.44 mmol) in DCM (10 mL). After 1.5 h, the solution is concentrated to dryness and the crude product is dissolved in EtOAc. The organic solution is washed with aqueous NaHC03, dry brine over Na2SO4, filtered, and concentrated. The crude amide is dissolved in diethyl ether then treated with HC1 (g). The crude salt is triturated with diethyl ether and hexane to give 0.13 g (65%) of 7 as a white solid. 1 H NMR, free base (CDC13, 300 MHz) d 7.89-7.87 (m, 1H), 7.32-7.24 (m, 4H), 7.01-6.79 (m, 5H), 5.01-4.98 (m, 1H), 4.68- 4.62 (m, 1H), 4.51-4.43 (m, 1H), 4.36-4.26 (m, 2H), 4.18-4.10 (m, 1H), 3.84-3.78 (m, 1H), 2.51-2.46 (m, 1H) ), 2.35-2.28 (m, 1H), 2.09-2.02 (m, 1H), 1.38-1.25 (m, 4H), 0.96-0.92 (m, 6H) ppm. Mass spectrum, m / z = 440 [(M + H) + J. < E3) Table 2.

EXAMPLE 4 [00165] This example illustrates the preparation of substituted pyrrolidines from Table 3. Scheme II The preparation of trans-2S-Amino-IV ~ (1S- { 2S- [3- (2-ethyl-phenoxy) -propenyl] -45-phenoxy-pyrrolidine-1-carbonyl} -2-methyl- propyl) -propionamide (14): trans-5-2 ± Sr- [3- (2-Ethyl-phenoxy) -propenyl] -45-phenoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (9) : to a solution of alcohol 8 (0.3 g, 0.94 mmol) in DCM (6 mL) is added 2-ethylphenol (0.14 g, 1.16 mmol) and Ph3P (0.27 g, 1.03 mmol). The solution is cooled to 0 degrees C and ADDP (0.28 g, 1.13 mmol) is added in one portion. After 10 min, the reaction mixture is allowed to warm to room temperature and stirring is continued for 16 hours. The white precipitate is removed by filtration and washed with DCM. The clarified filtrate is washed successively with 1M NaOH, water and brine. The organic phase is dried with Na2SC > 4 anhydrous, filtered and concentrated. The crude ether is purified by flash silica gel chromatography (3: 1 hexane / EtOAc) to give 0.18 g (45%) of 9 as a colorless oil. ¾ NMR (CDC13, 300 MHz) d 7.30 7.26 (m, 2H); 7.15 (m, 2H); 7.00-6.79 (m, 4H); 6.01-5.98 (m, 1H), 5.84 (m, 1H); 4.92 (br s, 1H); 4.53-4.43 (m, 3H); 3.76 (m, 2H); 2.65 (q, 2H); 2.39 (m, 1H); 2.16 (d, 1H); 1.46 (s, 9H), 1.21 (t, 3H) ppm. B. trans-5-25 '- [3- (2-Ethyl-phenoxy) -propenyl] -451-phenoxy-pyrrolidine (10): Trifluoroacetic acid (2 mL) is added at room temperature to a solution of 9 (0.18). g, 0.43 mmol) in DCM (10 mL). After 1 h, the solution is concentrated to dryness and the crude product is dissolved in EtOAc. The organic solution is washed with aqueous NaHC03, dry brine over anhydrous MgSO4, filtered and concentrated. The crude amine (10) is used without further purification (0.13 g is obtained). XH NMR (CDC13, 300 MHz) d 7.31-7.25 (m, 3H); 7.17-7.11 (m, 2H); 6.97 6.80 (m, 4H); 5.97-5.88 (m, 2H); 4.86 (m, 1H); 4.54-4.50 (m, 2H); 3.70 (q, 1H); 3.34 (d, 1H); 3.07 (d of d, 1H); 2.66 (q, 2H); 2.48-2.41 (m, 1H); 1.82-1.75 (m, 2H); 1.20 (t, 3H) ppm. C. Ter-butyl ester of trans-acid. { \ S-. { 25- [3- (2-Ethyl-phenoxy) -propenylj -4-S '-phenoxy-pyrrolidine-1-carbonyl} -2-methyl-propyl) -carbamic acid (11): 0- (7- azabenzotriazol-1-yl-N, N, N ', N' -tetramethyluronium-PFe (HATU, 0.23 g, 0.62 mmol) is added to a Solution of iV-Boc-Val (0.18 g, 0.82 mmol) in anhydrous NMP (3 nxL) at room temperature iV-Methylmorpholine (0.12 mL) is added to the reaction mixture After 10 min, amine 10 (0.13 g) , 0.41 mmol) in NMP (3 mL) is added.After 16 h, the reaction mixture is diluted with EtOAc and washed with dilute aqueous NaHCO3, 1 N HC1, water and brine.The organic phase is dried over anhydrous Na2SO4, filtered The crude amide is purified by flash silica gel chromatography (3: 2 hexane / EtOAc) to give 0.20 g (92%, 2 steps) of 11 as a colorless oil.1H NMR (CDC13, 300 MHz ) d 7.32 7.24 (m, 2H), 7.15-7.06 (m, 2H), 6.99 (t, 1H), 6.89-6.77 (m, 4H), 5.96-5.91 (m, 2H), 5.23-5.20 (m, 1H), 5.01-4.86 (m, 2H), 4.53 (m, 2H), 4.21-4.09 (m, 2H), 4.09-3.97 (m, 1H), 2.68 (q, 2H), 2.36-2.32 (m, 1H); 2.18 (d, 1H); 1 .97 1.91 (m, 1H); 1.44 (s, 9H); 1. 29 1.18 (m, 6H); 0.99 0.81 (m, 6H) ppm. ** D. rrai2s-21S'-Amino-l-. { 25 '- [3- (2-ethyl-phenoxy) -propenyl] -45' -phenoxy-pyrrolidin-1-yl} -3-methyl-butan-1-one (12): Trifluoroacetic acid (2 inL) is added at room temperature to a solution of 11 (0.20 g, 0.39 mmol) in DCM (10 mL). After 1 hour, the solution is concentrated to dryness and the crude product is dissolved in EtOAc. The organic solution is washed with aqueous NaHC03, brine, dried over anhydrous MgSO4, filtered and concentrated. The crude amine (12) is used without further purification (0.14 g obtained). 1 H NMR (CDC13, 300 MHz) d 1.28-7.26 (m, 2H); 7.15 (m, 2H); 6.99 (m, 1H); 6.89-6.76 (m, 4H); 6.10-5.86 (m, 2H); 5.01-4.95 (m, 2H); 4.56 (m, 3H); 3.92-3.79 (m, 1H); 3.31 (m, 1H); 2.66 (q, 2H); 2.32-2.16 (m, 1H); 1.68 (m, 4H); 1.28-1.19 (m, 3H); 0.97-0.81 (m, 6H) ppm. [00171] E. trans-[1S- (1S-. {2S- [3- (2-Ethyl-phenoxy) -propenyl] -4- [pound] -phenoxy-pyrrolidine-1-ter-butyl ester carbonyl) -2- methyl-propylcarbamoyl) -ethyl] -carbamic acid (13): O-CT-Azabenzotriazol-1-yl-N, N, N ', N' -tetramethyluronium PF6 (HATU, 0.19 g, 0.51 mmol ) is added to a solution of N Boc Ala (0.13 g, 0.67 mmol) in anhydrous NMP (3 mL) at room temperature. iV-Methylmorpholine (0.1 mL) is added to the reaction mixture. After 10 minutes, the amine (0.14 g, 0.34 mmol) in NMP (3 mL) is added. After 72 hours, the reaction mixture is diluted with EtOAc and washed with NaHCC > 3 diluted aqueous, HC1 1N, water and brine. The organic phase is dried over anhydrous Na2SO4, filtered and concentrated. The crude amide is purified by flash silica gel chromatography (1: 1 hexane / EtOAc) to give 0.11 g (49%, 2 steps) of 13 as a colorless oil. 1 H NMR (CDCl 3, 300 MHz) d 7.31 7.22 (m, 2H); 7.15-6.95 (m, 3H); 6.88-6.76 (m, 4H); 5.96-5.87 (m, 2H); 5.19 (br, 1H); 5.00 (m, 1H); 4.86 (t, 1H); 4.51-4.49 (m, 3H); 4.17-4.10 (m, 2H); 3.89-3.80 (m, 1H); 2.64 (q, 2H); 2.34-2.29 (m, 1H); 2.21-2.14 (m, 1H); 2.04-1.98 (m, 1H); 1.44 sec, 9H); 1.35-1.23 (m, 4H); 1.17 (t, 3H); 0.97-0.87 (m, 6H) ppm. [00172] F. Trans-2S-7Amino-N- (1S- {2"S '[3- (2-ethyl-phenoxy) propenyl] 45'-phenoxy-pyrrolidine-1-carbonyl1. -methyl-propyl) -propionamide (14): Trifluoroacetic acid (2 mL) is added at room temperature to a solution of 13 (0.11 g, 0.18 mmol) in DCM (10 mL) After 1 hour, the solution is concentrated to dryness and the crude product is dissolved in EtOAc The organic solution is washed with aqueous NaHCC > 3, brine, dried over anhydrous Na2SO4, filtered and concentrated to give 0.068 g (76%) of 14 as a white solid. (CDC13, 300 MHz) 8 7.86 (br, 1H), 7.31-7.22 (m, 2H), 7.15-7.05 (ra, 2H), 6.98 (t, 1H), 6.88-6.76 (ra, 4H), 5.97- 5.86 (ra, 2H), 5.00 4.98 (ra, 1H), 4.88-4.83 (m, 1H), 4.57-4.51 (m, 2H), 4.44 (t, 1H), 4.21 (d of d, 1H), 3.89 -3.82 (m, 1H); 2.64 (g, 2H); 2.33-2.29 (m, 1H); 2.17 (d, 1H); 2.04- 2.00 (ra, 1H); 1.36 1.25 (ra, 6H); t, 3H); 0.99-0.88 (ra, 6H) ppra.

(E4) Table 3 EXAMPLE 5 [00173] This example illustrates the preparation of pyrrolidine derivatives of Table 4. Scheme III Preparation of 2S-Amino-N- (1, S 1 -. {25 '- [3- (2-ethyl-phenoxy) -propyl] -45'-phenoxy-pyrrolidine-1-carbonyl} -2 -methyl-propyl) -propionamide (21): A. 25- (3-hydroxy-propyl) -4S-phenoxy-pyrrolidine-l-carboxylic acid tert-butyl ester (15): [Re: SRR-006-062 ] Palladium on carbon (10%, 0.3 g) is added to a solution of alcohol 8 (3 g, 9.4 mol) in EtOAc (30 iriL). The reaction mixture is placed in a Parr stirrer and pressurized to 3.1 bar (45 PSI) of H2 (g). The heterogeneous mixture is stirred for 24 hours at room temperature. The catalyst is removed by filtration through a 0.45 M PVDF filter disk (Millipore Millex HV (R)) and the clarified filtrate is concentrated in vacuo to yield 2.9 g (97%) of 15 which is used without further purification. 1 H NMR (CDC13, 300 MHz) d 7.29 (t, 2H); 6.96 (t, 1H); 6.85 (d, 2H); 4.88 (br s, 1H); 4.08-3.74 (m, 2H); 3.67-3.65 (m, 2H); 3.55 (d, 1H); 2. 27-2.23 (m, 2H); 2.05-1.90 (m, 2H); 1.76 1.65 (m, 1H); 1.55 (q, 2H); 1.47 (s, 9H) ppm. [00176] B. 25- [3- (2-Ethyl-phenoxy) -propyl] -45'-phenoxy-pyrrolidine-l-carboxylic acid tert-butyl ester (16): To a solution of alcohol 15 (0.61 g) , 1.91 mmol) in DCM (10 mL) is added 2-ethylphenol (0.28 g, 2.33 mmol) and Ph3P (0.55 g, 2.09 mmol). The solution is cooled to 0 degrees C and ADDP (0.58 g, 2.29 mmol) is added in one portion. After 10 minutes, the reaction mixture is allowed to warm to room temperature and stirring is continued for 16 h. The white precipitate is removed by filtration and washed with DCM. The clarified filtrate is washed successively with 1M NaOH, water and brine. The organic phase is dried with anhydrous a2SO4, filtered and concentrated. The crude ether is purified by flash silica gel chromatography (3: 1 hexane / EtOAc) to give 0.46 g of 16 as a colorless oil. 1 H NMR (CDC13, 300 MHz) d 7.28 (t, 2H); 7.13 (t, 2H); 6.96 (t, 1H); 6.89 6.84 (m, 3H); 6.78 (d, 1H); 4.91 4.87 (m, 1H); 3.96 (br, 4H); 3.56 (d, 1H); 2.63 (q, 2H); 2.28 2.26 (m, 1H); 2.11 2.06 (m, 2H); 1.86 1.77 (m, 3H); 1.46 (s, 9H); 1.17 (t, 3H) ppm. [00177] C. 2S- [3- (2-Ethyl-phenoxy) -propyl] -45'-phenoxy-pyrrolidine (17): Trifluoroacetic acid (2 mL) is added at room temperature to a solution of 16 (0.46 g) , 1.08 mmol) in DCM (10 mL). After 1 hour, the solution is concentrated to dryness and the crude product is dissolved in EtOAc. The organic solution is washed with aqueous NaHC03, dry brine over anhydrous Na2SO4, filtered and concentrated to give 0.30 g (85%) of 17 as a colorless oil. XR NMR (CDC13, 300 MHz) S 7.32 7.26 (m, 3H); 7.16-7.12 (m, 2H); 6.98-6.78 (m, 4H); 4.86 (s, 1H); 3.99-3.97 (m, 2H); 3.35 (d, 1H); 3.23 (m, 1H); 3.08 (mf 1H); 2.74-2.60 (m, 3H); 2.42 (m, 2H); 1.90-1.85 (m, 3H); 1.67-1.61 (m, 1H); 1.16 (t, 3H) ppm. [00178] D. Ter-butyl ester of (15. {21S '- [3- (2-Ethyl-phenoxy) -propyl] -45'-phenoxy-pyrrolidine-1-carbonyl} -2-methyl ester -propyl) -carbamic (18): O- (7- Azabenzotriazol-1-yl) -?,?,? ' , N '-tetramethyl-uronium PF6 (HATU, 0.39 g, 1.03 mmol) is added to a solution of N-Boc-Val (0.30 g, 1.38 mmol) in anhydrous NMP (3 mL) at room temperature. N-Methylmorpholine (0.2 mL) is added to a reaction mixture. After 10 min, amine 17 (0.22 g, 0.67 mmol) in NMP (3 mL) is added. After 16 h, the reaction mixture is diluted with EtOAc and washed with dilute aqueous NaHCO3, 1 N HC1, water and brine. The organic phase is dried over anhydrous Na2SO4, filtered and concentrated. The crude amide is purified by flash silica gel chromatography (3: 1 hexane / EtOAc) to give 0.30 g (83%) of 18 as a colorless oil. ½ NMR (CDC13, 300 MHz) d 7.33-7.26 (m, 2H); 7.12 (t, 2H); 6.99 (t, 1H); 6.89-6.77 (m, 4H); 5.28-5.24 (m, 1H); 5.00-4.98 (m, 1H); 4.39-4.36 (m, 1H); 4.22-4.17 (m, 2H); 4.02-3.94 (m, 2H); 3.72 (d of d, 1H); 2.61 (q, 2H); 2.30-2.24 (m, 1H); 2.14-2.07 (, 1H); 1.98 1.89 (m, 1H); 1.82 1.74 (m, 4H); 1.44 (sf 9H); 1.18 1.13 (m, 3H); 0.99 0.93 (m, 6H) ppm. [00179] E. 2S-Amino-l-. { 25 '- [3- (2-ethyl-phenoxy) propyl] -4S-phenoxy-pyrrolidin-1-yl} -3-methyl-butan-l-one (19): Trifluoroacetic acid (2 mL) is added at room temperature to a solution of 18 (0.30 g, 0.57 mmol) in DCM (10 mL). After 1 hour, the solution is concentrated to dryness and the crude product is dissolved in EtOAc. The organic solution is washed with aqueous NaHC03, brine, dried over anhydrous Na2SO4, filtered and concentrated to give 0.23 g of 19 as a colorless oil. 1H NMR (CDC13, 300 MHz) d 7.33 7.28 (m, 2H); 7.17 7.12 (m, 2H); 6.99 (t, 1H); 6.89 6.83 (m, 3H); 6.78 (d, 1H); 4.98 (br, 2H); 4.39 (br, 1H), 4.07 3.92 (m, 4H); 3.75 3.67 (m, 1H); 2.61 (q, 2H); 2.31 2.24 (m, 2H); 2.13 2.08 (m, 2H); 1.94 1.75 (m, 6H); 1.16 (t, 3H); 1.01 0.85 (m, 6H) ppm.

[00180] F. Ter-butyl ester of acid [15 '- (15'- { 2S- [3- (2-Ethyl-phenoxy) -pro [rho] il] -45 < r > - [ rho] henoxy-pyrrolidine-1-carbonyl} -2-methyl-propylcarbamoyl) -ethyl] -carbamic acid (20): O- (7-Azabenzotriazol-1-yl) -NrNAV <; '> ': iN' tetramethyluronium PF6 (HATU, 0.11 g, 0.27 mmol) is added to a solution of iV Boc Ala (0.07 g, 0.37 mmol) in anhydrous NMP (3 mL) at room temperature. N-methylmorpholine (0.05 mL) is added to the reaction mixture. After 10 minutes, amine 19 (0.078 g, 0.18 mmol) in NMP (1 mL) is added. After 16 hours, the reaction mixture is diluted with EtOAc and washed with dilute aqueous NaHCO3, 1N HC1, water and brine. The organic phase is dried over Na2SC > 4 anhydrous, filtered and concentrated. The crude amide is purified by flash silica gel chromatography (1: 1 hexane / EtOAc) to give 0.038 g of 20 as a colorless oil. ½ NMR (CDC13, 300 MHz) d 7.33 7.26 (m, 2H); 7.12 (t, 2H); 6.99 (t, 1H); 6.88 6.76 (m, 4H); 5.08 5.00 (m, 1H); 4.98 4.96 (m, 1H); 4.52 4.47 (m, 1H); 4,374.34 (m, 1H); 4.21 4.16 (m, 2H); 3.98 3.92 (m, 2H); 3.75 (d, 1H); 2.61 (q, 2H); 2.32 2.22 (m, 1H); 2.14 1.99 (m, 4H); 1.86 1.77 (m, 3H); 1.44 1.41 (m, 8H); 1.36 1.13 (m, 4H); 1.16 (t, 3H); 0.96 0.88 (m, 6H) ppm. [00181] G. 2S-AmüiO-TV- (I,? - { 2 [pound] - [3- (2-ethyl-phenoxy) -propyl] -4S- [rho] henoxy-pyrrolidine-1-carbonyl .} -2-methyl-propyl) -propionamide (21): Trifluoroacetic acid (1 mL) is added at room temperature to a solution of 20 (0.038 g, 0.06 mmol) in DCM (5 mL). After 1 hour, the solution is concentrated to dryness and the crude product is dissolved in EtOAc. The organic solution is washed with aqueous NaHC03, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude amine is dissolved in diethyl ether then treated with HC1 (g). The crude salt is triturated with diethyl ether and hexane to give 0.022 g of 21 as a white solid. 1 H NMR (CDCl 3, 300 MHz) d 1.87 (br, 1H); 7.33 7.25 (m, 2H); 7.12 (t, 2H); 6.96 (t, 1H), 6.89 6.77 (m, 4H); 4.98 4.96 (m, 1H); 4.45 (t, 1H); 4.37 4.25 (m, 2H); 4.00 3.94 (m, 3.77 (d, 1H), 2.61 (q, 2H), 2.32 2.21 (m, 1H), 2.14 2.04 (m, 3H), 1.61 (br, 2H), 1.35 1.25 H); 1.16 (t, 3H); 0.97 0.89 (m, 6H) ppm.

Table 4 EXAMPLE 6 [00182] This example illustrates pyrrolidine derivatives of Table 5. Scheme IV (a) The preparation of 2S-Amino-N- [1S- (2 [pound] -beizofuran-3-ylmethyl-pyrrolidine-1-carbonyl) -2-methyl-propyl] -propionamide (29): A. Ter-butyl. 2S- [3- (2-iodo-phenoxy) -propenyl] -pyrrolidine-l-carboxylic acid ester (23): To a solution of alcohol 22 (10.4 g, 0.04 mol) in DCM (300 mL) is added 2 -iodophenol (12.1 g, 0.05 mol) and Ph3P (14.4 g, 0.05 mol). At room temperature, ADDP (13.8 g, 0.05 mol) is added in one portion. After 16 hours, the white precipitate is removed by filtration and washed with DCM. The clarified filtrate is washed successively with 1M NaOH, water and brine. The organic phase is dried with anhydrous Na 2 SO and then filtered through a short column of silica gel. The product is eluted with DCM and then 1: 1 hexane / EtOAc to give 15.5 g (79%) of 23 as a colorless oil. 1 H NMR (CDC13, 300 MHz) d 7.76 (dd, J = 7.6, 1.1 Hz, 1H), 7.27 (app t, J = 7.6, 1.1 Hz, 1H), 6.78 (dd, J = 7.6, 1.1 Hz, 1H ), 6.70 (app t, J = 7.6, 1.1 Hz, 1H), 5.74 (m, 2H), 4.58 (app d, J = 4.7 Hz, 2H), 4.33 (m, 1H), 3.40 (m, 2H) , 2.02 1.75 (m, 4H), 1.43 (s, 9H) ppm. [00185] B. Ter-butyl ester of? 1 acid > -Benzofuran-3-ylmethyl-pyrrolidine-l-carboxylic acid (24):? a solution of 23 (15.5 g, 36.1 mmol) in anhydrous DMF (250 mL) are added n Bu4NCl (10.0 g, 36.1 mmol), K2C03 (5.0 g, 36.1 mmol), NaHCO3 (2.45 g, 36.1 mmol), and Pd (OAc) 2 (0.16 g, 0.72 mmol). The orange brown reaction mixture is submerged in a preheated oil bath (100 degrees C). After 2 hours, the reaction mixture is cooled to room temperature, then diluted with diethyl ether and water. The layers are separated and the aqueous phase is extracted twice with diethyl ether. The combined organic extract is washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude benzofuran is purified by flash chromatography on flash silica gel 4: 1 hexane / EtOAc) and then by normal phase HPLC (30% EtOAc / hexane) to give 4.6 g (42%) of 24 as a colorless oil. X H NMR (CDC13, 300 MHz) d 7.62 (m, 1 H), 7.46 (m, 1 H), 7.26 (m, 3 H), 4.13 (m, 1 H), 3.40 3.21 (m, 2 H), 3.15 (m, 1 H) ), 2.68 (m, 1H), 1.80 1.61 (m, 4H), 1.51 (s, 9H) ppm. [00186] C. 2 < S! -Benzofuran-3-ylmethyl-pyrrolidine (25): Trifluoroacetic acid (2 mL) are added at 0 degrees C to a solution of 24 (0.5 g, 1.65 mmol) in DCM (40 mL). After 2 hours, an additional portion of TFA (2 mL) is added. After 1 hour, the reaction is neutralized by the careful addition of aqueous NaHCO 3. The reaction mixture is diluted with water and the crude product is extracted with diethyl ether. The organic extract is washed with aqueous NaHCO3, brine, dried over Na2SC > 4 anhydrous, filtered and concentrated. The crude amine is purified by reverse phase HPLC (C18; 10 100% ACN / water, 0.1% TFA) which, after neutralization, yields 0.24 g (72%) of 25 as a colorless oil. 1 H NMR (CDC13, 300 MHz) d 7.53 (app d, J = 8.7 Hz, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.27 (dd, J = 7.0, 8.2 Hz, 1H), 7.21 ( dd, J = 7.0, 8.7 Hz, 1H), 6.96 (br s, 1H), 3.59 (m, 1H), 3.16 2.86 (m, 4H), 1.96 1.75 (m, 3H), 1.60 (m, 1H) ppm. [00187] D. [1, S- (25'-benzofuran-3-ylmethyl-pyrrolidine-l-carbonyl) -2-methyl-propyl] -carbamic acid tert-butyl ester (26): A solution of iV Boc L valina (121 mg, 0.56 mmol) in NMP (3 mL) is treated with HATU (182 mg, 0.48 mmol) followed by N-methylmorpholine (0.1 mL, 0.9 mmol) at room temperature. After 10 minutes, the amine 25 (80 mg, 0.4 mmol) in NMP (5 mL) is added dropwise. After 16 hours, the reaction is diluted with EtOAc, washed with saturated NaHCO3, 1M HC1, brine, dried over Na2SO4, filtered and concentrated. The residual oil is purified by HPLC (20% EtOAc / hexane) to give 111 mg (69%) of 26 as a colorless oil. XH NMR (CDC13, 300 ??) d 7.87 (d, J = 6.9 Hz, 1H), 7.48 7.32 (m, 2H), 7.30 7.24 (m, 4H), 5.35 (d, J = 9.3 Hz, 1H) , 4.53 4.47 (m, 1H), 4.31 (dd, J = 6.6, 9.6 Hz, 1H), 3.72 3.56 (m, 2H), 3. 31 (dd, J = 3.0, 13.2 Hz, 1H), 2.49 (dd, J = 10.5, 13.5 Hz5 1H), 2.05 1.74 (m, 6H), 1.44 (s, 9H), 1.03 (d, J = 6.9 Hz , 3H), 097 (d, J = 6.6 Hz, 3H) ppm. [00188] E. 25-7Amino-l- (21S '-benzofuran-3-ylmethyl-pyrrolidin-1-yl) -3-methyl-butan-1-one (27): A solution of carbamate 26 (111 mg, 0.28 mmol) in DCM (10 inL) is treated with TFA (1 mL) at room temperature. After 2 h, the reaction mixture is concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to give 67 mg (80%) of 27 as a light yellow oil. The product is used without further purification. 1 H NMR (CDC 13, 300 Hz) d 7.89 (d, J = 8.1 Hz, 1 H), 7.47 7.44 (m, 2 H), 7. 32 7.27 (m, 3H), 4.54 4.49 (m, 1H), 3.59 3.53 (m, 2H) 5 3. 33 (d, J = 13.5 Hz5 1H) 5 2.50 (dd, J = 10.8, 13.5 Hz, 1H) 5 2.03 1.72 (m, 6H), 1.04 (d, J = 7.2 Hz, 3H) 5 0.99 (d, J = 7.0 Hz5 3H) ppm. [00189] F. Ter-butyl ester of acid. { 1S- [1S- (2S-Berizofuran-3-ylmethyl-pyrrolidine-l-carbonyl) -2-methyl-propylcarbamoyl] -ethyl} -carbamic (28): A solution of JV Boc L alanine (46 mg, 0.24 mmol) in NMP (3 mL) is treated with HATU (72 mg, 0.19 mmol) followed by N-methylmorpholine (0.1 mL, 0.9 mmol) at room temperature. After 10 minutes, amine 27 (41 mg, 0.14 mmol) in NMP (5 mL) is added by drops. After 16 hours, the reaction is diluted to EtOAc, washed with saturated NaHCO3, 1M HC1 and brine, dried over Na2SO4, filtered and concentrated. The residual oil is purified by flash silica gel chromatography (1: 1 hexane / EtOAc) to give 62 mg (93%) of 28 as a colorless oil. 1 H NMR (CDC13, 300 MHz) d 7.85 (d, J = 6.6 Hz, 1H) 5 7.48 7.44 (m, 2H), 7.33 7.25 (m, 3H), 6.93 (d, J = 8.7 Hz, 1H), 5.08 (d, J = 7.8 Hz, 1H), 4.62 (dd, J = 6.3, 8.7 Hz5 1H), 4.50 4.43 (m, 1H), 4.23 4.16 (m, 1H), 3.74 3.55 (m, 3H), 3.32 ( dd, J = 2.4, 14.1 Hz, 1H), 2.49 (dd, J = 10.8, 13.5 Hz, 1H), 2.14 1.71 (m, 6H), 1.46 (s, 9H) 5 1.37 (d, J = 6.9 Hz, 3H) 5 1.02 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 7.2 Hz5 3H) ppm. [00190] G. 2S-Amino-N- [1S- (25'-berizofuran-3-y? Yhnethyl-pyrrolidine-1-carbonyl) -2-methyl-propyl] -propionamide (29): A solution of carbamate 28 (62 mg, 0.13 mmol) in DCM (10 mL) is treated with TFA (1 mL) at room temperature. After 1.5 h, the reaction is concentrated, diluted with EtOAc, washed with NaHCC > 3 saturated and brine, dried over Na 2 SO 4, filtered and concentrated. The residue is purified by flash silica gel chromatography (5% MeOH / DCM) to result in 38 mg (72%) of 29 as a colorless oil. 1 H NMR (CDC13, 300 MHz) d 7.92 (d, J = 9.3 Hz, 1H), 7.87 7.84 (m, 1H), 7.48 7.44 (m, 2H), 7.32 7.23 (m, 2H), 4.59 (dd, J = 6.9, 9.3 Hz, 1H), 4.52 4.45 (m, 1H), 3.84 3.76 (m, 1H), 3.67 3.60 (m, 1H), 3.57 3.50 (m, 1H), 3.34 (dd, J = 3.0, 13.0 Hz, 1H), 2.50 (dd, J = 10.5, 13.8 Hz, 1H), 2.16 1.91 (m, 3H), 1.82 1.69 (m, 2H), 1.65 (bs, 2H), 1.38 (d, J = 7.2 Hz , 3H), 1.03 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H) ppm. The free amine (29) is diluted with Et20 and treated with HCl (g) to form a white solid. The solution is concentrated and the solid is triturated with E 2 O and hexanes to provide 29 HCl.

Table 5 EXAMPLE 7 [00191] This example illustrates pyrrolidine derivatives of Table 6. Scheme IV (b) Preparation of 2-Amino-N-. { 1- [2- (5-hydroxy-benzofuran-3-ylmethyl) -pyrrolidine-1-carbonyl] -2-methyl-propyl} -propionamide (32): A. (l-. {l- [2- (5-Hydroxy-benzofuran-3-ylmethyl) -pyrrolidine-l-carbonyl] -2-methyl-propylcarbamoyl acid tert-butyl ester}-ethyl) -carbamic (31): A mixture of 30 (0.52 g, 0.90 mmol) and palladium in 10% carbon (0.05 g) in EtOAc (25 mL) is placed in Parr apparatus and pressurized to 3. bar (45 psi) with an atmosphere of ¾ · The reaction mixture is stirred for 24 h. TLC analysis revealed that only starting material without consuming therefore the catalyst was removed by filtration and the clarified filtrate is concentrated to dryness. The residue is redissolved in EtOAc (25 mL) and Pd in 10% carbon. (0.208 g) is added. The reaction mixture is stirred under an atmosphere of ¾ (3. one bar (45 psi)) for 4 h at which time a second portion of palladium catalyst (0.05 g) is added. Hydrogenation is continued until all the starting material is consumed (approximately 2 h). The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. The crude product is purified by flash silica gel chromatography (EtOAc / hexane, 1: 1) to give 0.37 g (84%) of 31 as a white solid. a H NMR (CDC13 300 MHz) 57.37 (s, 1H); 7.33 7.31 (m, 1H); 7.28 7.26 (m, 1H), 6.88 6.85 (m, 2H); 5.18 (br, 1H); 4.56 (t, 1H); 4.45 4.24 (m, 3H); 3.82 3.74 (m, 1H); 3.66 3.58 (m, 1H); 3.22 (d, 1H); 2.44 2.36 (m, 1H); 2.12 2.09 (m, 1H); 2.03 1.89 (m, 2H); 1.73 1.67 (m, 2H); 1.45 (s, 9H); 1.37 (d, 3H); 1.02 0.97 (m, 6H) ppm. B. 2-Amino-N-. { 1- [2- (5 ~ hydroxy-benzofuran-3-ylmethyl) -pyrrolidine-1-carbonyl] -2-methyl-propyl} -propionamide (32): To a solution of 31 (0.04 g, 0.082 mmol) in DCM (5 mL) is added TFA (1 mL) at room temperature. After 1 hour, the solvent is removed under reduced pressure. The residue is dissolved in EtOAc and washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product is purified by flash silica gel chromatography (10% MeOH / DCM) to result in 0.011 g (37%) of 32 as a white solid. ½ NMR (CDC13, 300 MHz) 68.54 (d, 1H); 7.37 (s, 1H); 7.31 (d, 1H); 7.09 (d, 1H); 6.83 (dd, 1H); 4.64 (t, 1H); 4.56 4.51 (m, 1H); 4.09 3.93 (m, 2H); 3.73 3.65 (m, 1H); 3.36 (dd, 1H); 2.35 (t, 1H); 2.19 1.94 (m, 3H); 1.77 1.69 (m, 2H); 1.33 (d, 2H); 1.25 1.19 (m, 1H); 1.04 1.00 (m, 5H); 0.94 (t, 1H) ppm.

(El) Table 6 EXAMPLE 8 example illustrates pyrrolidine derivatives in Table 7. Scheme IV (c) Preparation of 2-Amino ~ N-. { 1- [2- (5-methoxy-benzofuran-3-ylmethyl) -pyrrolidine-1-carbonyl] -2-methyl-propyl} -propionamide (34): A. (l- { 1- [2- (5-Ethoxy-benzofuran-3-yl-ethyl) -pyrrolidine-l-carbonyl] -2-methyl-propylcarbamoyl-tert-butyl ester} ethyl) -carbamic (33): To a solution of 32 (0.06 g, 0.12 mmol) in DCM (3 L) anhydrous are added MeOH (10 μ ??), Ph3P (0.036 g, 0.13 mmol), and ADDP (0.037 g, 0.14 mmol). The reaction mixture is maintained at room temperature for 16 h at which point the TLC analysis revealed incomplete reaction. A second portion of MeOH (100 // L), Ph3P (0.036 g, 0.13 mmol), and ADDP (0.037 g, 0.14 mmol) is added and the reaction mixture is maintained for an additional 5 h at room temperature. The reaction mixture is diluted with DCM and washed twice with 1N NaOH, followed by brine, dried over Na2SC > 4 anhydrous, filtered and concentrated. The crude product is purified by flash silica gel chromatography (EtOAc / hexane, 2: 1) to give 0.057 g (91%) of 33 as a white solid. ¾ NMR (CDC13, 300 MHz) 57.41 (s, 1H); 7.38 7.33 (m, 1H); 7.30 7.28 (m, 1H); 6.90 (dd, 1H); 6.77 (d, 1H); 4.98 (br, 1H); 4.64 4.59 (m, 1H); 4.48 4.43 (m, 1H); 4.21 4.14 (m, 1H); 3.88 (s, 3H); 3.72 3.53 (m, 2H); 3.30 3.25 (m, 1H); 2.51 2.43 (m, 1H); 2.13 1.72 (m, 5H); 1.45 (s, 9H); 1.37 (d, 3H); 1.03 0.95 (m, 6H) ppm. [00198] B. 2-7Amino-N-. { l [2- (5-methoxy-benzofuran-3-ylmethyl) -pyrrolidin-1-carbonyl] -2-methyl-propyl} -propionamide (34): To a solution of 33 (0.057 g, 0.11 mmol) in DCM (5 mL) is added TFA (1 mL) at room temperature. After 1 hour, the solvent is removed under reduced pressure. The residue is dissolved in EtOAc and washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product is purified by flash silica gel chromatography (10% MeOH / DCM) to result in 0.015 g (35%) of 34 as a white solid. ½ NMR (CDCl 3, 300 MHz) 57.42 (m, 1H); 7.35 (d, 1H); 7.28 (m, 1H); 6.90 (dd, 1H); 4.60 (m, 1H); 4.48-4.45 (m, 1H); 3.89-3.76 (m, 4H); 3.65-3.56 (m, 2H) 3.31 (dd, 1H); 2.52-2.44 (m, 1H); 2.13-1.72 (nt, 6H); 1.43-1.27 (m, 5H); 1.05-0.97 (m, 6H) ppm.

(EN) TABLE 7 EXAMPLE 9 [00199] This example illustrates pyrrolidine derivatives of Table 8. Scheme IV (d)

[00200] Preparation of 2-Amino-N-. { 2-methyl-l- [2- (5-pyridin-2-yl-benzofuran-3-ylmethyl) -pyrrolidine-1-carbonyl] -propyl} -propionamide (37): [00201] A. 3-. { l- [2- (2-tert-butoxycarbonylamino-propionylamino) -3-methyl-butyl] -pyrrolidin-2-ylmethyl} -benzofuran-5-yl-ester of trifluoromethanesulfonic acid (35): To a solution of 32 (0.16 g, 0.32 mmol) and DIPEA (60 μL, 0.32 mmol) in anhydrous DCM (4 mL) are added N-phenyl bis ( trifluoromethanesulfonimide) (0.14 g, 0.38 mmol) at 0 degrees C. After about 10 minutes, the reaction mixture is allowed to warm to room temperature and then maintained for 16 h. The reaction mixture is concentrated and the residue is dissolved in EtOAc, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product is purified by flash silica gel chromatography (EtOAc / hexane, 1: 1) to give 126 mg (63%) of 35 as a white solid. X H NMR (CDC13, 300 MHz) 57.73 (d, 1H); 7.55-7.48 (m, 2H); 7.20 (dd, 1H); 6.78-6.75 (m, 1H); 4.99 (br, 1H); 4.63-4.58 (m, 1H); 4.41-4.35 (m, 1H); 4.19 (m, 1H); 3.75-3.68 (m, 1H) / 3.64-3.57 (m, 1H); 3.29 (dd, 1H); 2.54-2.46 (m, 1H); 1.99-1.84 (m, 3H); 1.71-1.66 (m, 2H); 1.45 (s, 9H); 1.37 (d, 3H); 1.02-0.94 (m, 6H) ppm. [00202] B. (1 .2 Methyl 1 [2- (5-pyridine-3-yl benzofuran-3-ylmethyl) -pyrrolidine-1-carbonyl] -propylcarbamoyl} -ethyl-carbamic acid ester (36): A mixture of 35 (0.063 g) , 0.10 mmol), K2C03 (70 mg, 0.50 mmol), 3-pyridinboronic acid (0.015 g, 0.12 mmol), and (Ph3P) 4Pd (5 mg, 3 mol%) in anhydrous toluene (5 mL) is heated to 100 degrees. C in a sealed tube for 1 hour. The reaction mixture is cooled to room temperature, diluted with EtOAc, washed with NaHCC > 3 aqueous brine, dried over Na2SC > 4 anhydrous, filtered and concentrated. The crude product is purified by flash silica gel chromatography (EtOAc) to give 40 mg (72%) of 36 as an oil. ½ NMR (CDC13, 300 MHz) 68.94 (d, 1H); 8.59 (d, 1H); 8.01-7.95 '(m, 1H); 7.74-7.64 (m, | 1H); 7.58-7.37 (m, 4H); 6.94 (d, 1H); 4.61 (t, 1H); 4.50-4.47 (m, 1H); 4.30 (t, IHO, 4.21 (br, 1H), 3.79-3.71 (m, 1H), 3.66-3.59 (m, 1H), 2.42-3.36 (m, 1H), 2.58-2.50 (m, 1H), 2.13 -2.09 (m, 1H); 2.01-1.71 (m, 4H); 1.45 (m, 9H); 1.37 (d, 3H); 1.03-0.94 (m, 6H) ppm. [00203] C. 2-Amino- N- {2-methyl-l- [2- (5- [rho] iridin-2-yl-benzofuran-3-ylmethyl) -pyrrolidine-1-carbonyl] -propyl} -propionamide (37): To a solution of 36 (0.04 g, 0.07 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature After 1 hour, the solvent was removed under reduced pressure The residue was dissolved in EtOAc and washed with NaHCO> 3 aqueous, brine, dry over anhydrous Na2SO4, filter and concentrate The crude product is purified by flash silica gel chromatography (10% MeOH / DCM) to give 0.024 g (76%) of 37 as a white solid.1H NMR (CDC13, 300 MHz) 58.0 (s, 1H), 7.95 (d, 1H), 7.71-7.64 (m, 2H), 7.56-7.46 (m, 4H), 4.61-4.48 (m, 2H), 4.29 (t, 1H), 3.83- 3.77 (m, 1H), 3.67-3.54 (m, 2H), 3.41 (dd, 1H), 2.58-2.49 (m, 1H); 2.13-1.70 (m, 5H); 1.40-1.25 (m, 5H); 1.04-0.84 (m 6H) ppm.

TABLE 8 EXAMPLE 10 [00204] This example illustrates pyrrolidine derivatives of Table 9. Scheme V

[00205] The preparation of 25-Amino-N-. { 2-methyl-16r- [26 '- (2-pyridin-4-yl-benzofuran-3-ylmethyl) -pyrrolidine-1-carbonyl] -propyl} -propionamide (44): [00206] A. Ter-butyl ester of carboxylic acid [epsilon] iyo-2"S '- (2-Bromo-benzofuran-3-ylmethyl) -pyrrolidine 1 (38): A solution of 22 (1.4 g, 4.7 mmol) in CHC13 (20 mL) is cooled to 0 degrees C and deal with KOAc (2.5 g, 26 mmol). A solution of bromine (0.3 mL, 5.8 mmol) in CHC13 (10 mL) is added and added dropwise for 30 minutes. After addition, the solution maintains an orange yellow color. After TLC indicates consumption of starting material, the reaction mixture is diluted with H20, washed with saturated NA2S208, dried over Na2SO4, filtered and concentrated. Purification of the residue by flash silica gel chromatography (3: 1 hexane / EtOAc) resulted in 1.1 g (61%) of 38 as a yellow oil. ½ NMR (CDC13, 300 MHz) d 7.57-7.52 (m, 1H), 7.43-7.41 (m, 1H), 7.26-7.20 (m, 2H), 4.20 (m, 1H), 3.43-3.30 (m, 2H) ), 3.17-3.01 (m, 1H), 2.73-2.58 (m, 1H), 1.89-1.69 (m, 4H), 1.48 (s, 9H) ppm. [00207] B. 2S- (2-Bromo-benzomran-3-ylmethyl) -pyrrolidine (39): A solution of 38 (1.1 g, 2.9 mmol) in DCM (20 mL) is treated with TFA (2 pL) at room temperature. After 1.5 h, the reaction mixture is concentrated, diluted with EtOAc, washed with NaHCO3, saturated, brine, dried over Na2SO4, filtered and concentrated to give 0.8 g of 39 as an orange oil which is used without further purification. 1 H NMR (CDC13, 300 MHz) d 8.84 (br s, 1 H), 7.42-7.39 (m, 2 H), 7.28-7.21 (m, 2 H), 3.70-3.66 (m, 1 H), 3.48-3.39 (m, 1H), 3.31-3.21 (m, 2H) 2.95 (dd, J = 9.9 Hz, 13.5 Hz, 1H), 2.06-1.99 (m, 1H), 1.91-1.79 (m, 2H), 1.74-1.66 ( m, 1H) ppm. [00208] C. Ter-butyl ester of acid. { LiS '- [25 * - (2-Bromo-benzofuran-3-ylmethyl) -pyrrolidine-1-carbonyl] -2-methyl-propyl} Carbamic (40): A solution of N-Boc-L-valine (656 mg, 3.0 mmol) in NMP (6 mL) is treated with HATU (1.2 g, 3.1 mmol) followed by N-methylmorpholine (0.4 mL, 3.6 mmol) at room temperature. After 10 minutes, 39 crude (0.8 g, 2.9 mmol) in N P (6 mL) is added dropwise. After 16 hours, the reaction mixture is diluted with EtOAc, washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue is purified by flash silica gel chromatography (3: 1 hexane / EtOAc) to give 853 mg (61%) of 40 as a yellow foam. 1 H NMR (CDC13, 300 MHz) d 7.89-7.86 (m, 1H), 7.42-7.38 (m, 1H), 7.29- 7.25 (m, 3H), 5.35 (d, J = 9.3 Hz, 1H), 4.55- 4.51 (m, 1H), 4.29 (dd, J = 6.0, 9.6 Hz, 1H), 3.71-3.66 (m, 1H), 3.27 (dd, J = 3.3, 13.5 Hz, 1H), 2.45 (dd, J = 10.8, 13.5 Hz, 1H), 2.15-1.92 (m, 3H), 1.79-1.74 (m, 2H), 1.42 (s, 9H), 1.03 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 7.2 Hz, 3H) ppm. [00209] D. 25-Amino-l- [25- (2-bromo-benzofuran-1-ylmethyl) -pyrrolidin-1-yl] -3-methyl-butane-1-one (41): A solution of carbamate 40 ( 853 mg, 1.8 mmol) in DCM (20 mL) is treated with TFA (2 mL) at room temperature. After 1.5 hours, the reaction mixture is concentrated, diluted with EtOAc, washed with saturated NaHCO3, brine, dried, filtered and concentrated to give 0.66 g of 41 as a yellow foam that is used without further purification. 1HNMR (CDC13, 300 MHz) d 7.92 7.89 (m, 1H), 7.44-7.39 (m, 1H), 7.30-7.25 (m, 3H), 4.55 (m, 1H), 3.66-3.51 (m, 2H), 3.29 (dd, J = 2.4, 13.5 Hz, 1H), 2.45 (dd, J = 11.1, 12.9 Hz, 1H), 2.15-1.97 (m > 2H), 1.78-1.71 (m, 2H), 1.06 (d , J = 6.3 Hz, 3H), 1.01 (d, J = 6.6 Hz, 3H) ppm. [00210] E. (15-. {15r- [251- (2-Bromo-benzofuran-3-ylmethyl) -pyrrolidine-1-carbonyl] -2-methyl-propylcarbamoyl} -ethyl ester. -carbamic (42): A solution of N-Boc-L-alanine (394 mg, 2.1 mmol) in NMP (6 mL) is treated with HATO (763 mg, 2.0 mmol) followed by N-methylmorpholine (0.3 mL, 2.7 mmol) at room temperature. After 10 minutes, crude 41 (0.66 mg, 1.7 mmol) in NMP (6 mL) is added dropwise. After 16 hours, the reaction mixture is diluted with EtOAc, washed with saturated NaHCO3, 1M HC1, brine, dried over Na2SO4, filtered and concentrated. The residual oil is purified by flash silica gel chromatography (2: 1 hexane / EtOAc to 1: 1 hexane / EtOAc) to give 0.9 g (96%) of 42 as a whitish foam. ½ NMR (CDC13, 300 MHz) d 7.86-7.84 (m, 1H), 7.43-7.40 (m5 1H), 7.29-7.25 (m, 2H) 5 7.01 (d, J = 8.7 Hz, 1H), 5.10 (d , J = 6.6 Hz, 1H), 4.62 (dd, J = 6.3, 8.7 Hz, 1H), 4.53-4.48 (m, 1H), 4.23-4.19 (m, 1H), 3.75-3.66 (m, 2H), 3.27 (dd, J = 3.3, 13.5 Hz, 1H), 2.45 (dd, J = 10.5, 13.5 Hz, 1H), 2.16-2.08 (m, 2H ), 2.02-1.97 (m, 2H), 1.79-1.73 (m, 2H), 1.45 (s, 9H), 1.36 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.3 Hz, 3H), 0.97 (d, J = 7.2 Hz, 3H) ppm.

[00211] F. Terbutilic acid ester (IS-. {2-Methyl-15- [25- (2-pyridin-4-yl-benzofuran-3-ylmethyl) -pyrrolidine-1-carbonyl] -propylcarbamoyl}. .-ethyl) -carbamic (43): A solution of 42 (36 mg, 0.07 mmol) in toluene (4 mL) is treated with K2C03 (38 mg, 0.28 mmol) and Pd (PPh3) 4 (2 mg) followed by 4-pyridine boronic acid (12 mg, 0.1 mmol) in EtOH (2 mL). The reaction is heated to reflux overnight. The solution is cooled to room temperature, diluted with ¾0, extracted with EtOAc, brine, dried over Na2SC > 4, filter and concentrate to give 44 mg of 43 as a light yellow oil which is used without further purification. 1 H NMR (CDC 13, 300 Hz) J 8.74 (d, J = 5.1 Hz, 1 H), 7.99 (d, J = 5.7 Hz, 1 H), 7.86-7.81 (m, 1 H), 7.71-7.64 (m, 1 H) , 7.56-7.46 (m, 3H), 7.41-7.27 (m, 2H), 6.87 (d, J = 8.7 Hz, 1H), 5.01 (m, 1H), 4.62 (app t, J = 8.7 Hz, 1H) , 4.56-4.46 (m, 1H), 4.20 (m, 1H), 3.72-3.67 (m, 2H), 2.84 (dd, J = 11.7, 13.5 Hz, 1H), 2.16-1.93 (m, 2H), 1.78 -1.62 (m, 2H), 1.46 (s, 9H), 1.37 (d, J = 7.2 Hz5 3H), 1.04 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.3 Hz5 3H) ppm. [00212] G. 25 ~ Amino-iV-. { 2-methyl-11Sr- [2- (25'-pyridin-4-yl-benzofuran-3-ylmethyl) -pyrrolidine-1-carbonyl] -propyl} -propionamide (44): A solution of 43 (44 mg, 0.08 mmol) in DC (10 mL) is treated with TFA (1 mL) at room temperature. After 1.5 h, the reaction mixture is concentrated, diluted with EtOAc, washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue is purified by reverse phase HPLC (C18; 100% ACN / H20 with 1% AcOH buffer). Fractions containing pure product were lyophilized to give 21 mg of 44 as a white solid. 1 H NMR (CDC13, 300 MHz) d 8.75 (bs, 1H), 8.00 (m, 1H), 7.90-7.82 (m, 1H), 7.71-7.64 (m, 1H), 7.55-7.47 (m, 3H), 7.38-7.27 (m, 2H), 4.61-4.52 (m, 1H), 3.83-3.62 (m, 2H), 3.07-3.00 (m, 1H), 2.84 (dd, J = 11.1, 13.5 Hz, 1H), 2.16- 1.94 (m, 2H), 1.74-1.61 (m, 2H), 1.41 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.9 Hz) , 3H) ppm.

(ElO) TABLE 9 EXAMPLE 11 [00213] This example illustrates pyrrolidine derivatives of Table 10. Scheme V (a)

[00214] The preparation of 3- (3. {L- [2- (2-Amino-propionylamino) -3-methyl-butyryl] -pyrrolidin-2-ylmethyl} -benzofuran-2-ethyl ester -yl) -propionic (52): [00215] A. Benzyl 2- (2-bromo-benzofuran-3-ylmethyl) -pyrrolidine-l-carboxylic acid ester (46): to a cold solution (0 degrees C) of 45 (4.1 g, 12.2 mmol) in CHC13 (70 pL) is added KOAc (3.6 g, 36.7 mmol) followed by the dropwise addition of BR2 (2.3 g, 14.6 mmol) in CHC13 (30 mL) for 20 minutes. minutes After 30 minutes, the reaction mixture is diluted with brine and saturated with A2S208. The product is extracted with DCM and the combined DCM extracts are washed with brine, dried over anhydrous NaSO4, filtered and concentrated to give 5 g (quant.) Of 46 as an orange oil which is used without further purification. XH NMR (CDCl3f 300 MHz) d 7.75 7.72 & 6.98 (retainers, m and app t, J = 7.5 Hz, 1H), 7.44-7.10 (m, 8H), 5.24-5.17 (m, 2H), 4.28 & 4.17 (rotamer, 2 m, 1H), 3.54 3.38 (m, 2H), 3.21 & 3.00 (rotamer, 2 dd, J = 2.4, 13.5 Hz, 1H), 2.72-2.55 (m, 1H), 1.97-1.75 (m, 4H) ppm. [00216] B. Benzyl 2- [2- (2-Ethoxycarbonyl-vinyl) -benzofuran-3-ylmethyl] -pyrrolidine-1-carboxylic acid ester (47): A solution containing 46 crude (5.0 g, 12.1 mmol ), ethyl acrylate (2.7 g, 27.7 mmol), tetrabutylammonium chloride (3.5 g, 12.6 mmol), NaHCO3 (2.0 g, 23.8 mmol), and Pd (OAc) 2 (0.107 g, 0.46 mmol) in DMF (40 mL) ) is heated to 100 degrees C for 16 hours. After cooling to room temperature, the reaction mixture is diluted with diethyl ether and washed with water, brine, dried over anhydrous Na 2 SO 4, filtered and concentrated. The crude product is purified by chromatography on flash silica gel (EtOAc / hexane, 1: 3) to give 3.7 g (70%) of 47 as an orange oil. ½ NMR (CDC13, 300 MHz) 57.81 & 6.99 (rotamer, app d, J = 7.5 Hz, app t, J = 7.5 Hz, 1H), 7.61 (dd, J = 15.9, 18.3 Hz, 1H), 7.47-7.20 (m, 8H), 6.58 (dd, J = 5.7, 15.6 Hz, 1H), 5.27-5.16 (m, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.17-4.08 (m, 1H), 3.51-3.35 (m, 2H), 3.38 & 3.17 (rotamer, 2 dd, J = 3.6, 14.1 Hz, 1H), 2.89-2.69 (m, 1H), 1.94-1.64 (m, 4H), 1.36 (t, J = 7.2 Hz, 2H) ppm. [00217] C. 3- (3-Pyrrolidin-2-yl-methyl-benzofuran-2-yl) -propionic acid ethyl ester (48): A mixture containing 47 (1.0 g, 2.3 mmol) and Pd in 10% carbon (~ 1 g) in anhydrous MeOH (20 mL) is placed under a hydrogen atmosphere (3.1 bar (45 PSI)) and stirred using a Parr apparatus for 1 hour. The catalyst is removed by filtration and the solids are washed with EtOAc and MeOH. The clarified filtrate is concentrated to give 634 mg (91%) of 48 as an orange oil which is used without further purification. ¾ NMR (CDC13, 300 MHz) 57.51 7.49 (m, 1H), 7.38-7.35 (m, 1H), 7.21-7.17 (m, 2H), 4.16- 4.09 (m, 2H), 3.68-3.59 (m, 2H) ), 3.12-3.07 (m, 2H), 2.88-2.73 (m, 4H), 1.84-1.69 (m, 4H), 1.4-1.39 (m, 1H), 1.26-1.20 (m, 3H) ppm. [00218] D. Ethyl ester of 3- acid. { 3- [l- (2-tert-butoxycarbonylamino-3-methyl-butyryl) -pyrrolidin-2-ylmethyl] -benzofuran-2-yl} -propionic (49): A solution containing Boc L valine (352 mg, 1.6 mmol) in NMP (3 mL) is treated with H7ATU (543 mg, 1.4 mmol) followed by NMM (0.2 mL, 1.8 mmol) at room temperature . After 10 minutes, the amine 48 (0.4 g, 1.3 mmol) in NMP (5 mL) is added in one dropwise fashion. After 16 hours, the reaction mixture is diluted with diethyl ether and washed successively with NaHCO 3, 1 M HC1, water, and brine. The organic extract is dried over anhydrous Na 2 SO 4, filtered and concentrated to give 630 mg (96%) of 49 which is used without further purification. ½ NMR (CDC13, 300 MHz) 57.82-7.79 (m, 1H), 7.38-7.35 (m, 1H), 7.28-7.21 (m, 2H), 5.37 (d, J = 9.3 Hz, 1H), 4.50-4.44 (m, 1H), 4.31 (dd, J = 6.0, 9.0 Hz, 1H), 4.14 (q, J = 6.9 Hz, 2H), 3.72-3.60 (m, 3H), 3.38 (t, J = 7.2 Hz, 1H), 3.29 (dd, J = 3.0, 13.5 Hz, 1H), 3.12 (app t, J = 7.5 Hz, 2H), 2.80-2.74 (m, 4H), 2.46-2.35 (m, 2H), 2.11-1.92 (m, 2H), 1.81-1.73 (m, 1H), 1.69-1.65 (m, 1H), 1.44 (s, 9H), 1.25 (t, J = 6.0 Hz, 3H), 1.03 (d, J = 6.3 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H) ppm. Mass spectrum: m./z 501 [M + H] < + >; and, 523 [M + Na] +. [00219] E. Ethyl ester of 3- acid. { 3- [1- (2-Amino-3-methyl-butyryl) -pyrrolidin-2-ylmethyl] -benzofuran-2-yl} -propionic (50): To a solution of 49 (302 mg, 0.6 mmol) in DC (10 mL) is added TFA (2 mL) at room temperature. After 2 hours, the solvent is removed under reduced pressure. The residue is dissolved in EtOAc and washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to give 235 mg (97%) of 50 as an orange oil which is used without further purification. 1 H NMR (CDC 13, 300 MHz) 57.86-7.83 (m, 1 H), 7.43-7.34 (m, 1 H), 1.21-1.19 (m, 3 H), 4.49 (m, 1 H), 4.14 (q, J = 6.9 Hz, 2H), 3.60-3.53 (m, 2H), 3.32 (d, J = 12.9 Hz, 1H), 3.12 (app t, J = 7.2 Hz, 2H), 2.81-2.74 (m , 2H), 2.42 (app t, J = 12.3 Hz, 1H), 2.10-1.91 (m, 2H), 1.74 1.66 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.06-0.99 ( m, 6H) ppm. Mass spectrum: m / z 401 [M + H] +. [00220] F. Ethyl 3- (3- {-l- [2- (2-tert-butoxycarbonylamino-propionylamino) -3-methyl-butyryl] -pyrrolidin-2-ylmethyl} -benzofuran-2-ethyl ester -ilo) -propionic (51): A solution containing Boc-L-alanine (69 mg, 0.37 mmol) in NMP (3 mL) is treated with HATU (131 mg, 0.34 mmol) followed by NMM (0.1 mL, 0.9 mmol) at room temperature . After 10 min, 50 amine (111 mg, 0.28 mmol) in NMP (5 mL) is added in one dropwise fashion. After 5 hours, the reaction mixture is diluted with diethyl ether and washed successively with NaHCO 3, 1 M HC1, water and brine. The organic extract is dried over anhydrous Na 2 SO 4, filtered and concentrated to give 160 mg (quant.) of 51 that is used without further purification. ½ NMR (CDC13, 300 MHz) 67.81-7.78 (m, 1H), 7.38-7.36 (m, 1H), 7.28-7.21 (m, 3H), 6.86 (d, J = 8.7 Hz, 1H), 5.04 (d, J = 6.9 Hz, 1H), 4.61 (dd, J = 6.3, 8.7 Hz, 1H), 4.48-4.42 (m, 1H), 4.22 (m, 1H), 4.13 (q, J = 6.9 Hz, 2H), 3.73-3.62 (m, 2H), 3.41 3.36 (m, 2H), 3.28 (dd, J = 3.0, 13.5 Hz, 1H), 3.11 (app t, J = 6.9 Hz, 2H), 2.85-2.73 (m, 4H), 2.38 (app t, J = 8.1 Hz, 2H), 2..13-1.98 (m, 2H), 1.80-1.64 (m, 1H), 1.45 (s, 9H), 1.37 (d , J = 6.9 Hz, 3H), 1.26 (t, J = 7.5 Hz, 3H), 1.03-0.95 (m, 6H) ppm. Mass spectrum: m / z 572 [M + H] +; and 594 [M + Na] +. [00221] 3- (3. {L- [2- (2-7Amino-propionylamino) -3-methyl-butyryl] -pyrrolidin-2-ylmethyl} -benzofuran-3-ethyl ester il) -propionic (52): To a solution of 51 (160 mg, 0.28 mmol) in DCM (10 mL) is added TFA (2 mL) at room temperature. After 2.5 h, the solvent is removed under reduced pressure. The residue is dissolved in EtOAc and washed with NaHCC > 3 aqueous, brine, dry over anhydrous Na 2 SO 4, filter and concentrate. A portion of (50%) of the crude material is purified by reverse phase HPLC (C18, 10 100% ACN / water containing 0.1% HOAc) to give 56 mg of 52 as a white solid. H NMR (SO, 300 MHz) 68.03 (d, J = 8.7 Hz, 1H), 7.77. (m, 1H), 7.43-7.41 (m, 1H), 7.21 (m, 2H), 4.37 (app t, J 8.1 Hz, 1H), 4.19 (m, 1H), 4.01 (q, J = 7.2 Hz, 2H), 3.65 (m, 1H), 3.56 (app d, J = 6.6 Hz, 1H), 3.28 (m, 1H), 3.06 3.01 (m, 3H), 2.68 (app t, J = 7.2 Hz, 2H), 2.07-1.96 (m, 1H), 1.63 (m, 1H), 1.54 (m, 1H), 1.13-1.09 (m, 6H), 0.90 (d, J = 6.3 Hz, 3H), 0.85 (d, J = 6.3 Hz, 3H) ppm. Mass spectrum: m / z all [+ H] +; and 494 [M + Na] +.

TABLE 10 EXAMPLE 12 [00222] This example illustrates pyrrolidine derivatives of Table 11 and Table 12. Scheme V (b)

[00223] The lactam preparation derived from Ornithine (59): [00224] A. Ethyl ester of 3- acid. { 3 - [- l ~ (5- benzyloxycarbonylamino-2-terbutoxycarbonylaminopentanoyl) -pyrrolidine-2-ylmethyl] -benzofuran-2-yl} - propionic (53): A solution containing Boc L ornithine (2.3 g, 6.3 mmol) in NMP (5 mL) is treated with HATU (2.4 g, 6.3 mmol) followed by NMM (1.5 mL, 13.7 mmol) at room temperature. After 10 minutes, the amine 48 (1.6 g, 5.3 mmol) in NMP (10 mL) is added in one dropwise fashion. After 16 hours, the reaction mixture is diluted with diethyl ether and washed successively with NaHCO 3, 1 M HCl, water and brine. The organic extract is dried over anhydrous Na 2 SO 4, filtered and concentrated to give 3.0 g. (87%) of 53 as an orange oil that is used without further purification. 1 H NMR (CDC13, 300 MHz) 67.78-7.75 (m, 1H), 7.40-7.20 (m, 8H), 5.48 (d, J = 8.4 Hz, 1H), 5.10 (s, 2H), 4.48-4.42 (m, 1H), 4.17 4.09 (m, 2H), 3.64-3.56 (m, 1H), 3.27-3.19 (m, 1H), 3.12 (app t, J = 7.8 Hz, 1H), 2.81-2.74 (m, 2H), 2.52- 2.35 (m, 1H), 2.09-1.95 (m, 2H), 1.83-1.63 (m, 4H), 1.45 (s, 9H), 1.29-1.19 (m, 6H) ppm. [00225] B. Acid 3-. { 3- [1- (5- Benzyloxycarbonylamino-2-terbutoxycarbonylamino-pentanyl) -pyrrolidin-2-ylmethyl] -benzofuran-2-yl} -propioonics (54): A solution containing 53 crude (3.0 g, 4.6 mmol) in THF (20 mL) is treated with 3 M NaOH (8 mL) at room temperature. The reaction mixture is then heated to a slight reflux and maintained by? . The reaction mixture is concentrated in vacuo and the residue is dissolved in EtOAc. The organic solution is washed with 1 N HC1 then dried over anhydrous Na 2 SO 4, filtered and concentrated to give ~ 3 g (quant.) Of 54 as a whitish foam that is used directly without further purification. 1 H NMR (CDC13, 300 MHz) ni.69 1.61 (m, 1H), 7.39-7.20 (m, 8H), 5.70 (d, J = 8.4 Hz, 1H), 5.13-5.09 (m, 2H), 4.50- 4.45 (m, 1H), 3.67-3.54 (m, 1H), 3.22-3.18 (m, 2H), 3.13 (t, J = 6.9 Hz, 1H), 2.85-2.78 (m, 2H), 2.09-1.97 ( m, 3H), 1.76-1.62 (m, 4H), 1.43 (s, 9H) ppm. [00226] C. Acid 3-. { 3- [-1- (5-Amino-2-tert-butoxycarbonylamino-pentanoyl) -pyrrolidin-2-ylmethyl] -benzofuran-2-yl} -propionic (55): A solution of 54 crude (~ 3 g, 4.8 mmol) in MeOH (30 mL) is loaded with palladium on 10% carbon (~ 1 g) and placed under hydrogen gas atmosphere (3.1 bar ( 45 PSI)). The reaction mixture is stirred using a Parr apparatus for 2 hours. After removing the catalyst by filtration over celite, the clarified filtrate is concentrated in vacuo. The crude residue is taken up in DCM and dried using anhydrous Na 2 SO 4, filtered and concentrated to give 2.3 g (quant.) Of 55 as a foamy residue which is used without further purification. 1 NMR (CDC13, 300 MHz) 67.51 (m, 1H), 7.34-7.32 (m, 1H), 7.18-7.15 (m, 2H), 6.19 (m, 1H), 4.36 (m, 2H), 3.62-3.48 (m, 2H), 3.10-2.99 (m, 2H), 2.85-1.81 (m, 2H), 2.66-2.60 (m, 2H), 1.99-1.71 (m, 6H), 1.41 (s, 9H) ppm. Mass spectrum, m / z 488 [M + H] +. [00227] D. Lactam derived from Des alanine Ornithine protected with Boc (56): A solution containing 55 (2.3 g, 4.7 mmol) in NMP / DCM 1: 1 (30 mL) is treated with HATU (2.1 g, 5.5 mmol) and NMM (0.6 mL, 5.5 mmol) at room temperature. After 18 hours, the reaction mixture is diluted with diethyl ether and washed susively with aqueous Na 2 SO 4, dilute aqueous HC 1, water, brine, then dried over anhydrous Na 2 SO 4, filtered and concentrated to give 1.5 g (68%) of 56 as a whitish colored foam that is used without further purification. ½ NMR (CDC13, 300 MHz) hi. IQ-1.66 (m, 1H), 7.33 (m, 1H), 7.19-7.18 (m, 2H), 5.70 (m, 1H), 4.42 (m, 1H), 4.10 (m, 1H), 3.55 (m, 3H), 3.24-3.09 (m, 4H), 2.61-2.46 (m, 2H), 1.63 (m, 7H), 1.44 (s, 9H) ppm. Mass spectrum, m / z 470 [M + H] +, 492 [M + Na] +. [00228] E. Lactama derived from Des-alanine Ornithine (57): To a solution of 56 crude (1.5 g, 3.1 mmol) in DC (20 mL) is added TFA (4 mL) at room temperature. After 2 hours, the solvent is removed under reduced pressure. The residue is dissolved in EtOAc and washed with NaHCC >; 3 watery, and brine. The combined aqueous washings are back-extracted with 5% MeOH / DCM. The combined organic extracts are dried over anhydrous Na2SO, filtered and concentrated to give 0.8 g (68%) of 57 as a whitish foam that is used directly in the next reaction. "?? NMR (CDC13, 300 MHz) 57.41-7.38 (m, 1H), 121-120 (m, 3H), 5.99 (d, J = 9.3 Hz, 1H), 4.39-4.33 (m, 1H), 3.96. -3.84 (m, 1H), 3.70-3.65 (m, 2H), 3.55-3.38 (m, 2H), 3.20-3.05 (m, 2H), 2.90-2.83 (m, 3H), 2.77-2.71 (m, 2H), 2.66-2.62 (m, 2H), 2.19-1.98 (m, 2H), 1.78-1.66 (m, 2H), 1.38-1.08 (m, 2H) ppm.

[00229] F. Lactam derived from Ornithine pre-woven from Boc (58): A solution containing Boc L alanine (526 mg, 2.8 mmol) in NMP (5 mL) is treated with HATU (1.1 g, 2.9 mmol) followed by NMM (0.3 mL, 2.9 mmol) at room temperature. After 10 minutes, crude amine 57 (0.8 mg, 2.2 mmol) in NMP (10 mL) is added in a dropwise fashion. After 2 d, the reaction mixture is diluted with diethyl ether and washed successively with NaHCC > 3, 1 M HC1, water, and brine. The organic extract is dried over anhydrous Na2SO4, filtered and concentrated to give ~1 g (84%) of 58 as a yellow oil which is used without further purification. Mass spectrum: m / z 541 [M + H] +, and 563 [M + Na] +. [00230] G. Lactam derived from ornithine (59): To a solution of 58 crude (~ 1 g, 1.9 mmol) in DCM (10 mL) is added TFA (4 mL) at room temperature. After 1 hour, the solvent is removed under reduced pressure. The residue is dissolved in EtOAc and washed with aqueous NaHCO3, and brine. The combined aqueous washings were again extracted with 5% MeOH / DCM and the combined organic extracts were dried over anhydrous a2SO4, filtered and concentrated. A portion of the crude product is purified by reverse phase HPLC (Cl 8, 10-100% ACN / water containing 0.1% HOAc) to give 28 mg of 59 as a white solid. X H NMR (DMSO, 300 MHz) 58.14 (m, 1 H), 7.88 (m, 1 H), 7.68 7.66 (m, 1 H), 7.35 (m, 1 H), 7.12 (m, 2 E), 4.43 (m, 1 H) , 4.12 (m, 1H), 3.48 (m, 2H), 2.91 (m, 4H), 1.48-1.36 (m, 4H), 1.10 (d, J = 6.3 Hz, 3H) ppm. Mass spectrum: m / z 441 [M + H] +.

Table 11 Table 12.

EXAMPLE 13 [00231] This example illustrates pyrrolidine derivatives of Table 13. Scheme Ve

[00232] The preparation of cyclic ether derived from thyroxine (66). [00233] A. 2- [2- (3-Hydroxy-propenyl) -benzofuran-3-ylmethyl] -pyrrolidine-1-carboxylic acid benzyl ester (60): At 78 degrees C, BF3-etherate (0.6 mL, 4.8 mmol) is added to a solution containing 47 (1.7 g, 3.9 mmol) in anhydrous DCM (40 mL). After 10 minutes, DIBAL (1 M / DCM, 10 mL, 10 mmol) is added by droplets from an addition funnel. After 5 minutes following the complete addition of the DIBAL solution, EtOAc (10 mL) is added to neutralize the excess reagent. Dilute aqueous HC1 is added slowly and the reaction mixture is allowed to warm slowly to room temperature. The product is extracted with DCM and EtOAc and the combined organic extracts are washed with dilute aqueous HC1, water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product is purified by flash silica gel chromatography (EtOAc / hexane, 1: 2) to give 1.1 g (72%) of 60 as a yellow oil. 1 H NMR (CDC13, 300 MHz) 57.65 & 7.03 (rotem, dy app t, J = 6.9, 7.8 Hz, 1H), 7.38 (m, 5H), 7.26 7.19 (m, 2H), 6.70 6.52 (m, 2H), 5.26 5.14 (m, 2H), 4.38 (m, 1H), 4.28 (m, 1H), 4.14 (m, 1H), 3.43 (m, 2H), 3.27 & 3.02 (rotamer, 2 m, 1H), 2.76 2.68 (m, 1H), 2.45 (m, 1H), 1.77 1.68 (m, 5H) ppm. [00234] B. 3- (3-Pyrrolidin-2-ylmethyl-benzofuran-2-yl) -propan-1-ol (61): a mixture of 60 (1.1 g, 2.8 mmol) and Pd in 10 charcoal. % (1 g) in MeOH (40 mL) is placed under a hydrogen gas atmosphere (3.1 bar) (45 PSI) and shake for 2 h using a Parr apparatus. The catalyst is removed by filtration through a celite bed and the clarified filtrate is concentrated in vacuo to give 725 mg (quant.) Of 61 as a yellow oil which is used without further purification. 1 H NMR (CDC13, 300 MHz) 57.47-7.36 (m, 2H), 7.21-7.17 (m, 2H), 4.59 (br s, 2H), 3.57-3.50 (m, 2H), 3.40-3.31 (m, 1H ), 3.08-2.94 (m, 1H), 2.89-2.69 (m, 2H), 2.05-1.95 (m, 2H), 1.93-1.49 (m, 2H) ppm. [00235] C. tert butyl ester of (l- (4-Hydroxy-benzyl) -2-. {2- [2- (3-hydroxy-proproyl) -benzofuran-3-ylmethyl] -pyrrolidine-1-acid ester il.} -2-oxo-ethyl) -carbamic (62): Ona solution containing Boc L thyroxine (577 mg, 2.1 mmol) and HATU (716 mg, 1.8 mmol) in anhydrous NMP (6 mL) is treated with M (0.3 mL, 2.7 mmol) at room temperature. After 10 minutes, a solution containing 61 (429 mg, 1.7 mmol) in NMP (5 mL) is added. After 2 d, the reaction mixture is diluted with water and the product is extracted with diethyl ether. The combined ether extracts are washed with water and NaHCC >3 diluted aqueous, brine, dried over Na2SC > 4 anhydrous, filter and concentrate. The crude product is purified by flash silica gel chromatography (10% eOH / DCM) to result in 821 mg (92%) of 62 as a pale yellow foam. ½ NMR (CDC13, 300 MHz) 68.54 (br 2, 1H), 7.66-7.63 (m, 1H), 7.36-7.32 (m, 1H), 7.21-7.06 (m, 5H), 6.83 (d, J = 8.4 Hz, 2H), 5.58 (d, J = 9.0 Hz, 1H), 4.64-4.56 (m, 1H), 4.34 4.31 (m, 1H), 3.92-3.88 (m, 1H), 3.70 (app t, J = 5.7 Hz, 2H), 3.51-3.26 (m, 1H), 3.18-2.79 (m, 4H), 2.01-1.97 (m, 2H), 1.69-1.47 (m, 1H), 1.42 (s, 9H) ppm. [00236] D. Cyclic ether derived from Des-alanine Boc protected thyroxine (63): To a solution containing 62 (821 mg, 1.6 mmol) in DCM (40 mL) is added Ph3P (431 mg, 1.6 mmol) and ADDP (491 mg, 1.9 mmol) at room temperature. After 16 hours, the reaction mixture is concentrated in vacuo then redissolved in diethyl ether. The insoluble white solid is removed by filtration and the clarified filtrate is concentrated. The crude product is purified by flash silica gel chromatography (EtOAc / hexane, 1: 2 to 1: 1) to give 160 mg (19%) of 63 as a light yellow foam. ½ NMR (CDC13, 300 MHz) 67.47 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.28-7.24 (m, 2H), 7.22-7.11 (m, 2H), 7.00 (dd, J = 2.7, 8.1 Hz, 1H), 6.69 (dd, J = 3.0, 8.7 Hz, 1H), 5.28 (d, J = 9.6 Hz, 1H), 4.88 4.79 (m, 1H), 4.51- 4.41 (m, 1H), 4.23-4.17 (m, 1H), 3.97 3.89 (m, 1H), 3.84-3.76 (m, 1H), 3.46-3.29 (m, 2H), 2.75 2.62 (m, 4H), 2.17-2.09 (m, 1H), 1.99-1.90 (m, 1H), 1.72 1.54 (m, 2H), 1.4.5 (s, 9H) ppm. [00237] E. Cyclic ether derived from Des-alanine Thyroxine (64): To a solution of 63 (160 mg, 0.32 mmol) in DCM (10 mL) is added TFA (2 mL) at room temperature. After 1.5 h, the solvent is removed under reduced pressure. The residue is dissolved in EtOAc and washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to give 130 mg (quant.) Of 64 as a whitish solid which is used directly in the next reaction, ½ NMR (CDC13, 300 MHz) 67.46 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.21-7.19 (m, 2H), 7.16-7.10 (m, 2H), 6.97 ( dd, J = 2.4, 8.1 Hz, 1H), 6.70-6.68 (m, 1H), 4.47 (m, 1H), 4.21-4.13 (m, 2H), 3.93 (t, J = 9.3 Hz, 1H), 3.51 -3.36 (m, 4H), 2.73-2.68 (m, 4H), 2.15-2.07 (m, 1H), 1.98-1.90 (m, 1H), 1.70-1.46 (m, 3H), 1.19-1.13 (m, 1H), 0.64-0.55 (m, 1H) ppm. [00238] F. Cyclic ether derived from Boc protected Thyroxine (65): A solution containing Boc L alanine (63 mg, 0.33 mmol) in NMP (3 mL) is treated with HATU (125 mg, 0.33 mmol) followed by NMM. (0.1 mL, 0.9 mmol) at room temperature. After 10 minutes, crude amine 64 (125 mg, 0.31 mmol) in NMP (5 mL) is added in one dropwise fashion. After 16 hours, the reaction mixture is diluted with diethyl ether and washed successively with NaHCO 3, 1 M HC1, water, and brine. The organic extract is dried over anhydrous Na2SO4, filtered and concentrated. The crude product is purified by flash silica gel chromatography (EtOAc / hexane, 1: 1 s 2: 1) to give 137 mg (76%) of 65 as a light yellow solid. XH NMR (CDC13, 300 MHz) 67.46 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.19-7.12 (m, 3H), 7.05-6.99 (m, 2H), 6.70 (dd, J = 2.4, 8.4 Hz, 1H), 5.14-5.08 (m, 2H), 4.48-4.42 (m, 1H), 4.26-4.18 (m, 2H), 3.93 (app t, J = 9.3 Hz , 1H), 3.84-3.76 (m, 1H), 3.47-3.31 (m, 2H), 2.84-2.64 (m, 4H), 2.15-2.08 (m, 1H), 1.97-1.93 (m, 1H), 1.71 -1.52 (m, 3H), 1.48 (s, 9H), 1.38 (d, J = 7.2 Hz, 3H), 1.18-1.12 (m, 1H), 0.64-0.56 (m, 1H) ppm. [00239] G. Thyroxine-derived cyclic ether (66): To a solution of 65 (137 mg, 0.23 mmol) in DCM (10 mL) is added TFA (2 mL) at room temperature. After 1.5 hours, the solvent is removed under reduced pressure. The residue is dissolved in EtOAc and washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product is purified by reverse phase HPLC (C18), 10 100% ACN / water containing 0.1% HOAc) to give 90 mg (82%) of 66 as a white solid. X H NMR (DMSO, 300 MHz) 68.23 (d, J = 6.9 Hz, 1H), 7.46-7.39 (m, 3H), 7.23-7.12 (m, 2H), 7.01-6.99 (m, 2H), 6.85-6.82 (m, 1H), 4.86 (m, 1H), 4.27 (m, 1H), 4.16 (m, 1H), 3.98-3.84 (m, 1H), 3.44-3.33 (m, 1H), 3.16-3.10 (m , 1H), 2.76-2.67 (m, 3H), 1.99 (m, 1H), 1.57 (app t, J = 5.7 Hz, 2H), 1.45-1.39 (m, 1H), 1.16 (d, J = 6.3 Hz , 3H), 1.02-0.97 (m, 1H), 0.58-0.49 (m, 1H) ppm.

Mass spectrum: m / z 476.2 [+ H] +.

Table 13 EXAMPLE 14 [00240] This example illustrates pyrrolidine derivatives of Table 14 Scheme VI

[00241] The preparation of 2S-Amino-N-. { 1S- [2 £ - (1H-indol-3-ylmethyl) -pyrrolidine-1-carbonyl] -2-methyl-propyl} -propionamide (76): [00242] A. tert-butyl ester of trans-2S- (3-methanesulfonyloxy-propenyl) -pyrrolidine-l-carboxylic acid (67): To a solution of 22 (2 g, 8.8 mmol) in DCM (10 mL) triethylamine (2.5 mL, 17.6 mmol) is added. The solution is cooled in an ice bath and methanesulfonyl chloride (0.74 mL, 9.68 mmol) is added dropwise and stirred at room temperature for 30 minutes. Water (10 mL) is added and the product is extracted with DCM (3 x 50 mL). The organic layers are combined and washed with 5 mL HC1 1N, water (10 mL), and brine, and dried over anhydrous Na2SO4. Solvent is evaporated under reduced pressure to obtain 9.5 g of 67 which is used without purification. 1 H NMR (CDC13, 300 MHz): d 4.4-4.0 (m, 2 H), 3.42-3.21 (m, 3 H), 3.0 (s, 3 H), 2-1.6 (m, 4 H), 1.42 (s, 9 H) ) ppm. [00243] B. tert-butyl ester traiis-2S- acid. { 3- [Acetyl- (2-iodo-phenyl) -amino] -propenyl} -pyrrolidine-1-carboxylic acid (68): a solution of o-iodoacetanilide (1.1 g, 4.21 mmol) in DMF (10 mL) is cooled in an ice bath and NaH (60% dispersion in mineral oil, 0.24 g, 6.31 g. mmol) is added in portions and stirred at room temperature for 10 minutes. Crude mesylate 67 (1.28 g, 4.21 mmol) in DMF (5 mL) is added dropwise at room temperature and stirred for 30 minutes. Water (10 mL) is added and the product is extracted with diethyl ether (3 x 50 mL). The combined ether extracts are washed with water (3 x 50 mL) and brine, dried over Na2SO4. The solvent is evaporated under reduced pressure and purified by chromatography on silica gel (3: 1 hexanes / ethyl acetate) to give 1.17 g of 68 as a white solid. ½ NMR (CDC13, 300 MHz): d 7.85 (d, J = 9.9 Hz, 1H), 7.4-7.0 (m, 3H), 5.6 (m, 1H), 5.28 (m, 1H), 4.86 (m, 1H) ), 3.3 (m, 3H), 2.0-1.6 (m, 4H), 1.4 (s, 9H) ppm.

[00244] C. tert-butyl ester 2S- (1-Acetyl-lH-indol-3-ylmethyl) -pyrrolidine-l-carboxylic acid (69):? a solution of 68 (1.1 g, 2.33 mmol) in DF (15 mL) is added 2C03 (0.41 g, 3.02 mmol), NaHCO2 (0.16 g, 2.44 mmol) followed by tetrabutylammonium chloride (0.64 g, 2.33 mmol) and Pd ( OAc) 2 (0.02 g, 0.07 mmol) and the reaction flask is immersed in a preheated oil bath (100 degrees C). After 40 minutes, water (10 mL) is added and the product is extracted with diethyl ether (3 x 50 mL). The diethyl ether extracts were washed with water (3 x 50 mL), brine and dried over Na2SC > 4. Solvent is evaporated under reduced pressure and purified by flash silica gel chromatography (3: 1 hexanes / ethyl acetate) to give 0.37 g of 69 as a white solid. 1H RN (CDCl3, 300 MHz): d 8.4 (s, 1H), 7.78-7.6 (dd, J = 10.7, 10.7 Hz, 1H), 4.2-4.0 (m, 1H), 3.45-3.0 (m, 3H) , 2.7-2.6 (m, 1H), 2.6 (s, 3H), 1.9-1.65 (m, 4H), 1.5 (s, 9H) ppm. [00245] D. 1- (3-Pyrrolidin-25'-ylmethyl-indol-1-yl) -ethanone (70): To a solution of 69 (0.37 g, 1.08 mmol) in DCM (20 mL) is added TFA (4 mL) and stirred at room temperature for 30 minutes. Aqueous NaHC03 (5 mL) is added and the reaction mixture is concentrated under reduced pressure. The product is extracted with DCM (3 x 50 mL) and the organic extract is washed with NaHCC > 3 water, brine and water, and dry over anhydrous a2SO4. Solvent is removed under reduced pressure and purified by silica gel column chromatography (10: 1 DCM / MeOH) to give 0.26 g of 70 as a white solid. X H NMR (CDCl 3, 300 MHz): d 8.6 (d, J = 11 Hz, 1 H), 7.5 (d, J = 11 Hz, 1 H), 7.4-7.2 (m, 3 H), 3.8-3.6 (m, 1 H) ), 3.2-2.9 (m, 4H), 2.8 (s, 3H), 2.2-1.6 (ra, 4H) ppm. [00246] E. tert-butyl ester of acid. { [2, S- (l-Acetyl-lH-indol-3-ihnethyl) -pyrrolidine-l-carbonyl] -2-methyl-propyl} -carbamic (71): To a solution of BOC L valine (0.25 g, 1.18 mmol) in NMP (5 mL), add HATU (0.44 mg, 1.18 mmol) followed by NMM (0.3 mL).2.67 mmol). After 5 minutes, add 70 (0.25 g, 0.11 mmol) and stir at room temperature for 30 minutes. Ethyl acetate (20 mL) is added and the organic solution is washed with aqueous NaHCO3 (10 mL), 1N HCl (10 mL), water, and brine, dried over Na2SO4. Solvent is removed under reduced pressure and the product is purified by flash silica gel chromatography to give 0.36 mg of 71 as a white solid. 1 H NMR (CDCl 3, 300 Hz): 8.4 (m, 1 H), 7.88 (d, J = 11 Hz, 1 H), 7.4-7.2 (m, 3 H), 4.4 4.2 (m, 1 H), 3.8-3.4 (m, m, 3H), 3.38 (d, J = 11 Hz, 1H), 2.65 (d, J = 11 Hz, 1H), 2.6 (s, 3H), 2.5 2.4 (m, 1H), 2.1-1.7 (m, 4H), 1.4 (s, 9H), 1.05 (d, J = 5.5 Hz, 3H), 0.95 (d, J = 5.5 Hz, 3H) ppm. [00247] F. I- [2S- (l-Acetyl-lH-indol-3-ethylhexyl) -pyrrolidin-l-yl] -2S-amino-3-methyl-butan-l-one (72): To a solution of 71 (0.36 g, 0.81 ramol) in DCM (20 mL) was added TFA (4 mL) and the reaction mixture was stirred at room temperature for 30 minutes. Aqueous NaHC03 is added to the reaction mixture and TFA and DCM are removed under reduced pressure. The product is extracted with DCM (3 x 50 mL) and the extracts combined DCM washed with water and brine and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the product is purified by flash silica gel chromatography (10: 1 DCM / MeOH) to give 0.27 g of 72 as a white solid. a H NMR (CDC13 300 MHz): d 8.4 (m, 1H), 7.88 (d, J = 11 Hz, 1H), 7.4-7.2 (m, 3H), 4.4-4.2 (m, 1H), 3.8-3.4 ( m, 3H), 3.38 (d, J = 11 Hz, 1H), 2.65 (d, J = 11 Hz, 1H), 2.6 (s, 3H), 2.5-2.4 (m, 1H), 2.1-1.7 (m , 4H), 1.05 (d, J = 5.5 Hz, 3H), 0.95 (d, J = 5.5 Hz, 3H) ppm. [00248] G. tert-butyl ester (? - {? -? - (1-Acetyl-lH-indole-S-ylmethyl-pyrrolidine-1-carbonyl] -2-methyl-propylcarbamoyl}. ethyl) -carbamic (73): To a solution of BOC L alanine (0.13 g, 0.38 mmol) in NMP (3 mL) is added HATU (0.16 mg, 0.41 mmol) followed by NMM (0.1 mL, 0.95 mmol). After 5 minutes, 72 (0.12 g, 0.34 mmol) is added and the reaction mixture is stirred at room temperature for 30 minutes, ethyl acetate (20 rtIL) is added to the reaction mixture and the organic solution is washed with aqueous NaHCO3. (10 mL), 1 N HC1 (10 mL), water, and brine, dry Na2SO4 over Solvent is removed under reduced pressure and the product is purified by flash silica gel chromatography to result in 0.15 mg of 73 as a solid white ½ NMR (CDC13, 300 MHz): d 8.4 (m, 1H), 7.88 (d, J = 10.9 Hz, 1H), 7.4-7.2 (m, 3H), 7.0-6.8 (m 1H), 4.6 (m, 1H), 4.5-4.4 (m, 1H), 4.2 (m, 1H), 3.8-3.6 (m, 2H), 3.38 (d, J = 10.9 Hz, 1H), 2.65 (d, J = 10.9 Hz, 1H ), 2.6 (s, 3H), 2.5-2.4 (m, 1H), 2.1-1.7 (m, 4H), 1.45 (s, 9H), 1.4 (d, J = 10.9 Hz, 3H), 1.05 (d, J = 5.5 Hz, 3H), 0.95 (d, J = 5.5 Hz, 3H) ppm. [00249] H. N-US- [2S- (1-Acetyl-1H-indol-3-ylmethyl) -pyrrolidine-1-carbonyl] -2-methyl-propyl} -2S-amino-propionamide (74): To a solution of 73 (0.15 g, 0.29 mmol) in DCM (20 mL) is added TFA (4 mL) and the reaction mixture is stirred at room temperature for 30 minutes. Aqueous NaHC03 is added to the reaction mixture and TFA and DCM are removed under reduced pressure. The product is extracted with DCM (3 x 50 mL) and DCM extracts are washed with water, brine, and dried over Na2SC >; 4 anhydrous.

Solvent is removed under reduced pressure and the product is purified by flash silica gel chromatography (10: 1 DCM / MeOH) to give 0.12 g of 74 as a white solid. x NMR (CDC13, 300 MHz): d 8.4 (m, 1H), 7.88 (d, J = 10.9 Hz, 1H), 7.85 (d, J = 10.9 Hz, 1H), 7.4-7.2 (m, 3H), 4.6 (m, 1H), 4.5-4.4 (m, 1H), 3.8 (m, 1H), 3.75-3.4 (m, 2H), 3.38 (d, J = 10.9 Hz, 1H), 2.65 (d, J = 10.9 Hz, 1H), 2.6 (s, 3H), 2.5-2.4 (m, 1H), 2.1-1.7 (m, 4H), 1.4 (d, J = 10.9 Hz, 3H), 1.05 (d, J = 5.5 Hz, 3H), 0.95 (d, J = 5.5 Hz, 3H) ppm. [00250] 2 < stAmino-iV-. { 15- [25t- (lH-indol-3-ylmethyl) -pyrrolidine-1-carbonyl] -2-methyl-propyl} -propionamide (75): To a solution of 74 (0.12 g, 0.291 mmol) in dry MeOH (3 mL) is added 3 mL of 10% NaOH / eOH. After 15 minutes, water (2 mL) is added to the reaction mixture and the solvent is removed under reduced pressure. The product is extracted with ethyl acetate (3 x 50 mL) and the organic extracts are washed with water, brine, and dried over Na2SC > 4. The solvent is removed under reduced pressure and the product is purified by chromatography on silica gel (10: 1 DCM / MeOH) to give 0.06 g of 75 as a white solid. ½ NMR (CDC13, 300 MHz): S 8.4 (m, 1H), 7.88 (d, J = 10.9 Hz, 1H), 7.85 (d, J = 10.9 Hz, 1H), 7.4-7.2 (m, 3H), 4.6 (m, 1H), 4.5-4.4 (m, 1H), 3.8 (m, 1H), 3.75-3.4 (m, 2H), 3.38 (d, J = 10.9 Hz, 1H), 2.65 (d, J = 10.9 Hz, 1H), 2.5-2.4 (m, 1H), 2.1-1.7 (m, 4H), 1.4 (d, J = 10.9 Hz, 3H), 1.05 (d, J = 5.5 Hz, 3H), 0.95 ( d, J = 5.5 Hz, 3H) ppm.

(E14) Table 14.

EXAMPLE 15 [00251] This example illustrates pyrrolidine derivatives of Table 15. Scheme VII

[00252] The preparation of 25'-amino-iV- (2-methyl-15 '-. {25' - [1- (toluene-4-sulfonyl) -lH-indol-3-ylmethyl] -pyrrolidine-1 -carbonyl.}. -propyl) -propionamide (78). [00253] A. tert-butyl ester (1S-. {15 '- [21S' - (lH-Indol-3-ylmethyl) -pyrrolidine-1-carbonyl] -2-methyl-propylcarbamoyl}. ethyl) -carbamic (76): To a solution of 73 (0.70 g, 1.36 mmol) in dry MeOH (10 mL) is added 5 mL of 10% NaOH / MeOH and stirred for 15 minutes. Water (5 mL) is added to the reaction mixture and the solvent removed under reduced pressure. The product is extracted with ethyl acetate (3 x 50 mL) and the organic extracts are washed with water, brine, and dried over Na2SO4. Solvent is removed under reduced pressure and the product is purified by flash silica gel chromatography (10: 1 DCM / MeOH) to give 0.53 g of 76 as a white solid. 1 H NMR (CDC13, 3003VIHz): d 8.0 (s, 1H), 7.9 (d, J = 9.9 Hz, 1H), 7.38 (d, J = 9.9 Hz, 1H), 7.3-7.1 (m, 3H), 6.8 (m, 1H), 4.62 (m 1H), 4.5-4.4 (m 1H), 4.4-4.0 (m, 2H), 3.7-3.5 (m, 2H), 3.4 (m, 1H), 2.5 (m, 1H) ), 2.2-1.8 (m, 4H), 1.48 (s, 9H), 1.35 (d, J = 9.9 Hz, 3H), 1.05 (d, J = 5.5 Hz, 3H), 0.95 (d, J = 5.5 Hz) , 3H) ppm. [00254] B. tert-butyl ester [1 S (2-Methyl-15-. {25- [1- (toluene-4-sulfonyl) -lH-indol-3-ylmethyl] -pyrrolidine-1-carbonyl acid} -propylcarbamoyl) -ethyl] -carbamic acid (77): To a solution of 76 (0.05 g, 0.11 mmol) in DCM (1 mL) is added NaOH (0.01 g, 0.13 mmol) and stirred at room temperature for 30 minutes. minutes Tosyl chloride (0.03 g, 0.16 mmol) is added and the reaction mixture is heated to 35 degrees C for 1 hour. Water (5 mL) is added to the reaction mixture and the product is extracted with DCM (3 x 30 mL). The DCM extracts are washed with water, brine, and dried over Na2SO4. Solvent is removed under reduced pressure and the product is purified by silica gel chromatography (3: 1 hexane / ethyl acetate) to result in 61 mg of 77 as a white solid. XH NMR (CDC13, 300 MHz): d 7.95 (d, J = 9.9 Hz, 1H), 7.82 (d, J = 9.9 Hz, 1H), 7.7 (d, J = 9.9 Hz, 2H), 7.4-7.2 ( m, 5H), 6.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.3-4.18 (m, 2H), 3.8-3.5 (m, 2H), 3.3 (m, 1H) , 2.45 (m, 1H), 2.35 (s, 3H), 2.2-1.8 (m, 4H), 1.43 (s, 9H), 1.38 (d, J = 9.9 Hz, 3H), 1.05 (d, J = 5.5 Hz, 3H), 0.95 (d, J = 5.5 Hz, 3H) ppm. [00255] C. 2, S-Amino-iV- (2-methyl-15-. {25- [1- (toluene-4-sulfonyl) -lH-indol-3-ylmethyl] -pyrrolidine-1-carbonyl} -propyl) -propionamide (78): To a solution of 77 (0.06 g, 0.096 mmol) in DCM (10 mL) is added TFA (2 mL) and the reaction mixture is stirred at room temperature for 30 minutes. Aqueous NaHC03 is added to the reaction mixture and TFA and DCM are removed under reduced pressure. The product is extracted with DCM (3 x 25 mL) and the DCM extracts are washed with water, brine, and dried over anhydrous a2SO4. Solvent is removed under reduced pressure and the product is purified by flash silica gel chromatography (10: 1 DCM / MeOH) to result in 0.04 g of 78 as a white solid. XR NMR (CDC13, 300 MHz): d 7.95 (d, J = 9.9 Hz, 1H), 7.82 (d, J = 9.9 Hz, 1H), 7.7 (d, J = 9.9 Hz, 2H), 7.4-7.2 ( m, 5H), 6.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.3-4.18 (m, 2H), 3.8-3.5 (m, 2H), 3.3 (m, 1H), 2.45 (m, 1H), 2.35 (s, 3H), 2.2-1.8 (m, 4H), 1.38 (d, J = 9.9 Hz, 3H), 1.05 (d, J = 5.5 Hz, 3H), 0.95 (d, J = 5.5 Hz, 3H) ppm.

Table 15 EXAMPLE 16 [00256] This example illustrates pyrrolidone derivatives of Table 16. Scheme VIII

[00257] The preparation of N-. { l-Cyclohexyl-2- [2- (6-fluoro-l-. {2- [2- (2-methoxy-ethoxy) -ethoxy] -ethyl] -lH-indol-3-ylmethyl) -pyrrolidine -l-il] -2-oxo-ethyl} -2-methylamino propionamide (85): [00258] A. tert-butyl ester of 2- (6-Fluoro-1- { 2- [2- (2-methoxy-ethoxy) -ethoxy] -ethyl ester}-lH-indole-3-ylmethyl) -25'-pyrrolidone-l-carboxylic acid (80): To a suspension of NaH (72 mg, 1.8 mmol, 60% suspension of mineral oil) in DMF (1 mL?) 79 (180 mg, 0.60 mmol) in DMF (1 mL) are added at room temperature. The mixture is stirred for 1 hour at room temperature, followed by addition of tri (ethylene glycol) monomethyl ether (182 mg, 0.57 mmol) in DMF (1 mL). The resulting mixture is stirred at room temperature overnight, and neutralized by addition of aqueous NH 4 Cl solution at 0 degrees C. The crude product is extracted with EtOAc. The organic phase is washed with brine and dried over Na2SO4. After removing the solvent, the residue is purified by flash silica gel chromatography (50% EtOAc in hexanes) to result in 250 mg of 80 (93%). [TLC (60% EtOAc / hexane): Rf (80) = 0.22)]. 2R NMR (CDC13, 300 MHz) d 7.65-7.76 (1H), 7.33 (m, 1H), 7.20 (m, 1H), 7.09 (m, 1H), 6.95 (s, 1H), 4.27 (t, J = 8.4 Hz, 2H), 3.79 (t, J = 5.7 Hz, 2H), 3.40-3.70 (9H), 3.37 (s, 3H) , 3.10-3.40 (2H), 2.65 (m, 1H), 1.75 (brs, 4H), 1.55 (s, 9H) ppm. [00259] B. 6-Fluoro-l-. { 2- [2- (2-methoxy-ethoxy.i) -ethoxy] -ethyl} 3-pyrrolidin-2-ylmethyl-1H-indole (81): A solution of 80 (250 mg, 0.56 mmol) in DCM (5 mL) is treated with TFA (1 mL) at room temperature. After 2 hours, the reaction mixture is concentrated, diluted with EtOAc, washed with 1N aqueous NaOH and brine, dried over a2SO4, filtered and concentrated to give 190 mg. (98%) of 81 as a light yellow oil. The product is used without further purification. [00260] C. Ter-butyl ester of acid. { 1-Cyclohexyl-2- [2- (6-fluoro-1- {2- [2- (2-methoxy-ethoxy) -ethoxy] -ethyl} -lH-indol-3-ylmethyl) -pyrrolidine -l-il] -2-oxo-ethyl} -carbamic (82): To a solution of Boc L cyclohexylglycine (172 mg, 0.67 mmol) in N P (2 mL) is added HATÜ (255 mg, 0.67 mmol) followed by N M (0.1 mL, 0.95 mmol). After 5 minutes, 81 (190 mg, 0.55 mmol) in DCM (1 mL) is added and the reaction mixture is stirred at room temperature overnight. Ethyl acetate (20 mL) is added to the reaction mixture and the organic solution is washed with water. HC1 1N (5 mL), aqueous NaHCO3 (10 mL), and brine, dry over Na2SO4. The solvent is removed under reduced pressure and the product is purified by flash silica gel chromatography to result in 280 mg (85%) of 82 as a wax. [TLC (60% EtOAc / hexane): Rf (82) = 0.18)]. ¾ NMR (CDC13, 300 MHz) d 7.83 (m, 1H), 7.32 (m, 1H), 7.20 (m, 1H), 7.09 (m, 1H), 6.98 (s, 1H), 5.32 (m, 1H) , 4.0-4.6 (5H), 3.79 (t, J = 5.7 Hz, 2H), 3.40-3.70 (9H), 3.37 (s, 3H), 2.65 (m, 1H), 1.6 2.0 (10H), 1.46 (s) , 9H), 1.0-1.4 (6H) ppm. [00261] D. 2-Amino-2-cyclohexyl-1- [2- (6-fluoro-l-. {2- [2- (2-methoxy-ethoxy) -ethoxy] -ethyl] -lH -indol-3-ylmethyl) -pyrrolidin-1-yl] ethanone (83): A solution of 82 (250 mg, 0.43 mmol) in DCM (5 mL) is treated with TFA (1 mL) at room temperature. After 2 hours, the reaction mixture is concentrated, diluted with EtOAcs, washed with NaOH in water and brine, dried over Na 2 SO, filtered and concentrated to yield 210 mg (100%) of 83 as a light yellow wax. The product is used without further purification. [00262] E. tert-butyl ester of 1- (1-cyclohexyl-2- [2- (6-fluoro-1- {2 - [2- (2-methoxy-ethoxy) -ethoxy] ] -ethyl.}.-lH-indol-3-ylmethyl) -pyrrolidin-1-yl] -2-oxo-ethylcarbamoyl.] -ethyl) -methyl-carbamic acid (84): To a solution of Boc LN methylanaline ( 91 mg, 0.48 mmol) in NMP (2 mL) is added HATÜ (183 mg, 0.48 mmol) followed by N M (0.1 mL, 0.95 mmol). After 5 minutes, 83 (210 mg, 0.43 mmol) in DCM (1 mL) is added and the reaction mixture is stirred at room temperature overnight. Ethyl acetate (20 mL) is added to the reaction mixture and the organic solution is washed with water, 1N HC1 (5 mL), aqueous NaHCO3 (10 mL), and brine, dried over a2SO4. Solvent is removed under reduced pressure and the product is purified by flash silica gel chromatography to yield 188 mg (65%) of 84 as a wax. [TLC (80% EtOAc / hexane): Rf (84) = 0.20)]. ½ NMR (CDC13, 300 MHz) d 7.80 (m, 1H), 7.35 (m, 1H), 7.19 (m, 1H), 7.10 (m, 1H), 6.95 (s, 1H), 4.62 (m, 1H) , 4.46 (m, 1H), 4.20 (t, J = 6.7 Hz, 2H), 3.77 (, t, J = 5.4 Hz, 2H), 3.2-3.7 (5H), 3.36 (s, 3H), 2.48 (d , J = 7.5 Hz, 3H) (t, J = 5.7 Hz, 2H), 3.40-3.70 (9H), 3.37 (s, 3H), 2.65 (m, 1H), 2.57 (m, 1H), 1.6-2.0 (8H), 1.51 (S, 9H), 1.38 (d, J = 6.6 Hz, 3H), 1.0-1.4 (4H) ppm. [00263] F. tert-butyl ester of 2- (6-Fluoro-l-. {2- [2- (2-methoxy-ethoxy) -ethoxy] -ethyl} -yl-indole-3- acid ilmetil) -2. S'-pyrrolidone-l-carboxylic (85): A solution of 84 (188 mg, 0.28 mmol) in DCM (5 mL) is treated with TFA (1 mL) at room temperature. After 2 hours, the reaction mixture is concentrated, diluted with EtOAc, washed with aqueous NaOH and brine, dried over Na 2 SO 4, filtered and concentrated. The residue is purified by HPLC to yield 110 mg (65%) 85 acetate salt as a white solid. [TLC (20% MeOH in EtOAc): Rf (85) = 0.20)]. ¾ NMR (CDC13, 300 MHz) d 7.79 (br d, 2 H), 7.34 (d, J = 7.2 Hz, 1H), 7.21 (m, 1H), 7.10 (m, 1H), 6.96 (d, J = 9.0 Hz, 1H), 6.23 (br s, 2H), 4.61 (m, 1H), 4.44 (m, 1H) , 4.24 (t, J = . 4 Hz, 2H), 3.78 (t, J = 5.4 Hz, 2H), 3.4-3.8 (12H), 3.36 (s, 3H), 2.60 (m, lH), 2.48 (d, J = 7.5 Hz, 3H) , 1.6-2.0 (8H), 1.39 (d, J = 6.6 Hz, 3H), 1.0-1.4 (4H) ppm. Mass spectrum, m / z 571.3 [M + H] +.

(E16) Table 16.

[00264] Although the present invention has been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible. Therefore the spirit and scope of the appended claims will not be limited to the description and preferred versions contained within this specification.

Claims (30)

1. CLAIMS 1. A composition comprising: molecules and their pharmaceutically acceptable salts having the structure of formula (2): wherein: Ai and A2 are independently hydrogen, alkyl, aryl or alkylaryl group, Rla is H or a methyl group; Rlb is an alkyl or aryl group; Xi is a group -0-, -S-, -C¾-, or -NH- and J is a group -CH-, or -N-, provided that when J is -N-, ?? is the group -CH2-, or -NH-; Y is H, or an alkyl group; Z is a group -OH, aryloxy, alkoxy, benzyloxy, benzyloxy, amino, arylamino, alkylamino, benzylamino; R2 is a detectable label or is: M is an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene group, G is chosen from a bond, -0-; -N (R2d) - wherein R2a is H, alkyl, cycloalkyl or aryl; or -S (0) m- where m is 0, 1, or 2; and Rio is cycloalkyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl; n independently is the integer 0, 1, 2, 3, 4, or 5.
2. 2. The composition according to claim 1, and a pharmaceutically acceptable carrier.
3. 3. A composition characterized in that it comprises: molecules and their pharmaceutically acceptable salts having the structure of formula (3): where ?? is H, lower alkyl group, or optionally substituted lower alkyl; Rla and Rlb are separately H, lower alkyl group, optionally substituted lower alkyl, lower alkylene, optionally substituted lower alkenylene; or Ai together with either Ria or Rib, form an optionally-substituted heterocycloalkyl group with 3 to 6 atoms; Y is H, an alkyl group, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, aryl, heteroaryl, arylalkyl, optionally-substituted versions of these groups, substituted hydroxy versions of these groups, or Y together with Z, M, G, or Rio form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Y is linked to Z, M, G or R10; Z is H, an alkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, cycloalkyloxy, aryl, heteroaryl, aryloxy or heteroaryloxy group; or Z together with Y, M, G or Ri0 form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Z is linked to Y, M, G or R10; M is an optionally substituted alkyl, alkenyl, or alkynyl group; an alkyl, alkenyl or alkynyl group optionally substituted with 1 to 5 carbon atoms; an optionally substituted alkylene, alkenylene or alkynylene group; or an optionally substituted alkylene, alkenylene or alkynylene group with 1 to 5 carbon atoms; G is a bond, a heteroatom, - (C = 0) -; -S (0) t- where t = 0, 1, or 2; -NRi8-; -NCOR18-; or -NS (0) xR18- wherein x = 0, 1, or 2, and Ri8 is lower alkyl, optionally substituted lower alkyl or cycloalkyl or Ris is contained within a carbocyclic or heterocyclic ring containing 1 to 5 heteroatoms, where Laugh is linked to Z, M, or Ri0; Rio is an aryl group, heteroaryl, a fused aryl, a fused heteroaryl group; or Rio is any of the structures (4a), (4b), (4c) or (4d): (4b) (4c) (4d) wherein X2 is a heteroatom and independently groups R11, R'n, R12, any of R13-1-7, or any of Ri4-i7 is H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently Rn, R'n, R12, any of Ri3-i7, or any of Ri4_i7 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or heteroaryloxy optionally replaced; or independently Rn, R'n, Ri2, any of R13-17, or any of R1-17 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups Rn, R ', i2 either of RI3-17A or any of Ri_i7 is contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups in the Y, Z, M, G position , Rn, R'n, R12, any of R13-1-7, or any of Ri4-i7.
4. 4. The composition according to claim 3, and a pharmaceutically acceptable carrier.
5. 5. A composition characterized in that it comprises: molecules and their pharmaceutically acceptable salts having the structure of formula (3): where ?? is H, lower alkyl group, or optionally substituted lower alkyl; Ria and Ri are separately H, lower alkyl group, optionally substituted lower alkyl, lower alkylene, optionally substituted lower alkenylene; or Ai together with either Rla or Rib, form an optionally-substituted heterocycloalkyl group with 3 to 6 atoms; Y is H, an alkyl group, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, aryl, heteroaryl, arylalkyl, optionally-substituted versions of these groups, substituted hydroxy versions of these groups, or Y together with Z, M, G, or Rio form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Y is linked to Z, M, G or Ri0; Z is H, an alkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, cycloalkyloxy, aryl, heteroaryl, aryloxy or heteroaryloxy group; or Z together with Y, M, G or Ri0 form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Z is linked to Y, M, G or RÍO; M is an optionally substituted alkyl, alkenyl, or alkynyl group; an alkyl, alkenyl or alkynyl group optionally substituted with 1 to 5 carbon atoms; an optionally substituted alkylene, alkenylene or alkynylene group; or an optionally substituted alkylene, alkenylene or alkynylene group with 1 to 5 carbon atoms; G is a bond, a heteroatom, - (C = 0) -; -S (0) t- where t = 0, 1, or 2; -NR18-; -NC0Ri8-; or -NS (0) xRi8- wherein x = 0, 1, or 2, and Ris is lower alkyl, optionally substituted lower alkyl or cycloalkyl or Rig is contained within a carbocyclic or heterocyclic ring containing 1 to 5 heteroatoms, where Ris is linked to Z,, or Rio; Rio is any of the structures (4a), (4b), (4c) or (4d): (4a) (4b) (4c) (4d) wherein X2 is a heteroatom and independently groups Ru, R'n, R12, any of Ri3-i7, or any of Ri4-i7 is H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently Ru, R'n, Ri2, any of R13-17, or any of Ri4-i7 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or optionally substituted heteroaryloxy; or independently Rn, R'n, R12, any of Ri3-i7, or any of R14-17 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups Rn, R'n, any of Ri3-i7r or any of Ri4_i7 is contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups in the position Y, Z, M, G, Rn, R'n, R12, either of Ri3-i7r or any of i4_i7.
6. 6. The composition according to claim 5, and a pharmaceutically acceptable carrier.
7. 7. A composition comprising: molecules and their pharmaceutically acceptable salts having the general structure of the formula (5) (5) where? is H, or lower alkyl, or Ai and Rib together form a ring of 3 to 5 atoms; Ria is H; Rib is lower alkyl group, or together with Ai form a ring of 3 to 5 atoms; Y is an alkyl group, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of these groups, substituted hydroxy versions of these groups, or Y together with Zla, Z ib or Rio forms a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Y is linked to Z ia, Z ib, or Ri0; Z ia and ib are independently an H, or hydroxy, amino, alkylamino, dialkylamino, alkoxy, aryloxy, heteroaryloxy group; or Zia, Z ib, together with Y or Rio forms a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, where Zla or Zib, is linked to Y or Ri0; M is an optionally substituted alkyl group or optionally substituted alkylene of 1 to 5 carbon atoms; G is a bond, a hetero atom, (C = 0); NRi8; NCORig; or NS (0) xRi8 where x-0, 1, or 2, and Ri8 is a lower alkyl group, optionally substituted lower alkyl; Rio is an aryl, heteroaryl, or Rio group is any of structures (4a), (4b), (4c) or (4d): wherein X2 is a heteroatom and independently groups Rii R 'ii / - Ri2f any of R13-17, or any of R14-17 is H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino , alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently Rn, R'n, R12, any of Ri3-i7, or any of 14-17 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or optionally substituted heteroaryloxy; or independently Rn, R 'n, R12, any of Ri3_i7, or any of Ri4_i7 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups Rn, R 'n, R12, any of Ri3-i7 or any of Ri4-i7 is contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups in the Y, Z position ,, G, Rn, R'n, R12, any of R13-17, or any of Ri4-i7.
8. 8. The composition according to claim 7, characterized in that it has a Kd for IAP of less than about 1 micro molar.
9. 9. The composition according to claim 7, characterized in that Ai is H, methyl, or ethyl.
10. The composition according to claim 7, characterized in that Ria is H; Rib is a methyl or ethyl group.
11. The composition according to claim 7, characterized in that Y is an alkyl group of 1 to 10 carbon atoms, a branched alkyl group of 1 to 10 carbon atoms, an alkynyl group, a cycloalkyl group of 3 to 7 atoms carbon, optionally substituted versions of these groups, substituted hydroxy versions of these groups.
12. The composition according to claim 7, characterized in that Zla and Zib are independently H, a hydroxy, amino, alkylamino, dialkylamino, alkoxy, aryloxy, or heteroaryloxy group.
13. The composition according to claim 7 characterized in that M is an alkyl group or an alkylene of 1 to 5 carbon atoms.
14. 14. The composition according to claim 7 wherein Rio is: and R3, R '3, R4, R5, R'5, each independently are H, or alkyl, cycloalkyl, alkylene, aryl, heteroaryl, alkoxy optionally substituted alkyl, cycloalkyl, alkylene, aryl, heteroaryl, halo, cyano, (CH2) PC (= 0) 0H, (CH2) PC (= 0) 0 alkyl, or (CH2) PC (= 0) NH2 and wherein p independently is the integer 0, 1, 2, or 3.
15. 15. composition according to claims 7, 8, 9, 10, 11, and 12 characterized in that io is any of structures (4a), (4b), (4c) or (4d): wherein X2 is a heteroatom and independently Riif R'iif ¾2 groups either of R13-1-7, or any of Ri -i7 is H, halogen, alkyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino , dialkylamino, alkyloxyalkyl, aryloxy or heteroaryloxy; independently Ru, R'n, Ri2r any of Ri3-i7, or any of R1 -1-7 is H, alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or optionally substituted heteroaryloxy; or independently Ru, R'n, i2r any of Ri3-i7, or any of R14-17 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups.
16. 16. The composition according to claim 7, characterized in that R10 has the structure of formula (4a): wherein X2 is a heteroatom and independently the groups u, R12, or any of R14-17 is H, or optional substituents including halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, alkyloxyalkyl , sulfonate, aryloxy or heteroaryloxy independently Ru, R12r or any of R14-17 are H, optionally substituted alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy; independently Ru, R ', R12, or any of Ri4-i7 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups.
17. 17. The composition according to claim 7, characterized in that it has a Kd for IAP of less than about 0.1 micro molar.
18. 18. The composition according to claim 7, and a pharmaceutically acceptable carrier.
19. 19. Method for treating cells, characterized in that it comprises: administering to cells having a proliferation disorder, an amount of IAP binding compound of claims 3 or 5 that reduces the cell proliferation disorder in the cell sample.
20. 20. The method according to claim 19, characterized in that the IAP linking compound has EC50 less than about 1 micro-molar.
21. 21. The method according to claim 19, characterized in that the IAP linking compound has EC50 less than about 0.06 micro molar.
22. 22. The method according to claim 21, characterized in that the compound has a Kd for LAP less than about 0.1 micro molar.
23. 23. A compound of the formula (2): m wherein: Ai and A2 are hydrogen, an alkyl, aryl or alkylaryl group, Rla can be H or a methyl group; Rlb is an alkyl or aryl group; Xi can be a group -0-, -S-, -CH2-, or -NH-, and J is a group -CH-, or -N-, provided that when J is -N-, Xi is -C¾- , or a group -NH-; Y is H, or an alkyl group; Z is H, a group -OH, aryloxy, alkoxy, benzyloxy, amino, arylamino, alkylamino, benzylamino; R2 is a detectable label or is: M is alkylene, alkenylene, alkylenlene, heteroalkylene, heteroalkenylene, or heteroalquinlene group, G is chosen from a bond, 0; N (R2ci) wherein R2ci is H, alkyl, cycloalkyl, or aryl; or S (0) n, where m is 0, 1, or 2; Rio is cycloalkyl, aryl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl; n is independently the integer 0, 1, 2, 3, 4, or 5.
24. 24. A compound of the formula (3): where ?? is H, lower alkyl group, or optionally substituted lower alkyl; Ria and Rlb are separately H, lower alkyl group, optionally substituted lower alkyl, lower alkylene, optionally substituted lower alkenylene; or Ai together with either Ria or Rlb, form an optionally-substituted heterocycloalkyl group with 3 to 6 atoms; Y is H, an alkyl group, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, aryl, heteroaryl, arylalkyl, optionally-substituted versions of these groups, substituted hydroxy versions of these groups, or? together with Z, M, G, or Rio form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Y is linked to Z, M, G or Ri0; Z is H, an alkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, cycloalkyloxy, aryl, heteroaryl, aryloxy or heteroaryloxy group; or Z together with Y, M, G or Rio form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Z is linked to Y, M, G or Ri0; M is an optionally substituted alkyl, alkenyl, or alkynyl group; an alkyl, alkenyl or alkynyl group optionally substituted with 1 to 5 carbon atoms; an optionally substituted alkylene, alkenylene or alkynylene group; or an optionally substituted alkylene, alkenylene or alkynylene group with 1 to 5 carbon atoms; G is a bond, a heteroatom, - (C = 0) -; -S (0) t- where t = 0, 1, or 2; - Ri8-; -NCO 18-; or -NS (0) xRi8- wherein x = 0, 1, or 2, and Ris is lower alkyl, optionally substituted lower alkyl or cycloalkyl or Ri8 is contained within a carbocyclic or heterocyclic ring containing 1 to 5 heteroatoms, where Ris is linked to Z, M, or i0; Rio is an aryl group, heteroaryl, a fused aryl, a fused heteroaryl group; or Rio is any of the structures (4a), (4b), (4c) or (4d): wherein X2 is a heteroatom and independently groups Rii? '? /? Ri2f any of R13-.17, or any of Ri-i7 is H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether , amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently Ru, R'n, R12, any of i3-i7, or any of Ri-n is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or optionally substituted heteroaryloxy; or independently Ru, R'u, R12, any of R13-17, or any of R14-17 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups R, R'u, R12, any of R13-17 / or any of R14-17 is contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups in the Y position, Z, M, G, Ru, R'u, R12, either of Ri3_i7, or any of R1 -17.
25. 25. A compound of the formula where ?? is H, lower alkyl group, or optionally substituted lower alkyl; Rla and Rlb are separately H, lower alkyl group, optionally substituted lower alkyl, lower alkylene, optionally substituted lower alkenylene; or together with either Ria or Rib, form an optionally-substituted heterocycloalkyl group with 3 to 6 atoms; Y is H, an alkyl group, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, aryl, heteroaryl, arylalkyl, optionally-substituted versions of these groups, substituted hydroxy versions of these groups, or Y together with Z, , G, or Rio form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Y is linked to Z, M, G or Rio Z is H, an alkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, cycloalkyloxy, aryl, heteroaryl, aryloxy or heteroaryloxy; or Z together with Y, M, G or Ri0 form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Z is linked to Y, M, G or Rio M is an alkyl, alkenyl, or alkynyl group optionally substituted; an alkyl, alkenyl or alkynyl group optionally substituted with 1 to 5 carbon atoms; an optionally substituted alkylene, alkenylene or alkynylene group; or an optionally substituted alkylene, alkenylene or alkynylene group with 1 to 5 carbon atoms; G is a bond, a heteroatom, - (C = 0) -; -S (0) t- where t = 0, 1, or 2; - Ri8-; -NC0R18-; or -NS (0) xR18- wherein x = 0, 1, or 2, and R18 is lower alkyl, optionally substituted lower alkyl or cycloalkyl or R18 is contained within a carbocyclic or heterocyclic ring containing 1 to 5 heteroatoms, where Laugh is linked to Z, M, or Ri0; Rio is any of the structures (4a), (4b), (4c) or (4d): wherein X2 is a heteroatom and independently groups R11, R'n, ¾2 either of Ri3-i7, or any of Ri-i7 is H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino , alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently Rn, R'n, R12, any of R13-17, or any of R14-1-7 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, optionally substituted aryloxy or heteroaryloxy; or independently Rn, R'n, R12, any of Ri3-i7, or any of Ri-i7 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups Rn, R'n, R12, any of Ri3-i7 or any of R14-17 is contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups in the Y, Z position , M, G, Rn, R'n, R12, any of Ri3-i7, or any of Ri4-i7.
26. 26. A compound of the formula (5) wherein Ai is H, or lower alkyl, or Ai and Rib together form a ring of 3 to 5 atoms; Ria is H; Rib is lower alkyl group, or together with Ai form a ring of 3 to 5 atoms; Y is an alkyl group, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of these groups, substituted hydroxy versions of these groups, or Y together with Zia, Zib or Rio forms a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Y is linked to Zia, ib, or Rio; Zia and ib are independently an H, or hydroxy, amino, alkylamino, dialkylamino, alkoxy, aryloxy, heteroaryloxy group; or Zia, Zib, together with Y or Ri0 forms a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, wherein Zaa or Zib, is linked to Y or Rio; M is an optionally substituted alkyl group or optionally substituted alkylene of 1 to 5 carbon atoms; G is a link, a heteroatom, (C = 0); NRi8; NCOR18; or NS (0) xRi8 where x = 0, 1, or 2, and Ris is a lower alkyl group, optionally substituted lower alkyl; Rio is an aryl group, heteroaryl, or Rio is any of the 'structures (4a), (4b), (4c) or (4d): wherein X2 is a heteroatom and independently groups iif 'iif R12, any of Ri3-i, or any of Ri4-i7 is H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino , dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently ¾i, R'n, Ri2r any of R13-17, or any of Ri4-i7 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or heteroaryloxy optionally substituted; or independently Ru, R'u, Ri2, any of Ri3-n, or any of R14-17 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups Ru, R'u, Ri2r any of I3-I7A or any of R14-17 is contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups in the Y, Z position, M, G, Ru, R'u, R12, any of R13-17, or any of R14-17.
27. 27. A compound of the general formula (5) wherein Ai is H, or lower alkyl; Ria is H; Rib is a lower alkyl group; Y is an alkyl group, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of these groups, substituted hydroxy versions of these groups; Zia and Zib are independently H, a hydroxy, alkoxy, aryloxy, or heteroaryloxy group; M is an optionally substituted alkyl group or optionally substituted alkylene of 1 to 5 carbon atoms; G is a bond, a heteroatom, or NCORie and íe is a lower alkyl group, optionally substituted lower alkyl; R10 is any of structures (4a), (4b), (4c) or (4d): wherein X2 is a heteroatom and independently groups Rii R'ii i2 any of R13-17, or any of R14-17 is H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino , dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently Rn, R'11, Ri2r any of R13-17, or any of R14-1-7 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or optionally substituted heteroaryloxy; independently Ru, R'u, R12, any of Ri3-i, or any of R1-17 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups ¾a, R'u, Ri2r either of R13-17 / or any of Ri4_i7 is contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups in the Y, Z, M position , G, Ru, R'u, R12, any of R13-17, or any of R1 -17.
28. 28. A compound of the formula (5) where ?? is H, or methyl; Rla is H; Rib is methyl or ethyl; Y is an alkyl group, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of these groups, or substituted hydroxy versions of these groups; Zla and Zlb are independently H, a hydroxy group, or alkoxy; M is a wherein X2 is a heteroatom and independently groups Rii / R'iif any of R13-17, or any of R14-.17 is H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently Rn, R'n, R12 / any of R13-17, or any of R14-17 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or optionally substituted heteroaryloxy; independently Ru, R'11, R12, any of R13-17, or any of R14-17 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups Ru, R'ii, Ri2r any of ¾3-? 7 / · or any of Ri4-i7 is contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups in the Y position , Z, M, G, Ru, R ', R12, any of Ri3_i7, or any of R14-17.
29. 29. The compound of Formula (5) according to claim 28, characterized in that Rio is:
30. 30. The compound of Formula (5) according to claim 28, characterized in that X2 is nitrogen.