MXPA06011583A - Inhibitors of iap - Google Patents

Abstract

Novel compounds that inhibit the binding of the Smac protein to Inhibitor of Apoptosis Proteins (IAPs) of the formula (I).

Description

INHIBITORS OF APOPTOSIS PROTEINS (1AP) The present invention relates in general to novel compounds that inhibit the binding of the Smac protein to the Apoptosis Protein Inhibitor (IAP). The present invention includes novel compounds, novel compositions, methods for their use, and methods for their manufacture, wherein these compounds are in general! pharmacologically useful as agents in therapies whose mechanism of action relies on the inhibition of Smac / IAP interaction, and more particularly useful in therapies for the treatment of proliferative diseases, including cancer.

BACKGROUND Programmed cell death plays a critical role in regulating the number of cells and eliminating stressed or damaged cells from normal tissues. In fact, the network of apoptotic signaling mechanisms inherent in most types of cells provides a major barrier to the development and progress of human cancer. Because the radiation and most commonly used chemotherapies rely on activation of apoptotic pathways to kill cancer cells, tumor cells that are able to evade programmed cell death often become resistant to treatment. Apoptosis signaling networks are classified as intrinsic when mediated by death-ligand receptor interactions, or as extrinsic when mediated by cellular stress and mitochondrial permeabilization. Both paths finally converge in the individual Caspasas. Once activated, the Caspasas dissociate a number of substrates related to cell death, effecting the destruction of the cell. Tumor cells have devised a number of strategies to circumvent apoptosis. A recently reported molecular mechanism involves the over-expression of members of the IAP (Apoptosis Inhibitor) family of proteins. Inhibitors of apoptosis proteins sabotage apoptosis through their direct interaction with, and neutralization of, Caspases. Inhibitors of prototype apoptosis proteins, XIAP and clAP, have three functional domains referred to as BIR domains 1, 2 and 3. The BIR3 domain interacts directly with Caspase 9, and inhibits its ability to bind and dissociate its natural substrate, Procaspase 3. It has been reported that a pro-apoptotic mitochondrial protein, Smac (also known as DIABLO) , is able to neutralize LIAP and / or clAP through its linkage with a peptide binding pocket (Smac binding site) on the surface of BIR3, thereby precluding the interaction between XIAP and / or clAP and Caspase 9. The present invention relates to to therapeutic molecules that bind to the binding pocket of Smac, thereby promoting apoptosis in rapidly dividing cells. These therapeutic molecules are useful for the treatment of proliferative diseases, including cancer. In other words, Smac analogs would bind to the BIR3 domain of apoptosis protein inhibitors, and remove the inhibition of apoptosis inhibitors of activated Caspase 9, which would then go on to induce apoptosis.

Brief Description of the Invention The present invention relates in general to novel compounds that inhibit the binding of the Smac protein to the Apoptosis Protein Inhibitor (IAP). The present invention includes novel compounds, novel compositions, methods for their use, and methods for their manufacture, wherein these compounds are in general pharmacologically useful as agents in therapies whose mechanism of action is based on the inhibition of Smac / IAP interaction. , and more particularly useful in therapies for the treatment of proliferative diseases, including cancer.

DETAILED DESCRIPTION The present invention relates to compounds of the formula (I): (l) where: Ri is H; alkyl of 1 to 4 carbon atoms; alkenyl of 1 to 4 carbon atoms; alkynyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 10 carbon atoms, which are unsubstituted or substituted; R2 is H; alkyl of 1 to 4 carbon atoms; alkenyl of 1 to 4 carbon atoms; alkynyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 10 carbon atoms, which are unsubstituted or substituted; R3 is H; -CF3; -C2F5; alkyl of 1 to 4 carbon atoms; alkenyl of 1 to 4 carbon atoms; alkynyl of 1 to 4 carbon atoms; -CH2-Z; or R2 and 3, together with nitrogen, form a ring het; Z is H; -OH; F; Cl; -CH3; -CH2CI; -CH2F, or -CH2OH; R 4 is straight or branched alkyl of 1 to 16 carbon atoms; alkenyl of 1 to 16 carbon atoms; alkynyl of 1 to 16 carbon atoms; or cycloalkyl of 3 to 10 carbon atoms; - (CH2)? - 6-Z ?; -CH2) 0-6-aryl; and - (CH2) 0.6-het; wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted; Z-i is -N (R8) -C (O) -alkyl of 1 to 10 carbon atoms; - N (R8) -C (O) - (CH2) 1,6-cycloalkyl of 3 to 7 carbon atoms; -N (R8) -C (O) - (CH2) 0.-phenyl; -N (R8) -C (O) - (CH2) 1.6-het; -C (O) -N (R9) (R10); -C (O) -O-alkyl of 1 to 10 carbon atoms; -C (O) -O- (CH 2) 1,6-cycloalkyl of 3 to 7 carbon atoms; -C (O) -O- (CH2) 0-6-phenyl; -C (O) -O- (CH2) 1.6-het; -O-C (O) -alkyl of 1 to 10 carbon atoms; - O-C (O) - (CH 2) 1,6-cycloalkyl of 3 to 7 carbon atoms; -O-C (O) - (CH2) 0-6-phenyl; -O-C (O) - (CH2)? 6-het; wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted; het is a 5 to 7 membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, and S, or a fused ring system of 8 to 12 members, including at least one heterocyclic ring of 5 to 7 members containing 1, 2, or 3 heteroatoms selected from N, O, and S, whose heterocyclic ring or fused ring system is unsubstituted or substituted on a carbon or nitrogen atom; R8 is H; -CH3; -CF3; -CH2OH, or -CH2C !; R9 and Rio are each independently H; alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms; - (CH2) -. 6-cycloalkyl of 3 to 7 carbon atoms; - (CH2) 0-6-fsnyl; wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted, or Rg and R10, together with nitrogen, form het; R5 is H; alkyl of 1 to 10 carbon atoms; ariio; phenyl; cycloalkyl of 3 to 7 carbon atoms; - (CH2) 0-6-phenyl; - (CH2) 0. 4CH - ((CH2) 1_4-phenyl) 2; - (CH2) 0-6-CH (phenyl!) 2; -indanilo; -C (O) -alkyl of 1 to 10 carbon atoms; -C (O) - (CH 2) 1,6-cycloalkyl of 3 to 7 carbon atoms; -C (O) - (CH2) 0.6-phenyle; - (CH2) o -6-C (O) -phenyl; - (CH2) 0_6-het; -C (0) - (CH2) -? _ 6-het; or R5 is a residue of an amino acid, wherein the substituents of alkyl, cycloalkyl, phenyl, and aryl are unsubstituted or substituted; U is as shown in structure II: where: n = 0 to 5; X is -CH or N; Ra and Rb are independently an atom of O, S, or N, or alkyl of 0 to 8 carbon atoms, wherein one or more of the carbon atoms in the alkyl chain can be replaced by a heteroatom selected from O, S, or N, and wherein the alkyl may be unsubstituted or substituted; Rd is selected from: (a) -Re-Q - (Rf) p (Rg) q; or (b) Ar! - D - Ar2; Rc is H, or Rc and Rd can together form a cycloalkyl or het; wherein, if Rd and Rc form a cycloalkyl or het, R5 is attached to the ring formed at a C or N atom; p and q are independently 0 or 1; Re is alkyl of 1 to 8 carbon atoms or alkylidene, and Re may be unsubstituted or substituted; Q is N, O, S, S (O), or S (O) 2; Ar-i and Ar2 are substituted or unsubstituted aryl, or het; Rf and Rg are each independently H; alkyl of 1 to 10 carbon atoms; alkyl of 1 to 10 carbon atoms-aryl; -OH; - O-alkyl of 1 to 10 carbon atoms; - (CH2) 0.6-cycloalkyl of 3 to 7 carbon atoms; -O- (CH2) 0.6-aryl; phenyl; aril; phenyl-phenyl; - (CH2) 1.6-het; -O- (CH2) 1.6-het; -OR ,,; -C (O) -R11; -C (O) -N (Rn) (R12); -N (Rn) (R12); -S-Rn; -S (O) -R? -S (O) 2R1 ?; -S (O) 2-NR 11 R 12; -NR? R S (O) 2 -R12; S-alkyl of 1 to 10 carbon atoms; aryl-alkyl of 1 to 4 carbon atoms; het-alkyl of 1 to 4 carbon atoms, wherein alkyl, cycloalkyl, het, and aryl are unsubstituted or substituted; -SO 2 -alkyl of 1 to 2 carbon atoms; -SO 2 -alkyl of 1 to 2 carbon atoms-phenyl; -O-alkyl of 1 to 4 carbon atoms; or Rg and Rf form a ring selected from het or aryl; D is -CO-; -C (O) -alkylene of 1 to 7 carbon atoms or arylene; -CF2-; -OR-; -S (O) r, where r is from 0 to 2; 1,3-dioxolane; or alkyl of 1 to 7 carbon atoms-OH; wherein alkyl, alkylene, or arylene may be unsubstituted or substituted with one or more halogens, OH, -O-alkyl of 1 to 6 carbon atoms, -S-alkyl of 1 to 6 carbon atoms, or -CF3; or D is -N (Rh), where Rh is H; alkyl of 1 to 7 carbon atoms (unsubstituted or substituted); aril; -O- (cycloalkyl of 1 to 7 carbon atoms) (unsubstituted or substituted); C (O) -alkyl of 1 to 10 carbon atoms; C (O) -alkyl of 0 to 10 carbon atoms-aryl; C-O-alkyl of 1 to 10 carbon atoms; C-O-alkyl of 0 to 10 carbon atoms-aryl, or S02-alkoyl of 1 to 10 carbon atoms; SO2- (alkyl of 0 to 10 carbon atoms-aryl); R6, R7, R'6, and R'7 are each independently H; -alkyl of 1 to 10 carbon atoms; -alkoxyl of 1 to 10 carbon atoms; aryl-alkoxy of 1 to 10 carbon atoms; -OH; -O-alkyl of 1 to 10 carbon atoms; - (CH2) 0.6-cycloalkyl of 3 to 7 carbon atoms; -O- (CH2) 0.e-aryl; phenyl; - (CH2) 1.6- et; -O- (CH2) -, 6-het; -OR "; -C (O) R? -C (O) -N (R11) (R12); -N (R11) (R12); -MR? -S (O) -R11; - S (O) 2-Rn; -S (O) 2-NR 11 R 12; -NRn-S (O) 2-R 12; wherein alkyl, cycloalkyl, and aryl are unsubstituted or substituted; and R6, R7, M and R'7 can be joined to form a ring system; R11 and R12 are independently H; alkyl of 1 to 10 carbon atoms; - (CH2) 0.6-cycloalkyl of 3 to 7 carbon atoms; - (CH2) o-6- (CHo -? (Aryl)? _ 2; -C (O) -alkyl of 1 to 10 carbon atoms; -C (O) - (CH2) 1.6-cycloalkyl of 3 to 7 atoms carbon; -C (O) -O- (CH2) oe-aryl; -C (O) - (CH2) 0-6-O-fluorenyl; -C (O) -NH- (CH2) 0.6-aryl; -C (O) - (CH2) 0.6-aryl; -C (O) - (CH2) 1.6-het; -C (S) -alkyl of 1 to 10 carbon atoms; -C (S) - (CH2) 1.6-cycloalkyl of 3 to 7 carbon atoms; -C (S) -O- (CH2) o-β-aryl; -C (S) - (CH2) o -6-O-fluorenyl; -C (S) -NH- (CH2) o -6-aryl; -C (S) - (CH2) 0-ß-aryl; -C (S) - (CH2)? 6-het; wherein alkyl, cycloalkyl, and aryl are unsubstituted or substituted, or R], and R12 are a substituent that facilitates the transport of the molecule through a cell membrane, or RM and R12, together with the nitrogen atom, form het; R ^ and R12 may be unsubstituted or substituted by one or more substituents selected from alkyl of 1 to 10 carbon atoms, halogen, OH, -O-alkyl of 1 to 6 carbon atoms, -S-alkyl of 1 to 6 carbon atoms or, or -CF3: the substituted cycloalkyl substituents of R ^ and R12 are substituted by one or more substituents selected from alkene of 1 to 10 carbon atoms; alkyl of 1 to 6 carbon atoms; halogen; OH; -O-alkyl of 1 to 6 carbon atoms; -S-alkyl of 1 to 6 carbon atoms, or -CF3; and substituted phenyl or aryl of R-n and R 2 are substituted by one or more substituents selected from halogen; hydroxyl; alkyl of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; nitro; -CN; -O-C (O) -alkyl of 1 to 4 carbon atoms, and -C (O) -O-aryl of 1 to 4 carbon atoms; or pharmaceutically acceptable salts thereof. The present invention also relates to the use of a compound of the formula I in the treatment of proliferative diseases, especially those that depend on the binding of the Smac protein to the Apoptosis Protein Inhibitor (IAP), or for the manufacture of pharmaceutical compositions to be used in the treatment of these diseases; to methods of using the compounds of the formula (I) in the treatment of the above-mentioned diseases, to pharmaceutical preparations comprising compounds of the formula (I) for the treatment of said diseases, to compounds of the formula (I) for use in the treatment of these diseases. The general terms used hereinbefore and hereinafter, preferably have, within the context of this disclosure, the following meanings, unless otherwise indicated: "Aryl" is an aromatic radical having 6 to 14 carbon atoms, which may be fused or non-fused, and which is unsubstituted or substituted by one or more, preferably one or two substituents, wherein the substituents are as described below. The preferred "aryl" is phenyl, naphthyl, or adenyl. "Het" refers to heteroaryl and heterocyclic rings and fused rings containing aromatic and non-aromatic heterocyclic rings. "Het" is a 5- to 7-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O, and S, or a fused ring system of 8 to 12 members that includes at least one heterocyclic ring of 5. to 7 members, containing 1, 2, or 3 heteroatoms selected from N, O, and S. Suitable substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphino, 1,3-diazapane, , 4-diazapane, 1,4-oxazepane, 1,4-oxathiapane, furyl, thienyl, pyrrole, pyrazole, triazole, 1,2,3-triazole, tetrazolyl, oxadiazole, thiophene, imidazole, pyrrolidine, pyrrolidone, thiazole, oxazole pyridine, pyrimidine, isoxazolyl, pyrazine, quinoline, isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine, indole, benzofuran, benzothio-furan, benzolol, benzoxazole, pyrroloquinoline, and the like, unsubstituted and substituted. Het substituents are unsubstituted or substituted on a carbon atom by halogen, especially fluorine or chlorine, hydroxyl, alkyl of 1 to 4 carbon atoms, such as methyl and ethyl, alkoxy of 1 to 4 carbon atoms, especially methoxy and ethoxy, nitro, -OC (O) -alkyl of 1 to 4 carbon atoms, or -C (O) -O-alkyl of 1 to 4 carbon atoms, or on a nitrogen for alkyl of 1 to 4 carbon atoms. carbon, especially methyl or ethyl, -OC (O) -alkyl of 1 to 4 carbon atoms, or -C (O) -O-alkyl of 1 to 4 carbon atoms, such as carbomethoxy or carboethoxy. When two substituents, together with a commonly linked nitrogen, are het, it is understood that the resulting heterocyclic ring is a nitrogen-containing ring, such as aziridine, azetidine, azole, piperidine, piperazine, morphillin, pyrrole, pyrazole, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, and the like. Halogen is fluorine, chlorine, bromine, or iodine, especially fluorine or chlorine. Unless otherwise specified, "alkyl" includes straight or branched chain alkyl, such as methyl, ethyl, normal propyl, isopropyl, normal butyl, secondary butyl, tertiary butyl, normal pentyl and branched pentyl, normal hexyl and hexyl branched, and similar. A "cycloalkyl" group means cycloalkyl of 3 to 10 carbon atoms having from 3 to 8 ring carbon atoms, and may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. Preferably, cycloalkyl is cycloheptyl. The cycloalkyl group may be unsubstituted or substituted with any of the substituents defined below, preferably halogen, hydroxyl, or alkyl of 1 to 4 carbon atoms, such as methyl. The amino acid residues include a residue of a conventional amino acid, such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. Amino acid residues also include the side chains of non-common and modified amino acids. Uncommon and modified amino acids are known to those skilled in the art (see, for example, G. B. Fields, Z. Tiam, and G. Barany; Synthetic Peptides A Users Guide, University of Wisconsin Biochemistry Center, Chapter 3 (1992)), and include amino acids such as 4-hydroxyproline, 5-hydroxylysine, desmosine, beta-alanine, alpha-, gamma-, and beta-aminobutyric acid, 2- or 3-aminoisobutyric acid, 2,3-diaminopropionic acid, diphenylalanine, hydroxyproline, and the like. If the side chain of the amino acid residue contains a derivable group, such as COOH, -OH, or amino, the side chain can be derived by a substituent that reacts with the derivable group. For example, acidic amino acids, such as aspartic and glutamic acid, or hydroxy-substituted side chains, such as those of serine or threonine, can be derivatized to form an ester, or the amino side chains can form amide or alkylamino derivatives. In particular, the derivative can be a substituent that facilitates transport through a cell membrane. In addition, any carboxylic acid group in the amino acid residue, for example an alpha-carboxylic acid group, can be derivatized as described above, to form an ester or amide. Substituents that facilitate the transport of the molecule through a cell membrane are known to those skilled in the art of medicinal chemistry (see, for example, Gangewar S., GM Pauletti, Wang B., Siahaan TJ, Stella VJ, Borchardt RT, Drug Discovery Today, Volume 2, pages 148-155 (1997), and Bundgaard H. and Moss J., Pharmaceutical Research, Volume 7, page 885 (1990)). In general terms, these substituents are lipophilic substituents. These hydrophilic substituents include an alkyl of 6 to 30 carbon atoms, which is saturated, mono-unsaturated, polyunsaturated, including polyene interrupted by methylene, phenyl, phenyl which is substituted by one or two alkyl groups of 1 to 8 carbon atoms, cycloalkyl of 5 to 9 carbon atoms, cycloalkyl of 5 to 9 carbon atoms which is substituted by one or two alkyl groups of 1 to 8 carbon atoms, -Xi-phenyl, -Xi-phenyl which is substituted on the phenyl ring by one or two alkyl groups of 1 to 8 carbon atoms, Xi-cycloalkyl of 5 to 9 carbon atoms, or X ^ cycloalkyl of 5 to 9 carbon atoms which is substituted by one or two alkyl groups of 1 to 8 carbon atoms; wherein X ^ is alkyl of 1 to 24 carbon atoms which is saturated, mono-unsaturated, or polyunsaturated, and is straight or branched chain.

Unsubstituted means that the only substituent is hydrogen. Any of the aryl, het, alkyl, cycloalkyl, or heterocyclic groups defined above may be unsubstituted or independently substituted by up to four, preferably one, two, or three substituents, selected from the group consisting of: halogen (such as Cl). or Br); hydroxyl; lower alkyl (such as lower alkyl of 1 to 3 carbon atoms); lower alkyl which may be substituted with any of the substituents defined herein; lower alkenyl; lower alkynyl; lower alkanoyl; alkoxy (such as methoxy); aryl (such as phenyl or benzyl); substituted aryl (such as fluoro-phenyl or methoxy-phenyl); mono- or di-substituted amino; amino-lower alkyl (such as di-methyl-amino); acetyl-amino; amino-lower alkoxy (such as ethoxy-amine); nitro; cyano; cyano-lower alkyl; carboxyl; esterified carboxyl (such as lower alkoxycarbonyl, for example methoxycarbonyl); n-propoxycarbonyl or iso-propoxycarbonyl; alkanoyl; benzoyl; carbamoyl; N-mono- or N, N-di-substituted carbamoyl; carbamates; carbamic acid alkyl esters; amidino, guanidine; urea; ureido; mercapto; sulfo; lower thioalkyl; sulfoamino; sulfonamide; benzosulfonamide; sulfonate; sulfanyl-lower alkyl (such as methyl sulfanyl); sulfoamino; substituted or unsubstituted sulfonamide (such as benzo sulfonamide); substituted or unsubstituted sulfonate (such as chlorophenyl sulfonate); lower alkyl-sulfinyl; phenyl sulfylnyl; phenyl-lower alkyl-sulfinyl; alkyl phenyl sulfinyl; lower alkane sulfonyl; phenyl sulfonyl; phenyl-lower alkyl sulfonyl; alkyl phenyl sulfonyl; halo-lower alkyl mercapto; halo-lower alkyl sulfonyl; such as in particular tri-fluoro-methanesulfonyl; phosphono (-P (= O) (OH) 2); hydroxy-lower alkoxy-phosphoryl or di-lower alkoxy-phosphoryl; substituted urea (such as 3-trifluoromethyl-phenyl-urea); carbamic acid alkyl ester or carbamates (such as ethyl-N-phenyl carbamate) or -NR4R5, wherein R4 and R5 may be the same or different, and are independently H; lower alkyl (e.g., methyl, ethyl, or propyl); or R4 and R5, together with the N atom, form a 3- to 8-membered heterocyclic ring containing from 1 to 4 nitrogen, oxygen, or sulfur atoms (eg, piperazinyl, pyrazinyl, lower alkyl-piperazinyl, pyridyl, indolyl, thiophenyl, thiazolyl, n-methyl-piperazinyl, benzothiophenyl, pyrrolidinyl, piperidino, or imidazolinyl), wherein the heterocyclic ring may be substituted with any of the substituents defined herein. Preferably, the aforementioned alkyl, cycloalkyl, aryl, or het groups may be substituted by halogen, carbonyl, thiol, S (O), S (O 2), -OH, -SH, -OCH 3, -SCH 3, -CN , -SCN, or nitro. When the plural form is used for the compounds, salts, pharmaceutical preparations, diseases, and the like, it is intended that it also means a single compound, salt, or the like. It will be apparent to one skilled in the art that a compound of the invention can exist as a salt form, especially as an acid addition salt or as a base addition salt. When a compound can exist in a salt form, these salt forms are included within the scope of the invention. Although any form of salt may be useful in chemical manipulations, such as purification procedures, only pharmaceutically acceptable salts are useful for pharmaceutical products. The pharmaceutically acceptable salts include, when appropriate, the base addition salts and the pharmaceutically acceptable acid addition salts, for example the metal salts, such as the alkali and alkaline earth metal salts, the ammonium salts, the salts of organic amine addition, amino acid addition salts, and sulfonate salts. The acid addition salts include the inorganic acid addition salts, such as hydrochloride, sulfate and phosphate, and the organic acid addition salts, such as alkyl sulfonate, aryl sulfonate, acetate, maleate, fumarate, tartrate, citrate, and lactate. Examples of the metal salts are the alkali metal salts, such as the lithium salt, the sodium salt, and the potassium salt; the alkaline earth metal salts, such as the magnesium salt and the calcium salt; the aluminum salt, and the zinc salt. Examples of the ammonium salts are the ammonium salt and the tetra-methyl-ammonium salt. Examples of the organic amine addition salts are the salts with morpholine and piperidine. Examples of the addition salts are amino acids are the salts with glycine, phenylalanine, glutamic acid, and lysine. Sulfonate salts include mesylate, tosylate, and benzenesulfonic acid salts. In view of the close relationship between the compounds in free form and those in the form of their salts, including the salts that can be used as intermediates, for example in the purification or identification of the compounds, tautomers or tautomeric mixtures and their salts, any reference to the compounds hereinabove and hereinafter, especially to the compounds of the formula I, should be understood to also refer to the corresponding tautomers of these compounds, especially the compounds of the formula I, the tautomeric mixtures of these compounds, in particular of the compounds of the formula I, or the salts of any of these, as appropriate and convenient and if not mentioned otherwise. Any asymmetric carbon atom may be present in the (R), (S), or (R, S) configuration, preferably in the (R) or (S) configuration. Substituents in a ring, in atoms with saturated bonds, if possible, may be present in the cis (= Z-) or trans (= E-) form. Accordingly, the compounds may be present as mixtures of isomers, or preferably as pure isomers, preferably as pure diastereomers of enantiomers or as pure enantiomers.

Preferred embodiments according to the invention: In the following preferred embodiments, the general expression may be replaced by the corresponding more specific definitions provided above and below, thereby producing stronger preferred embodiments of the invention. The use of the compounds of the formula I or the pharmaceutically acceptable salts thereof is preferred, wherein the disease to be treated is a proliferative disease, depending on the binding of the Smac protein to the Apoptosis Protein (IAP) inhibitor. .

One embodiment of the present invention relates to compounds of the formula (I): where: R-i is H; alkyl of 1 to 4 carbon atoms; 1 to alkenyl 4 carbon atoms; alkynyl of 1 to 4 carbon atoms, or cycloalkyl, which are unsubstituted or substituted by one or more substituents selected from halogen, -OH, -SH, -OCH3, -SCH3, -CH, -SCN, and nitro; R2 is H; alkyl of 1 to 4 carbon atoms; alkenyl from 1 to 4 carbon atoms; alkynyl of 1 to 4 carbon atoms, or cycloalkyl, which are unsubstituted or substituted by one or more substituents selected from halogen, -OH, -SH, -OCH3, -SCH3, -CH, -SCN, and nitro; R3 is H; -CF3; -C2F5; alkyl of 1 to 4 carbon atoms; alkenyl of 1 to 4 carbon atoms; alkynyl of 1 to 4 carbon atoms; -CH2-Z; or R2 and R3, together with nitrogen, form a het; Z is H; -OH; F; Cl; -CH3; -CF3, -CH2Ci; -CH2F, or -CH2OH; R is straight or branched alkyl of 1 to 16 carbon atoms; alkenyl of 1 to 16 carbon atoms; alkynyl of 1 to 16 carbon atoms; or cycloalkyl of 3 to 16 carbon atoms; - (CH2) 1.6-Z1; -CH2) 0-6-phenyl; and - (CH2) 0.6-het; wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted; Z- \ is -N (R8) -C (O) -alkyl of 1 to 10 carbon atoms; -N (R8) -C (O) - (CH2)? -6-cycloalkyl of 3 to 7 carbon atoms; -N (R8) -C (O) - (CH2) 0.-phenyl; -N (R8) -C (0) - (CH2) 1.6-het; -C (O) -N (R9) (R10); -C (O) -O-alkyl of 1 to 10 carbon atoms; -C (O) -O- (CH 2) 1,6-cycloalkyl of 3 to 7 carbon atoms; -C (O) -O- (CH2) 0.6-phenyl; -C (O) -O- (CH2) 1.6-het; -O-C (O) -Alkyl of 1 to 10 carbon atoms; -0-C (O) - (CH2)? _6-cycloalkyl of 3 to 7 carbon atoms; -O-C (O) - (CH2) 0-6-phenyl; -O-C (O) - (CH2) 1.6-het; wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted; het is a 5 to 7 membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, and S, or a fused ring system of 8 to 12 members, including at least one heterocyclic ring of 5 to 7 members containing 1, 2, or 3 heteroatoms selected from N, O, and S, whose heterocyclic ring or fused ring system is unsubstituted or substituted on a carbon atom by halogen, hydroxyl, alkyl of 1 to 4 carbon atoms carbon, alkoxy of 1 to 4 carbon atoms, nitro, -OC (O) -alkyl of 1 to 4 carbon atoms, or -C (O) -O-alkyl of 1 to 4 carbon atoms, or on a nitrogen by alkyl of 1 to 4 carbon atoms, -OC (O) -alkyl of 1 to 4 carbon atoms, or -C (O) -O-alkyl of 1 to 4 carbon atoms; R8 is H; -CH3; -CF3; -CH2OH, or -CH2CI; R9 and R10 are each independently H; alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms; - (CH2) 1. 6-cycloalkyl of 3 to 7 carbon atoms; - (CH2) 0.6-phenyl; wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted, or R9 and Rio, together with nitrogen, form het; R5 is H; alkyl of 1 to 10 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; - (CH2)? 6-cycloalkyl of 3 to 7 carbon atoms; -alkyl of 1 to 10 carbon atoms-aryl; (CH2) 0-6-cycloalkyl of 3 to 7 carbon atoms- (CH2) 0-6-phenyl; - (CH2) 0- CH - ((CH2)? 4-phenyl) 2; - (CH2) 0.6-CH (phenyl) 2; - (CH2) 0-6C (O) -phenyl-indanyl; aryl-C (O) -alkyl of 1 to 10 carbon atoms; -C (0) - (CH 2) 1,6-cycloalkyl of 3 to 7 carbon atoms; -C (O) - (CH2) 0.6-phenyl; - (CH2) or -6-het; -C (O) - (CH2) 1.6-het; or R5 is a residue of an amino acid, wherein alkyl, cycloalkyl, phenyl, and aryl are unsubstituted or substituted; U is as shown in structure II: where: n = 0 to 5; X is -CH or N; Ra and Rb are independently an atom of O, S, or N, or alkyl of 0 to 8 carbon atoms, wherein one or more of the carbon atoms in the alkyl chain can be replaced by a heteroatom selected from O, S, or N, and wherein the alkyl may be unsubstituted or substituted; Rd is selected from: (a) -Re-Q - (Rf) p (Rg) q; or (b) Ar! - D - Ar2; Rc is H, or Rc and Rd together form cycloalkyl or het; wherein, if Rd and Rc form a cycloalkyl or hetero ring, R5 is attached to the ring formed at a C or N atom; p and q are independently 0 or 1; Re is alkyl of 1 to 8 carbon atoms or alkylidene, preferably methylidene, and Re may be unsubstituted or substituted; Q is N, O, S, S (O), or S (O) 2; Ar- [and Ar2 are substituted or unsubstituted aryl, or het; Rf and Rg are each independently H; alkyl of 1 to 10 carbon atoms; alkyl of 1 to 10 carbon atoms-aryl; -OH; - O-alkyl of 1 to 10 carbon atoms; - (CH2) o-e-cycloalkyl of 3 to 7 carbon atoms; -O- (CH2) 0-6-aplo; phenyl; aril; phenyl-phenyl; - (CH2) 1.6-het; -O- (CH2) 1.6-het; -0R11; -C (0) -R? -C (O) -N (R11) (R? 2); -N (Rn) (R? 2); -S-R11; -S (0) -Rn; -S (O) 2R11; -S (O) 2-NR 11 R 12; -NR? R S (O) 2 -R12; S-alkyl of 1 to 10 carbon atoms; aryl-alkyl of 1 to 4 carbon atoms; het-alkyl of 1 to 4 carbon atoms, wherein alkyl, cycloalkyl, het, and aryl are unsubstituted or substituted; -SO 2 -alkyl of 1 to 2 carbon atoms; -SO 2 -alkyl of 1 to 2 carbon atoms-phenyl; -O-alkyl of 1 to 4 carbon atoms; or Rg and Rf form a ring selected from het or aryl; D is -CO-; -C (O) -alenekylene of 1 to 7 carbon atoms or arylene; -CF2-; -OR-; -S (O) r, where r is from 0 to 2; 1,3-dioxolane; or alkyl of 1 to 7 carbon atoms-OH; wherein alkyl, alkylene, or arylene may be unsubstituted or substituted with one or more halogens, OH, -O-alkyl of 1 to 6 carbon atoms, -S-aikyl of 1 to 6 carbon atoms, or -CF3; or D is -N (Rh), where Rh is H; alkyl of 1 to 7 carbon atoms (unsubstituted or substituted); aril; -O- (cycloalkyl of 1 to 7 carbon atoms) (unsubstituted or substituted); C (O) -alkyl of 1 to 10 carbon atoms; C (O) -alkyl of 0 to 10 carbon atoms-aryl; C-O-alkyl of 1 to 10 carbon atoms; C-O-alkyl of 0 to 10 carbon atoms-aryl, or SO 2 -alkyl of 1 to 10 carbon atoms; S02- (alkyl of 0 to 10 carbon atoms-aryl); R6, R7, R'6, and R'7 are each independently H; -alkyl of 1 to 10 carbon atoms; -alkoxyl of 1 to 10 carbon atoms; aryl-alkoxy of 1 to 10 carbon atoms; -OH; -O-alkyl of 1 to 10 carbon atoms; - (CH2) 0-6-cycloalkyl of 3 to 7 carbon atoms; -O- (CH2) 0-e-aryl; phenyl; - (CH2) 1.6-het; -O- (CH2) 1.6-het; -OR ,,; -C (0) R "; -C (O) -N (R11) (R12); -N (R11) (R12); -MR"; -S (0) -R "; - S (O) 2-R1-l; -S (O) 2-NR 11 R 12; -NR11-S (O) 2-R12; wherein alkyl, cycloalkyl, and aryl are unsubstituted or substituted; and R6, R7, R'e, and R'7 can be joined to form a ring system; R-11 and R12 are independently H; alkyl of 1 to 10 carbon atoms; - (CH2) 0-6-cycloalkyl of 3 to 7 carbon atoms; - (CH2) 0-6- (CHo -? (Aryl) 1.2; -C (O) -acyl of 1 to 10 carbon atoms; -C (O) - (CH2) 1,6-cycloalkyl of 3 to 7 carbon atoms; carbon; -C (O) -O- (CH2) 0-e-aryl; -C (O) - (CH2) 0-6-O-phenylrenyl; -C (O) -NH- (CH2) 0-6 -alloy; -C (0) - (CH 2) o 6 -aryl; -C (O) - (CH 2) 1,6-het; -C (S) -alkyl of 1 to 10 carbon atoms; (S) - (CH2) 1,6-cycloalkyl of 3 to 7 carbon atoms; -C (S) -O- (CH2) 0.6-aryl; -C (S) - (CH2) 0.6-O-fluorenyl; -C (S) -NH- (CH2) or -6-aryl; -C (S) - (CH2) 0.6-aryl; -C (S) - (CH2) 1.6-het; wherein alkyl, cycloalkyl, and aryl are unsubstituted or substituted, or Rn and R12 are a substituent that facilitates the transport of the molecule through a cell membrane, or R11 and? 2, together with the nitrogen atom, are het aryl of RM and? 2 can be phenyl , naphthyl, or indanyl which is unsubstituted or substituted, alkyl of Rn and R12 may be unsubstituted or substituted by one or more substituents selected from alkene of 1 to 10 carbon atoms, halogen, OH, -O-alkyl of 1 to 6 ato carbon atoms, -S-alkyl of 1 to 6 carbon atoms, and -CF3; cycloalkyl of R, -, and R12 may be unsubstituted or substituted by one or more selected from alkene of 1 to 10 carbon atoms, one or more halogens, alkyl of 1 to 6 carbon atoms, halogen, OH, -O -alkyl of 1 to 6 carbon atoms, -S-alkyl of 1 to 6 carbon atoms, or -CF3; and phenyl or aryl of R ,, and R 2 may be unsubstituted or substituted by one or more substituents selected from halogen; hydroxyl; alkyl of 1 to 4 carbon atoms; alkoxyl 1 to 4 carbon atoms; nitro; -CN; -O-C (O) -alkyl of 1 to 4 carbon atoms, and -C (O) -O-aryl of 1 to 4 carbon atoms; or pharmaceutically acceptable salts thereof. A further embodiment of the present invention relates to the use of a compound of the formula I in the treatment of proliferative diseases, especially those that depend on the binding of the Smac protein to the Apoptosis Protein Inhibitor (IAP), or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases, to methods of using the compounds of the formula (I) in the treatment of said diseases, to pharmaceutical preparations comprising the compounds of the formula (I) for the treatment of the aforementioned diseases, and compounds of the formula (I) for use in the treatment of these diseases. One embodiment of the present invention relates to & compounds of the formula (I) wherein: R i and R 2 are independently H, or substituted or unsubstituted alkyl of 1 to 4 carbon atoms; R 4 is straight or branched alkyl of 1 to 16 carbon atoms; alkenyl of 1 to 16 carbon atoms, or cycloalkyl of 3 to 10 carbon atoms, wherein alkyl or cycloalkyl may be unsubstituted or substituted; R5 is H; alkyl of 1 to 10 carbon atoms; alkyl of 1 to 10 carbon atoms-aryl; -C (O) - (CH 2) 0-6-phenyl; - (CH2) 0_6C (O) -phenyl; aryl, indanyl; naphthyl; or R5 is a residue of an amino acid, wherein the alkyl or aryl substituents are unsubstituted or substituted; U is as shown in structure ll: where: n = 0 to 5; X is -CH or N; Ra and Rb are independently an atom of O, S, or N, or alkyl of 0 to 8 carbon atoms, wherein one or more of the carbon atoms in the alkyl chain can be replaced by a heteroatom selected from O, S, or N, and wherein the alkyl may be unsubstituted or substituted; Rd is selected from: (a) -Re-Q - (Rf) p (Rg) q; or (b) Ar, - D - Ar2; Rc is H, or Rc and Rd together form cycloalkyl or het; wherein, if Rd and Rc form a cycloalkyl or hetero ring, R 5 is attached to the ring formed on a C or N atom; p and q are independently 0 or 1; Re is alkyl of 1 to 8 carbon atoms or methylidene, which may be unsubstituted or substituted; Q is N, O, S, S (O), or S (O) 2; Ari and Ar2 are substituted or unsubstituted aryl, or het; Rf and Rg are each independently H, or alkyl of 0 to 10 carbon atoms; alkyl of 1 to 10 carbon atoms-aryl; aryl-alkyl of 1 to 10 carbon atoms; het-alkyl of 1 to 10 carbon atoms; -C (O) -alkyl of 1 to 4 carbon atoms-phenyl; -C (O) -alkyl of 1 to 4 carbon atoms; -SO 2 -alkyl of 1 to 2 carbon atoms; -SO 2 -alkyl of 1 to 2 carbon atoms-phenyl; -O-alkyl of 1 to 4 carbon atoms; D is -C (O) -; alkylene of 1 to 7 carbon atoms or arylene; -OR-; -S (O) r, where r is from 0 to 2; wherein alkyl, alkylene, or arylene may be unsubstituted or substituted with one or more halogens; -OH, -O-alkyl of 1 to 6 carbon atoms, -S-alkyl of 1 to 6 carbon atoms, or -CF3; or D is -NRh, where Rh is H; alkyl of 1 to 7 carbon atoms (unsubstituted or substituted); aril; -O-cycloalkyl of 1 to 7 carbon atoms (unsubstituted or substituted); CO-alkyl of 0 to 10 carbon atoms, or aryl, or SO 2 -alkyl of 0 to 10 carbon atoms, or aryl; and R6, R, R'e, and R are each independently H; -alkyl of 1 to 10 carbon atoms; u -OH, -alkoxyl, or aryloxy; or pharmaceutically acceptable salts thereof.

In a further embodiment, U is a saturated or unsaturated bicyclic ring system, which consists of the entire carbon skeleton, or with one or more heteroatoms, such as O, N, S, but preferably as shown in the structure III: wherein: any of the ring carbon atoms may be unsubstituted or substituted with any of the substituents defined above for R6, R7, R'ß, and M X is CH or N; V is O, F2, CI2, Br2, l2 > S, YH, H2, NH, or alkyl of 1 to 4 carbon atoms; W is -CH or -N; n is from 0 to 3; and m is from 0 to 3. In a preferred embodiment, the ring atoms may be substituted with substituents independently selected from halogen, H, OH, lower alkyl, or lower alkoxy, wherein alkyl or alkoxy are unsubstituted or substituted by halogen , OH, lower alkyl, or lower alkoxy. In a further embodiment, U of formula II or III, together with R5, forms a fused ring system. Especially preferred is a compound of the formula (I) wherein: R, and R 3 are preferably methyl or ethyl; R2 is especially H; methyl; ethyl; chloro-methyl; dichloro-methyl, or trifluoromethyl; R 4 is -alkyl of 1 to 4 carbon atoms; -Cycloalkyl of 3 to 7 carbon atoms; - (CH2) 1.6-cycloalkyl; or - (CH2) 0.6-aryl. R is in particular ethyl; propyl; isopropyl; tertiary butyl; cyclopentyl; or cyclohexyl; -CH2-cyclopentyl; -CH2-cyclohexyl, or -CH2-phenyl. R5 is -alkyl of 1 to 4 carbon atoms-phenyl; -C (O) -alkyl of 1 to 4 carbon atoms-phenyl; -alkyl of 1 to 4 carbon atoms-C (O) -phenyl, or aryl; R5 is in particular phenyl-methyl, phenylethyl, and phenyl-propyl; indanyl, naphthyl; -C (O) -CH2-phenyl, or -CH2-C (O) -phenyl; R6 and R7 are H or methyl; U has the structure of formula III: wherein: any of the ring carbon atoms may be unsubstituted or substituted with any of the substituents defined above for R6, R7, R'ß, and R'7; X is N; V is O or H2; W is -N; n is 1; and m is 1 or 2. Especially preferred is a compound of the formula (I) wherein: R, and R 3 are preferably methyl or ethyl; R2 is H; R 4 is alkyl of 1 to 4 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkyl of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms; phenyl-alkyl of 1 to 7 carbon atoms, or aryl. R is in particular methyl; ethyl; butyl; isopropyl; tertiary butyl; or cyclohexyl; -CH2-cyclopentyl; -CH2-cyclohexyl; -CH2-cyclopropyl; phenyl, or -CH2-phenyl; R5 is -alkyl of 1 to 4 carbon atoms-phenyl; -C (O) -alkyl of 1 to 4 carbon atoms-phenyl; -alkyl of 1 to 4 carbon atoms-C (O) -phenyl, or aryl. R5 is in particular phenyl-ethyl; indanyl, naphthyl; -C (O) -CH2-phenyl; -CH2-C (O) -phenyl, or (CF3O) phenyl-ethyl; R6, R'ßl R7, and R'7 are H; U has the structure of formula III wherein: any of the ring carbon atoms may be unsubstituted or substituted with any of the substituents defined above for R6, R7, R'6, and R'7; X is N; V is O or H2; W is -N; n is 1; and m is 1 or 2. Another embodiment refers to a compound of the formula (I) wherein: R, and R 3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is H; U has the structure of formula II where: X is N; n is O; Rc is H; Ar, and Ar2 are substituted or unsubstituted phenyl or het, in particular tetrazolyl, 1,2,3-triazole, pyrazole, oxazole, pyrrolyl, triazine, pyrimidine, imidazole, oxadiazole; and D is alkyl of 1 carbon atom, which may be optionally substituted with halogen, especially F. Another embodiment refers to a compound of the formula (I) wherein: R, and R 3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkyl of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms; phenyl-alkyl of 1 to 7 carbon atoms, or aryl. R 4 is in particular methyl, ethyl, butyl, isopropyl, tertiary butyl, or cyclohexyl; -CH2-cyclopentyl, -CH2-cyclohexyl; -CH2-cyclopropyl; phenyl, or -CH2-phenyl; R5 is H; U has the structure of formula 11 where: X is N; Re, R'e, R7, and R'7 are H; or R6 is -C (O) -alkyl of 1 to 4 carbon atoms-phenyl, and R'6, R7, and R'7 are H; n is O; Rc is H; Ar, and Ar2 are substituted or unsubstituted phenyl or het, in particular triazine, pyrimidine, pyridine, oxazole, 2,4-difluoro-phenyl, Cl-phenyl, or fluoro-phenyl; and D is N (Rh), where Rh is H, Me, -CHO, -SO2, -C (O), -CHOH, -CF3, or -SO2CH3. Another embodiment refers to a compound of the formula (I) wherein: R, and R 3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkyl of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms; phenyl-alkyl of 1 to 7 carbon atoms, or aryl. R 4 is in particular methyl, ethyl, butyl, isopropyl, tertiary butyl, or cyclohexyl; -CH2-cyclopentyl, -CH2-cyclohexyl; -CH2-cyclopropyl; phenyl, or -CH2-phenyl; R5 is H; U has the structure of formula II where: X is N; Re, R'e, R7, and R'7 are H; n is O; Rc is H; Ar? and Ar2 are substituted or unsubstituted phenyl or het, in particular pyrimidine, pyridine, oxazole, 2-methyl-oxazole; and D is -O-. Another embodiment refers to a compound of the formula (I) wherein: Ri and R3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is H; U has the structure of formula II where: X is N; Re, R'e, R7, and R'7 are H; n is O; Rc is H; Ar, and Ar2 are substituted or unsubstituted phenyl or het; and D is S, S (O), or S (O) 2. Another embodiment refers to a compound of the formula (I) wherein: R, and R 3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is H; U has the structure of formula II where: X is N; n is O; Rc is H; Ar, and Ar2 are substituted or unsubstituted phenyl or het, in particular oxazole, thiazole, and oxadiazole; and D is C (O), or 1,3-d-oxolane. Another embodiment refers to a compound of the formula (I) wherein: R, and R 3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is H or phenyl-alkyl of 1 to 10 carbon atoms, such as phenyl-ethyl; U has the structure of formula II where: X is N; n is O; Rc and Rd are a heterocyclic ring, in particular pyrrolidine; pyrrolidin-2-one; or pyrrolidin-3-one. Another embodiment refers to a compound of the formula (I) wherein: Ri and R3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is H, indanyl, or phenyl; U has the structure of formula II where: X is N; Q is O; Re, R'e, R7, and R'7 are H; n is O; Re is alkyl of 1 carbon atom; and p and q are 0. An additional embodiment refers to a compound of the formula (I) wherein: Ri and R3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular, sopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is H, indanyl, or phenyl; U has the structure of formula II where: X is N; Q is N; n is O; Re is alkyl of 1 carbon atom; and Rg is H, alkyl of 1 to 8 carbon atoms, methyl, ethyl, hexyl, heptyl, octyl; or CH2CF3; or aryl-alkyl of 1 to 4 carbon atoms, in particular phenyl-ethyl, furanyl-ethyl; cycloalkyl of 3 to 7 carbon atoms, in particular cyclohexyl; ethyl phenyl; -C (O) -alkyl of 1 to 4 carbon atoms-phenyl; -C (O) -alkyl of 1 to 4 carbon atoms, -alkyl of 1 to 4 carbon atoms-aryl, in particular -CH2-phenyl; -CH2-thiophene, -CH2-furan, -CH2-pyrrolidinyl, -CH2-imidazole, -CH2-triazole, -CH2-imidazole; and Rf is alkyl of 1 to 2 carbon atoms; alkyl of 1 to 2 carbon atoms-phenyl; -SO 2 -alkyl of 1 to 2 carbon atoms; - SO 2 -alkyl of 1 to 2 carbon atoms-phenyl; -O-alkyl of 1 to 4 carbon atoms, in particular O-ethyl; phenyl-phenyl, 2,3,4-tetrahydro-naphthalene, and indanyl. A further embodiment refers to a compound of the formula (I) wherein: R, and R 3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is H, indanyl, or phenyl; U has the structure of formula II where: X is N; Q is N; Re, R'e, R7, and R'7 are H; n is O; Re is alkyl of 1 carbon atom; and Rg and Rf form a ring selected from het or aryl, in particular 2,3,4,5-tetra-hydro-benzo- [c] -azepine; 1, 2,3,4-tetrahydroquinoline; indanyl which may be substituted with alkyl of 1 to 4 carbon atoms-phenyl. A further embodiment refers to a compound of the formula (I) wherein: R, and R 3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is phenyl; U has the structure of formula II where: X is N; Q is O, S, S (O), or S (O) 2; Re, R'e, R7, and R'7 are H; n is O; Re is alkyl of 1 carbon atom; q is 0; Rc is H; and Rf is alkyl of 2 carbon atoms. A further embodiment refers to a compound of the formula (I) wherein: R, and R3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is phenyl; U has the structure of formula 11 where: X is N; Q is N; Re, R'e, R7, and R'7 are H; n is O; Re is CH; q is 0; Rc is H; and Rf is O-alkyl of 1 carbon atom. In a particularly important embodiment of the present invention, R3 and R have the stereochemistry indicated in formula IV, the definitions of the variable substituents and preferences described hereinbefore also being applied to the compounds having the stereochemistry indicated in the formula IV: Especially preferred is a compound with the stereochemistry of the formula (IV), wherein: Ri and R3 are preferably methyl or ethyl; R2 is H, methyl, ethyl, or substituted methyl, especially chloro-methyl, dichloro-methyl, and trifluoromethyl; preferably R2 is H or unsubstituted methyl; R 4 is alkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is -alkyl of 1 to 4 carbon atoms-phenyl, in particular phenyl-methyl, phenyl-ethyl, and phenyl-propyl, indanyl, naphthyl; and R6 and R7 are H or methyl. The preferred stereochemistry for U is as shown in Figure V: In a particular embodiment of the present invention, one or both of R6, R7, R'6, and R'7 is H. If one of R6, R7, R'6, and R 'is different from H, it is especially hydroxyl or phenoxy.

Synthetic procedure Abbreviations: C H CI2 methylene chloride CH3CN acetonitrile DIBAL di-isobutyl aluminum hydride DIPEA di-isopropyl-ethyl-amine DME dimethyl ether of ethylene glycol DMF N, N-dimethyl-formamide DTBB 4, 4'-d i-te rb uti lb i phenyl EtOAc ethyl acetate HBTU hexafluoro-phosphate O-benzyltriazol-1-yl-N, N, N ', N '-tetra-methyl-uronium HOBt 1 -hydroxy-benzotriazole HPLC high-pressure liquid chromatography KOTMS potassium trimethyl-silanoate MeOH methanol MgSO4 magnesium sulfate MnO2 manganese dioxide Na2CO3 sodium carbonate NaHCO3 sodium bicarbonate NaOH sodium hydroxide Tetraquis tetrakis - (triphenyl-phosphine) -palladium (0) TFA trifluoroacetic acid THF tetrahydrofuran The compounds of formula (I) can be prepared as illustrated below in scheme 1 (for compounds # 9-25, 29-31): General synthesis scheme for compounds of formula 1 wherein W = N and X and X 'are independently selected from the substituents defined above for R6: KOTMS is defined as potassium trimethyl silanoate. Step A PG = benzyl or a benzyl protecting group. Step B n = 0, 1, or 2.

Step C Step D separate diastereomers Step E Step F Step G Step H Scheme 1 Step A: This step involves the formation of an aziridine ring by means of conventional base mediated conditions. Step B: This step involves the formation of a secondary amine by means of the reaction of an alkyl bromide with an excess of amine in the presence of a base. Step C: This step involves coupling a secondary amine with an activated derivative of the aziridine methyl ester to form an azide substituted by amide.

Step D: This step involves intra-molecular cycloaddition of aziridine to alkene bound through a thermally accessible azomethine ylide intermediate. Step E: This step involves the reduction of the amide to an amine by means of conventional reduction conditions, using DIBAL-H. Step F: This step involves the removal of the benzyl protecting group using conventional palladium conditions under a hydrogen atmosphere. Step G: This step involves coupling the scaffold with a natural or unnatural amino acid protected by t-Boc, using standard peptide coupling conditions, followed by removal of the t-Boc group with TFA. Step H: This step involves the coupling of the amine generated in the previous step, with a natural or unnatural amino acid protected by t-Boc or tertiary, using conventional peptide coupling conditions, followed by the removal of the t-Boc group with TFA if applicable. The product is then purified by high performance liquid chromatography (HPLC).

The compounds of the formula (I) can be prepared as illustrated below, in scheme 2 (for compounds # 26-28): 68% B Scheme 2 The compounds of the formula (I) can be prepared as illustrated below in scheme 3 (for compounds # 32-33): Scheme 3 The compounds of the formula (I) can be prepared as illustrated below in scheme 4 (for compounds # 34-35): Scheme 4 Compounds 36 to 38 can be prepared in a manner analogous to the preparation of compounds 34 to 35 according to Scheme 4. As described above, the compounds of the present invention are useful for the treatment of proliferative diseases. Accordingly, the present invention further relates to a method for the treatment of a proliferative disease, which comprises administering a therapeutically effective amount of a compound of the invention to a mammal, preferably a human, in need of such treatment. A proliferative disease is primarily a tumor disease (or cancer) (and / or any metastases). The compounds of the invention are particularly useful for the treatment of a tumor, which is a breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermoid cancer, melanoma, ovarian cancer, pancreatic cancer, neuroblastoma, cancer. head and / or neck or bladder cancer, or in a broader sense, renal, brain, or gastric cancer; in particular (i) a breast tumor; an epidermoid tumor, such as an epidermoid tumor of the head and / or neck, or a tumor of the mouth; a lung tumor, for example, a small cell lung tumor or a non-small cell tumor; a gastrointestinal tumor, for example a colorectal tumor; or a genitourinary tumor, for example a prostate tumor (especially a prostate tumor refractory to hormones); or (ii) a proliferative disease that is refractory to treatment with other chemotherapeutic agents; or (iii) a tumor that is refractory to treatment with other chemotherapeutic agents due to multidrug resistance. In a broader sense of the invention, a proliferative disease may additionally be a hyperproliferative condition, such as leukaemias, hyperplasias, fibrosis (especially pulmonary, but also other types of fibrosis, such as renal fibrosis), angiogenesis, psoriasis, atherosclerosis, and proliferation of smooth muscle in the blood vessels, such as stenosis or restenosis following angioplasty. When a tumor, a tumor disease, a carcinoma, or a cancer is mentioned, metastasis in the original organ or tissue and / or in any other location is also alternatively or in addition involved, regardless of the site of the tumor and / or the site of the tumor. the metastasis. The compound of the invention is selectively toxic or more toxic to rapidly proliferating cells than to normal cells, in particular in human cancer cells, for example, for cancerous tumors, the compound has significant antiproliferative effects and promotes differentiation , for example, cell cycle arrest and apoptosis. The compounds of the present invention can be administered alone or in combination with other anticancer agents, such as compounds that inhibit tumor angigogenesis, eg, protease inhibitors, inhibitors of epidermal growth factor receptor kinase, inhibitors. of vascular endothelial growth factor receptor kinase, and the like; cytotoxic drugs, such as antimetabolites, such as purine analogues and pyrimidine antimetabolites; antimitotic agents such as microtubule stabilizing drugs and antimitotic alkaloids; platinum coordination complexes; anti-tumor antibiotics; alkylating agents, such as nitrogen mustards and nitrosoureas; endocrine agents, such as adrenocorticosteroids, androgens, anti-androgens, estrogens, anti-estrogens, aromatase inhibitors, gonadotropin-releasing hormone agonists, and somatostatin analogs, and compounds that direct an enzyme or receptor that is overexpressed and / or that is otherwise involved in a specific metabolic pathway that increases in the tumor cell, for example phosphodiesterase inhibitors of ATP and GTP, inhibitors of histone deacetylase, protein kinase inhibitors, such as serine, threonine, and tyrosine kinase inhibitors, for example, Abelson protein tyrosine kinase and the various factors of growth, its receptors and kinase inhibitors, accordingly, such as inhibitors of epidermal growth factor receptor kinase, inhibitors of vascular endothelial growth factor receptor kinase, inhibitors of fibroblast growth factor, inhibitors of growth factor receptor insulin type, and inhibitors of platelet-derived growth factor receptor kinase, and the like; inhibitors of methionine aminopeptidase, proteasome inhibitors, and cyclo-oxygenase inhibitors, for example inhibitors of cyclo-oxygenase-1 or -2. The present invention further relates to a method for promoting apoptosis in rapidly proliferating cells, which comprises contacting rapidly proliferating cells with an effective apoptosis promoting amount of a non-naturally occurring compound that binds to the Smac binding site of the XIAP and / or clAP proteins. Preferably, the compound that does not occur naturally is a compound of the present formula I or IV. The present invention also relates to a method for the treatment or inhibition of myeloma, especially multiple myeloma.

The term "myeloma", as used herein, refers to a tumor composed of cells of the type normally found in the bone marrow. The term "multiple myeloma", as used herein, means a disseminated malignant neoplasm of plasma cells, which is characterized by multiple bone marrow tumor foci and secretion of an M component (a monoclonal immunoglobulin fragment), associated with widespread osteolytic lesions that result in bone pain, pathological fractures, hypercalcemia, and normochromic normocytic anemia. Multiple myeloma is incurable through the use of conventional and high-dose chemotherapies. The invention relates to a method for the treatment of myeloma, especially melanoma that is resistant to conventional chemotherapy.

Pharmaceutical Compositions The invention also relates to pharmaceutical compositions comprising a compound of formula I, its use in the therapeutic treatment (in a broader aspect of the invention, also prophylactic), or a method of treating a disease dependent on kinase, especially the preferred diseases mentioned above, to the compounds for said use, and to pharmaceutical preparations and their manufacture, especially for the mentioned uses. The present invention also relates to pro-drugs of a compound of the formula I which are converted in vivo into the compound of the formula i as such. Accordingly, it should be understood that any reference to a compound of formula I also refers to the corresponding prodrugs of the compound of formula 1, as appropriate and convenient. The pharmacologically acceptable compounds of the present invention may be present in, or may be employed, for example, for the preparation of pharmaceutical compositions comprising an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, as an ingredient active, together or in admixture with one or more pharmaceutically acceptable, inorganic or organic, solid or liquid vehicles (carrier materials). The invention also relates to a pharmaceutical composition that is suitable for administration to a warm-blooded animal, especially a human (or to cells or cell lines derived from a warm-blooded animal, especially a human being, e.g. lymphocytes), for the treatment of (this, in a broader aspect of the invention, also includes the prevention of (= prophylaxis against) a disease that responds to the inhibition of protein kinase activity, which comprises a The amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, which is preferably effective for said inhibition, together with at least one pharmaceutically acceptable carrier. The pharmaceutical compositions according to the invention are those for enteral administration, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, to warm-blooded animals (especially to a human), which comprise a dose effective of the pharmacologically active ingredient, alone or together with a significant amount of a pharmaceutically acceptable carrier. The dose of the active ingredient depends on the species of warm-blooded animal, the body weight, the age and the individual condition, the individual pharmacokinetic data, the disease to be treated, and the mode of administration. .

The invention also relates to a method for the treatment of a disease that responds to the inhibition of a protein kinase and / or a proliferative disease, which comprises administering (against the aforementioned diseases) a particularly therapeutically effective amount of a compound of the formula I according to the invention, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, especially a warm-blooded animal, for example a human being, which, taking into account one of the mentioned diseases, requires said treatment. The dose of a compound of the formula I or a pharmaceutically acceptable salt thereof, for administration to warm-blooded animals, for example humans of a body weight of about 70 kilograms, is preferably from about 3 milligrams to about 10 grams, more preferably from about 10 milligrams to about 1.5 grams, most preferably from about 100 milligrams to about 1000 milligrams / person / day, preferably divided into 1 to 3 individual doses, which may, for example, be of the same size.

Usually, children receive half the dose for adults. The pharmaceutical compositions comprise from about 1 percent to about 95 percent, preferably from about 20 percent to about 90 percent active ingredient. The pharmaceutical compositions according to the invention may be, for example, in a unit dosage form, such as in the form of ampoules, flasks, suppositories, dragees, tablets, or capsules. The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional processes of dissolution, lyophilization, mixing, granulation, or confectionery.

Combinations A compound of the formula I can also be used advantageously in combination with other anti-proliferative agents. These anti-proliferative agents include, but are not limited to, aromatase inhibitors; anti-estrogens; Topoisomerase I inhibitors; topoisomerase II inhibitors; active agents in microtubules; alkylating agents; inhibitors of histone deacetylase; compounds that induce cellular differentiation processes; cyclo-oxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platinum compounds; steering compounds / reduction of the kinase activity of a protein or lipid, and other anti-angiogenic compounds; compounds that direct, reduce, or inhibit the phosphatase activity of a protein or lipid; gonadorelin agonists; anti-androgens; inhibitors of methionine aminopeptidase; bisphosphonates; biological response modifiers; anti-proliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; agents used in the treatment of hematological malignancies; compounds that direct, reduce, or inhibit the activity of Flt-3; Hsp90 inhibitors; Temozolomide (TEMODAL®); and leucovorin. The term "aromatase inhibitor", as used herein, refers to a compound that inhibits the production of estrogen, ie, the conversion of the substrates of androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially atamestane, exemestane, and formestane, and in particular, non-steroids, especially aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole . Exemestane can be administered, for example, in the form as it is traded, for example under the registered trademark AROMASIN. The formestane can be administered, for example, in the form as it is traded, for example under the registered trademark LENTARON. Fadrozole can be administered, for example, in the form as it is traded, for example under the registered trademark AFEMA. Anastrozole can be administered, for example, in the form as it is traded, for example under the registered trademark ARIMIDEX. The letrozole can be administered, for example, in the form as it is traded, for example under the registered trademark FEMARA or FEMAR. The aminoglutethimide can be administered, for example, in the form as it is traded, for example under the registered trademark ORIMETEN. A combination of the invention comprising a chemotherapeutic agent that is an aromatase inhibitor, is particularly useful for the treatment of tumors positive for the hormone receptor, for example, breast tumors. The term "antiestrogen", as used herein, refers to a compound that antagonizes the effect of estrogen at the level of the estrogen receptor. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen can be administered, for example, in the form as it is traded, for example under the registered trademark NOLVADEX. Raloxifene hydrochloride can be administered, for example, in the way it is traded, for example under the registered trademark EVISTA. The fulvestrant can be formulated as disclosed in US Pat. No. 4,659,516, or it can be administered, for example, in the form as it is traded, for example under the registered trademark FASLODEX. A combination of the invention comprising a chemotherapeutic agent that is an antiestrogen, is particularly useful for the treatment of tumors positive for the estrogen receptor, for example breast tumors. The term "anti-androgen", as used herein, refers to any substance that is capable of inhibiting the biological effects of androgenic hormones, and includes, but is not limited to, bicalutamide (CASODEX), which is it can formulate, for example, as disclosed in US Pat. No. 4,636,505. The term "gonadorelin agonist", as used herein, includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is disclosed in U.S. Patent Number US 4,100,274, and may be administered, for example, in the form as it is marketed, for example under the registered trademark ZOLADEX. Abarelix can be formulated, for example, as disclosed in U.S. Patent No. US 5,843,901. The term "topoisomerase I inhibitor", as used herein, includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148 (compound A1 of International Publication Number WO 99/17804). The irinotecan can be administered, for example, in the way it is traded, for example under the trademark registered CAMPTOSAR. The topotecan can be administered, for example, in the form as it is traded, for example under the registered trademark HYCAMTIN. The term "topoisomerase II inhibitor", as used herein, includes, but is not limited to, anthracyclines, such as doxorubicin (including liposomal formulation, eg CAELYX), daunorubicin, epicin, idarubicin, and nemorubicin; the anthraquinones mitoxantrone and losoxantrone; and the podophyllotoxins etoposide and teniposide. The etoposide can be administered, for example, in the form as it is traded, for example under the registered trademark ETOPOPHOS. The teniposide can be administered, for example, in the form as it is traded, for example under the registered trademark VM 26-BRISTOL. The doxorubicin can be administered, for example, in the form as it is traded, for example under the registered trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can be administered, for example, in the form as it is traded, for example under the registered trademark ZAVEDOS. The mitoxantrone can be administered, for example, in the form as it is traded, for example under the registered trademark NOVANTRON. The term "microtubule active agent" refers to microtubule stabilizing agents, microtubule destabilizers, and microtubulin polymerization inhibitors, including, but not limited to, taxanes, for example paclitaxel and docetaxel, vinca alkaloids, for example vinblastine, in particular vinblastine sulphate, vincristine, especially vincristine sulfate, and vinorelbine, discodermolides, colchicine and epothilones and derivatives thereof, for example epothilone B or D, or derivatives thereof. Paclitaxel can be administered, for example, in the form as it is traded, for example TAXOL. docetaxel can be administered, for example, in the form as it is traded, for example under the registered trademark TAXOTERE. The vinblastine sulfate can be administered, for example, in the form as it is traded, for example under the registered trademark VINBLASTIN R.P. The vincristine sulfate can be administered, for example, in the form as it is traded, for example under the registered trademark FARMISTIN. The disk-mold can be obtained, for example, as disclosed in U.S. Patent No. 5,010,099. Also included are Epothilone derivatives, which are disclosed in Patent Numbers WO 98/10121, US 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461, and WO 00/31247. Especially preferred are Epothilone A and / or B. The term "alkylating agent", as used herein, includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide can be administered, for example, in the form as it is traded, for example under the registered trademark CYCLOSTIN. Ifosfamide can be administered, for example, in the form as it is traded, for example under the registered trademark HOLOXAN. The term "histone deacetylase inhibitors" or "HDAC inhibitors" refers to compounds that inhibit histone deacetylase and that possess antiproliferative activity. This includes the compounds disclosed in International Publication Number WO 02/22577, especially N-hydroxy-3- [4 - [[(2-hydroxy-ethyl) [2- (1H-indol-3-yl)] -ethyl] -amino] -methyl] -phenyl] -2E-2-propenamide, N-hydroxy-3- [4 - [[2- (2-methyl-1 H -indol-3-yl) -ethyl] -amino] -methyl] -phenyl] -2E-2-propenamide, and the pharmaceutically acceptable salts thereof. It also includes, in particular, the hydroxamic acid of Suberoil-anilide (SAHA). The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating agents, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and phobic acid antagonists, such as pemetrexed. Capecitabine can be administered, for example, in the form as it is traded, for example under the registered trademark XELODA. Gemcitabine can be administered, for example, in the form as it is traded, for example under the registered trademark GEMZAR. Also included is the monoclonal antibody trastuzumab, which can be administered, for example, in the form as it is traded, for example under the registered trademark HERCEPTIN. The term "platinum compound", as used herein, includes, but is not limited to, carboplatin, cis-platin, cisplatin, and oxaliplatin. Carboplatin can be administered, for example, in the form as it is traded, for example under the registered trademark CARBOPLAT. Oxaliplatin can be administered, for example, in the form as it is traded, for example under the registered trademark ELOXATIN. The term "compounds that direct / reduce the kinase activity of a protein or lipid and other anti-angiogenic compounds", as used herein, includes, but is not limited to: protein tyrosine and / or serine protein kinase inhibitors and / or threonine, or lipid kinase inhibitors, for example: a) compounds that direct, reduce, or inhibit the activity of fibroblast growth factor receptors (FGF-Rs); b) compounds that direct, reduce, or inhibit the activity of the insulin-like growth factor receptor (IGF-IR), such as compounds that direct, reduce, or inhibit the activity of IGF-IR, especially the compounds that direct , reduce, or inhibit the IGF-IR receptor, such as the compounds disclosed in International Publication Number WO 02/092599; c) compounds that direct, reduce, or inhibit the activity of the Trk receptor tyrosine kinase family; d) compounds that direct, reduce, or inhibit the activity of the tyrosine kinase family, to Axl receptor; e) compounds that direct, reduce, or inhibit the activity of the c-Met receptor; f) compounds that direct, reduce, or inhibit the activity of protein kinase C (PKC) members and the Raf family of serine / threonine kinases, members of the MEK family, SRC, JAK, FAK, PDK, and Ras / MAPK, or of the kinase family Pl (3), or of the family of kinase related to Pl (3) -kinae, and / or the members of the cyclin-dependent kinase family (CDK), and are especially the staurosporine derivatives disclosed in U.S. Patent No. 5,093,330, for example midostaurin, examples of additional compounds include, for example, UCN-01, safingol, BAY 43-9006, Briostatin 1, Periphosin, llmofosin, RO 318220 and RO 320432, GO 6976, Isis 3521, LY333531 / LY379196, Isoquinoline compounds, such as those disclosed in International Publication Number WO 00/09495; FTIs; PD184352 or QAN697 (a P13K inhibitor); g) compounds that direct, reduce, or inhibit the activity of a protein tyrosine kinase, such as imatinib mesylate (GLIVEC / GLEEVEC) or tyrphostin. A tyrphostin is preferably a low molecular weight compound (Mr < 1500), or a pharmaceutically acceptable salt thereof, especially a compound selected from the benzylidenemalonitrile class, or the class of S-arylbenzemalonitrile or bisubstrate compounds. of quinoline, more especially any compound selected from the group consisting of Tyrphostin A23 / RG-50810; AG 99; Tyrphostín AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 enantiomer (+); Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957, and adafostin (4- {[[(2,5-dihydroxy-phenyl) -methyl] -amino} -adhexyl ester.-benzoic acid, NSC 680410, adaphostin); and h) compounds that direct, reduce, or inhibit the activity of the tyrosine kinase family of epidermal growth factor receptors (EGF-R, ErbB2, ErbB3, ErbB4 as homo- or hetero-dimers), such as the compounds they direct , reduce, or inhibit the activity of the epidermal growth factor receptor family, are especially compounds, proteins, or antibodies that inhibit members of the EGF receptor tyrosine kinase family, eg, EGF receptors , ErbB2, ErbB3, and ErbB4, or that bind to EGF or to EGF-related ligands, and are in particular the compounds, proteins, or generic monoclonal antibodies and specifically disclosed in International Publication Number WO 97/02266, for example the compound of Example 39, or in Patent Numbers EP 0,564,409; WO 99/03854; EP 0520722; EP 0,566,226; EP 0,787,722; EP 0,837,063; US 5,747,498; WO 98/10767; WO 97/30034; WO 97/49688; WO 97/38983, and in particular, WO 96/30347 (for example, the compound known as CP 358774), WO 96/33980 (for example, compound ZD 1839), and WO 95/03283 (for example, the compound ZM 105180); for example trastuzumab (HERCEPTIN), cetuximab, Iressa, Tarceva, CI-033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, or E7.6.3, and 7H-pyrrolo- [2,3-d] -pyrimidine derivatives, which are disclosed in International Publication Number WO 03/013541. Other anti-angiogenic compounds include compounds that have another mechanism for their activity, for example, unrelated to the inhibition of protein or lipid kinase, for example thalidomide (THALOMID) and TNP-470. Compounds that direct, reduce, or inhibit the activity of a protein or lipid phosphatase are, for example, the phosphatase 1, phosphatase 2A, PTEN, or CDC25 inhibitors, for example okadaic acid or a derivative thereof. The compounds that induce cell differentiation processes are, for example, retinoic acid, a-,? -, or d-tocopherol, or a-,? -, or d-tocotrienol. The term "cyclooxygenase inhibitor", as used herein, includes, but is not limited to, for example, Cox-2 inhibitors, 2-aryl-amino-phenyl-acetic acid substituted by 5-alkyl and its derivatives, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib, or a 5-alkyl-2-aryl-amino-phenyl-acetic acid, for example, 5-methyl-2- (2'-) acid chloro-6'-fluoro-anilino) -phenyl-acetic, lumiracoxib. The term "mTOR inhibitors" refers to compounds that inhibit the mammalian target of rapamycin (mTOR), and which possess antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican ™), CCI-779, and ABT578 . The term "bisphosphonates", as used herein, includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic, and zoledronic acid. The "etridonic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark DIDRONEL. The "clodronic acid" can be administered, for example, in the way it is traded, for example under the registered trademark BONEFOS. The "tiludronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark SKELID. The "pamidronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark AREDIAMR. The "alendronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark FOSAMAX. The "ibandronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark BONDRANAT. The "risedronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark ACTONEL. The "zoledronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark ZOMETA. The term "heparanase inhibitor," as used herein, refers to compounds that direct, reduce, or inhibit the degradation of heparin sulfate. The term includes, but is not limited to, PI-88. The term "biological response modifier", as used herein, refers to a lymphokine or to interferons, for example interferon- ?. The term "inhibitor of Ras oncogenic isoforms", for example H-Ras, K-Ras, or N-Ras, as used herein, refers to compounds that direct, reduce, or inhibit the oncogenic activity of Ras, for example a "farnesyl transferase inhibitor", for example L-744832, DK8G557, or R115777 (Zarnestra).

The term "telomerase inhibitor", as used herein, refers to compounds that direct, reduce, or inhibit telomerase activity. The compounds that direct, reduce, or inhibit telomerase activity are in particular compounds that inhibit the telomerase receptor, for example telomestatin. The term "methionine aminopeptidase inhibitor", as used herein, refers to compounds that direct, reduce, or inhibit the activity of methionine aminopeptidase. The compounds that direct, reduce, or inhibit the activity of the methionine aminopeptidase are, for example, bengamide or a derivative thereof. The term "proteasome inhibitor," as used herein, refers to compounds that direct, reduce, or inhibit proteasome activity. Compounds that direct, reduce, or inhibit proteasome activity include, for example, PS-341 and MLN 341. The term "matrix metalloproteinase inhibitor" or ("MMP inhibitor"), as used herein, includes, but is not limited to, peptido-mimetic and non-peptido-mimetic collagen inhibitors, derivatives of tetracycline, for example the peptidomimetic hydroxamate inhibitor, batimastat, and its orally bioavailable analogue marimastate (BB-2516), prinomastat (AG3340), metastate (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996 . The term "agents used in the treatment of hematological malignancies", as used herein, includes, but is not limited to, tyrosine kinase inhibitors type FMS, for example compounds that direct, reduce, or inhibit the activity of Flt-3; interferon, 2-b-D-arabinofuransilcitosina (ara-c), and bisulfano; and ALK inhibitors, for example the compounds they direct, reduce, or inhibit the anaplastic lymphoma kinase. The term "compounds that direct, reduce, or inhibit the activity of Flt-3" are especially compounds, proteins, or antibodies that inhibit Flt-3, for example PKC412, midoesturin, a staurosporine derivative, SU11248, and MLN518. The term "HSP90 inhibitors", as used herein, includes, but is not limited to, compounds that direct, reduce, or inhibit the intrinsic ATPase activity of HSP90; those that degrade, direct, reduce, or inhibit the HSP90 client proteins by means of the proteasome pathway of ubiquitin. Compounds which direct, reduce, or inhibit the intrinsic ATPase activity of HSP90 are in particular compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, for example 17-allylamino, 17-demethoxy-geldanamycin (17AAG), a derivative of geldanamycin; other compounds related to geldanamycin; radicicol and HDAC inhibitors. The term "antiproliferative antibodies," as used herein, includes, but is not limited to, trastuzumab (Herceptin ™), Trastuzumab-DM1, erlotinib (Tarceva ™), bevacizumab (Avastin ™), rituximab (Rituxan®), PRO64553 (anti -CD40), and Antibody 2C4.

Antibodies mean, for example, intact monoclonal antibodies, polyclonal antibodies, multi-specific antibodies formed from at least 2 intact antibodies, and antibody fragments, as long as they exhibit the desired biological activity. For the treatment of acute myeloid leukemia (AML), the compounds of formula I can be used in combination with conventional leukemia therapies, especially in combination with therapies employed for the treatment of acute myeloid leukemia. In particular, the compounds of formula I can be administered in combination with, for example, farnesyl transferase inhibitors and / or other drugs useful for the treatment of acute myeloid leukemia, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatin, and PKC412. The structure of active agents identified by code numbers, generic or commercial names, can be taken from the current edition of the standard compendium "The Merck Index" or databases, for example Patents International (for example, IMS World Publications). The above-mentioned compounds, which can be used in combination with a compound of the formula I, can be prepared and administered as described in the art, such as in the documents cited above. A compound of formula I can also be used with advantage in combination with known therapeutic processes, for example, the administration of hormones or especially radiation. A compound of the formula I can be used in particular as a radiosensitizer, in particular for the treatment of tumors exhibiting poor sensitivity to radiotherapy. "Combination" means either a fixed combination in a unit dosage form, or a kit of parts for combined administration, wherein a compound of the formula I and a combination component can be administered independently at the same time or separately within time intervals that allow especially that the combination components show a cooperative, for example synergistic, effect or any combination thereof.

EXAMPLES The following examples are intended to illustrate, but not to further limit, the invention.

Example 1 N- [1-Cyclohexyl-2-oxo-2- (6-phenethyl-octahydro-pyrrolo [2,3-c] -pyridin-1-yl) -ethyl] -2-methyl-amino-propionamide (9 ) Compound 9 according to Formula I is prepared according to the procedure stipulated in Scheme 5.

Approx.1: 1 ratio, separable Scheme 5 Methyl ester of 1- (1-naphthalen-1-yl-ethyl) -aziridine-2-carboxylic acid (1). To a solution of (S) - (-) - 1- (1-naphthyl) -ethyl-amine (20.8 grams, 120 mmol) in acetonitrile (HPLC grade, 600 milliliters), K2CO3 (52.7 grams, 360 mg) is added. millimoles) and methyl 2,3-dibromo-propionate (30 grams, 120 millimoles). The solution is stirred overnight at room temperature. The solution is evaporated to dryness, then H2O / EtOAc (1: 1) (600 milliliters) is added, and the mixture is extracted with EtOAc (100 milliliters, 4 times). The organic extracts are combined, dried and concentrated in vacuo. The residue is purified by evaporation chromatography (silica gel; Hexane / EtOAc, 1: 2) to provide 24 grams (78 percent) of the title compound as a mixture of two diastereomers in an equimolar ratio. M + H + = 256.10. But-3-enyl-phenethylamine (2). To a solution of 2-phenylethylamine (72 milliliters, 570 millimoles) is added K2CO3 (82 grams, 570 millimoles) and 4-bromo-1-butene (25 grams, 185 millimoles). The solution is stirred overnight at room temperature. The solution is evaporated to dryness, and H2O / EtOAc (1: 1) (600 milliliters) is added. The mixture is extracted with EtOAc (150 milliliters, 4 times).

The organic extracts are combined, dried and concentrated in vacuo. The residue is purified by evaporation chromatography (silica gel; Hexane / EtOAc, 1: 8) to give 20 grams (62 percent) of the title compound. M + H + = 176.10. 1 - (1-Naphthalen-1-yl-ethyl) -aziridine-2-carboxylic acid but-3-enyl-phenethyl-amide (3). To a solution of 1 (12.6 grams, 49.75 millimoles) in tetrahydrofuran (200 milliliters), potassium trimethylsilanoate (6.38 grams, 49.75 millimoles) is added. The mixture is stirred overnight at room temperature. The mixture is concentrated and the residue is dissolved in dichloromethane (200 milliliters), and cooled to 0 ° C. Trimethyl-acetyl chloride (5.94 grams, 49.25 mmol) is slowly added, and the mixture is heated at room temperature for 2 hours. The mixture is cooled to -78 ° C, 2 (8.63 grams, 49.25 mmol) is added, and stirring is continued at -78 ° C for 1.5 hours.

Saturated sodium bicarbonate (100 milliliters) is added, and the mixture is allowed to warm to room temperature. The mixture is extracted with EtOAc (100 milliliters, 4 times), and the organic extracts are combined, dried, and concentrated in vacuo. The residue is purified by evaporation chromatography (silica gel; Hexane / EtOAc, 1: 8), to provide 15 grams (76 percent) of the title compound as a mixture of two diastereomers in an equimolar ratio. M + H + = 399.37. 1- (1-naphthalen-1-yl-ethyl) -6-phenethyl-octahydro-pyrrolo- [2,3-c] -pyridin-7-one (4). A solution of 3 (15 grams, 58.7 mmol) in o-dichlorobenzene (100 milliliters) is heated at 250 ° C for 1200 seconds in a microwave reactor. The mixture is purified by evaporation chromatography (silica gel: Hexane / EtOAc, 1: 1, second spot) to give 5 grams (33 percent) of the title compound as an enantiomerically pure compound. M + H + = 399.32. 1- (1-naphthalen-1-yl-ethyl) -6-phenethyl-octahydro-pyrrolo- [2,3-c] -pyridine (5). To a solution of 4 (4.8 grams, 12 mmol) in tetrahydrofuran (100 milliliters), 1 M DIBAL in toluene (50 milliliters, 50 mmol) is added slowly at -78 ° C. The mixture is stirred at room temperature for 1 hour, and quenched with 20 milliliters of water. The solvent is evaporated, the residue is diluted with 100 milliliters of 1: 1 saturated Rochells salt / 15% NaOH, and this is extracted with EtOAc (50 milliliters, 4 times). The organic extracts are combined, dried and concentrated in vacuo. The residue is purified by evaporation chromatography (silica gel; Hexane / EtOAc, 1: 9), to provide 2.3 grams (48 percent) of the title compound. M + H + = 385.26. 6-phenethyl-octahydro-pyrrolo- [2,3-c] -pyridine (6). To a solution of 5 (2.3 grams, 6 mmol) in MeOH / CH2Cl2 (1: 1, 200 milliliters), Pd (OH) 2 (300 milligrams) is added. The mixture is stirred under an atmosphere of hydrogen at 3.5 kg / cm2 for 10 hours. The mixture is filtered through a pad of Celite, the filtrate is concentrated, and the residue is used directly in the next step without further purification. M + H + = 231.17. Compound (7). To a solution of 6 in dichloromethane (25 milliliters), di-iso-propyl-ethyl-amine (4.17 milliliters, 24 millimoles), t-Boc-L-cyclohexylene glycine (1.54 grams, 6 millimoles), and a solution are added in sequence. of HOBt 0.45 M / HBTU in N, N-dimethylformamide (16 milliliters, 7.19 mmol). The mixture is stirred overnight at room temperature, then diluted with EtOAc (200 milliliters), and washed in sequence with 1M aqueous citric acid (50 milliliters), water (50 milliliters), saturated aqueous NaHCO3 (50 milliliters), and brine (50 milliliters, 2 times). The organic layer is dried and concentrated in vacuo. The residue is purified by evaporation chromatography (silica gel; Hexane / EtOAc, 1: 9), to give a yellow oil. The yellow oil is dissolved in dichloromethane (20 milliliters), trifluoroacetic acid (10 milliliters) is added, and the mixture is stirred at room temperature for 3 hours. The mixture is concentrated, and the residue is dissolved in dichloromethane (100 milliliters), and neutralized with saturated sodium bicarbonate. The solution is extracted with dichloromethane (50 milliliters, 3 times). The organic extracts are combined, dried, and concentrated in vacuo to give 1.75 grams (79 percent in two steps) of the title compound, which is used in the next step without further purification or characterization. Compound (9). To a solution of 7 (1.75 grams, 4.74 mmol) in dichloromethane (25 milliliters), are added in sequence, di-iso-propyl-ethyl-amine (3.30 milliliters, 19 mmol), t-Boc-N-methyl- L-alanine (0.97 grams, 4.74 mmol), and a solution of HOBt 0.45 M / HBTU in N, N-dimethyl formamide (13 milliliters, 5.691 millimoles). The mixture is stirred overnight at room temperature. The mixture is diluted with EtOAc (200 milliliters), and washed in sequence with 1 M citric acid (50 milliliters), water (50 milliliters), saturated aqueous NaHCO3 (50 milliliters), and brine (50 milliliters, 2 times). The organic layer is dried and concentrated in vacuo. The residue is dissolved in dichloromethane (20 milliliters), trifluoroacetic acid (10 milliliters) is added, and the mixture is stirred at room temperature for 3 hours. The mixture is concentrated and the residue is dissolved in dichloromethane (100 milliliters), and neutralized with saturated sodium bicarbonate. The solution is extracted with dichloromethane (50 milliliters, 3 times). The organic extracts are combined, dried and concentrated in vacuo. The residue is purified by HPLC (C-18 silica gel, 20% CH 3 CN / H 2 O in 0.5 percent trifluoroacetic acid), to provide 1 gram (36 percent in two steps) of the title compound as the salt of trifluoroacetic acid. M + H + = 455.39.

Example 2 (S) -N - ((S) -1-cyclohexyl-2 { (2S, 3R) -2 - [(ethyl-phenethyl-amino) -methyl] -3-methy1-pyrrolidin-1- il.} -2-oxo-ethyl) -2-methyl-amino-propionamide (23) IJ But-3-enyl - ((S) -1-phenyl-ethyl) -amine (A): To a solution of S - (-) - 1-phenylethylamine (15.75 grams, 130 mmol) in 150 milliliters of N, N-dimethyl formamide at 0 ° C, K2CO3 (53.9 grams, 390 millimoles) is added in small portions. After stirring at 0 ° C for 10 minutes, 4-bromo-butene (13.5 grams, 100 mmol) is added dropwise, followed by Nal (58.5 grams, 390 mmol) in small portions. The reaction mixture, a white suspension, is heated to 95 ° C and stirred overnight for 16 hours. The solution is cooled to room temperature and diluted with 200 milliliters of ether, and washed with 100 milliliters of water 3 times. The organic layer is dried over Na2SO4 and concentrated. The crude product is purified by distillation (from about 65 ° C to 70 ° C under a high vacuum), to give a colorless liquid (13.5 grams, 76.7 percent). (NMR and MS confirmed data, U-4117-28-23). [But-3-enyl - ((S) -1-phenyl-ethyl) -amino] -acetic acid ethyl ester (B): To a solution of but-3-enyl - ((S) -1-phenyl) -ethyl) -amine (6.37 grams, 36.4 millimoles) in 150 milliliters of N, N-dimethyl formamide at 0 ° C, K2CO3 (10.0 grams) is added., 72.8 millimoles) in small portions. After stirring at 0 ° C for 10 minutes, ethyl bromoacetate (8.35 grams, 54.6 mmol) is slowly added. The reaction mixture, a white suspension, is stirred at room temperature overnight for 16 hours. The solution is diluted with 200 milliliters of ether, and washed with 100 milliliters of water 3 times. The crude product is purified by chromatography (hexane / CH2CI2: 50/50), to give a pale liquid (8.5 grams, 94.5 percent). (NMR and MS confirmed data, U-4117-58). Ethyl ester of (2S, 3R) -3-but-3-enyl-1 - ((S) -1-phenyl-ethyl) -pyrrolidine-2-carboxylic acid (C): To a solution of di-isopropyl- amine (3.6 grams, 35.7 millimoles) in tetrahydrofuran (80 milliliters) at -40 ° C, BuLi (14.28 milliliters, 35.7 millimoles, 2.5M in hexane) is added slowly. The solution is heated to 0 ° C and stirred for 30 minutes to form an LDA solution. The LDA solution is cooled to -70 ° C, and added slowly to a solution of [but-3-enyl - ((S) -1-pheny-ethyl) -amino] -acetic acid ethyl ester (7.8 grams , 29.8 mmol) in tetrahydrofuran (80 milliliters) at -70 ° C.

The clear yellowish reaction solution is stirred at -20 ° C for 30 minutes to become a deep yellow solution, and then cooled to -70 ° C. To the solution is added dropwise ** ZnBr2 ** (16.76 grams, 74.5 mmol) in ether (50 milliliters) at -70 ° C. After stirring at room temperature for 1.5 hours, the reaction solution is cooled to 0 ° C, and slowly added to a solution of CuCN (3.47 grams, 38.74 mmol) and LiCI (3.29 grams, 77.48 mmol) in tetrahydrofuran (80 milliliters). After stirring at 0 ° C for 10 minutes, allyl bromide (7.26 grams, 60 mmol) is added dropwise to the reaction solution and heated very slowly to room temperature. After stirring overnight at room temperature, the reaction is quenched by the addition of 60 milliliters of saturated NH 4 Cl, and extracted with 150 milliliters of ether 3 times. The combined organic layers are concentrated. The crude product is purified by chromatography (hexane / EtOAc: 85/15), to give a colorless liquid (7.4 grams, 82.6 percent). (NMR and MS confirmed data, U-4117-40-19, U-4117-34-35). ** ZnBr2 ** is dried at 150 ° C under high vacuum for 1 hour before use **. Ethyl ester of (2S, 3R) -1 - ((2E, 4Z) - (S) -1,2-dimethyl-hexa-2,4-dienyl) -3- (3-oxo-propyl) -pyrroidin -2-carboxylic acid (D): (2S, 3R) -3-But-e-enyl-1 - ((S) -1-phenyl-ethyl) -pyrrolidine-2-carboxylic acid ethyl ester (1.0 grams, 3.32 mmol) in EtOH (10 milliliters) with HCl (0.5 milliliters, 37 percent), and cooled to -70 ° C. Ozone gas is bubbled through the solution for about 10 minutes or until the solution becomes a very light blue. Nitrogen gas is bubbled through the solution for 15 minutes to remove excess ozone in the solution. Zn powder (0.43 grams, 6.6 millimoles) and HCl (0.5 milliliters, 37 percent) are added to the cold solution and stirred at room temperature for 20 minutes. After filtration, the solution is diluted with 50 milliliters of CH 2 Cl 2, and washed with saturated NaHCO 3 (10 milliliters), and 20 milliliters of water 2 times. After drying and concentrating, a colorless liquid (1.0 grams) is obtained without further purification for the reaction of the next step. (NMR and MS confirmed data, U-4117-51-30). Ethyl ester of (2S, 3R) -3- (3-phenethyl-amino-propyl) -1 - ((S) -1-phenyl-ethyl) -pyrrolidine-2-carboxylic acid (E): To a solution of (2S, 3R) -1 - ((2E, 4Z) - (S) -1,2-dimethyl-hexa-2,4-dienyl) -3- (3-oxo-propyl) -pyrrolidine ethyl ester -2-carboxylic acid (1 gram, crude) in EtOH (10 milliliters), phenethylamine (0.44 grams, 3.65 millimoles) is added at room temperature. After stirring at room temperature for 30 minutes, NaBH3CN (0.3 grams, 4.87 millimoles) is added in one portion. After stirring at room temperature for 1.5 hours, the reaction solution is diluted with 50 milliliters of ether and washed with 20 milliliters of brine. The ether layer is concentrated, and the crude product is purified by chromatography (CH2Cl2 / MeOH: 97/3), to give a pale liquid (405 milligrams, 30.0 percent). (NMR and MS confirmed data, U-4117-52-20). (3aS, 7aS) -6-phenethyl-1 - ((S) -1-phenyl-ethyl) -octahydro-pyrrolo- [2,3-c] -pyridin-7-one (F): Ethyl ester is dissolved of (2S, 3R) -3- (3-phenethyl-amino-propyl) -1 - ((S) -1-phenyl-ethyl) -pyrrolidine-2-carboxylic acid (340 milligrams, 0.83 millimoles) in 20 milliliters of MeOH / KOH / H2O (10 milliliters / 5 grams / 5 milliliters). After stirring at 80 ° C for 2 hours, the solution is cooled to 0 ° C and neutralized by the addition of HCl (37 percent) to a pH = 5. After concentration, the crude product is dissolved in 1 ml. milliliter of CH2Cl2, and filtered through a plug of short silica gel, and eluted with CH2Cl2 / MeOH (93/7), to give a pale glaze solid (250 milligrams, 78.9 percent) as the acid. (NMR and MS confirmed data, U-4117-60-22). To a solution (approximately 0.05 to 0.1 M) of acid (1 equivalent) in N, N-dimethyl formamide at room temperature, di-isopropylethylamine (5 equivalents) is added. After stirring at room temperature for 20 minutes, a solution (approximately 0.05 to 0.1 M) of 1-hydroxybenzotriazole (1.2 equivalents) and hexafluoro-phosphate of O-benzyltriazole-1-i! -N, N, N ', is added. N'-tetramethyl uronium (1.2 equivalents) in N, N-dimethyl formamide to the reaction mixture, and stirring is continued for 1.5 hours (or monitored by thin layer chromatography). The reaction solution is diluted with ether (twice X3 by volume of the solution). The combined organic solution is concentrated. The crude product is diluted with CH2Cl2, dried over Na2SO, and purified by chromatography (CH2Cl2 / MeOH: 97/3), to give the pure product (yield of about 70 to 95 percent). (NMR and MS confirmed data, U-4117-102).

Procedure for compound F: A solution of (2S, 3R) -3- (2-phenethyl-amino-ethyl) -1 - ((S) -1-phenyl-ethyl) -pyrrolidin-2-methyl ester carboxylic (400 milligrams, 1.05 millimoles) and 2-hydroxy-pyridine (100 milligrams, 1.05 millimoles) in tetrahydrofuran (10 milliliters) is stirred at 40 ° C for 24 hours. The reaction is diluted with 50 milliliters of ether, and washed with 120 milliliters of water 2 times. It is then dried and concentrated to give a pale liquid (350 milligrams, LC / MS showed a clean product only) without further purification for the next step reaction. (3aR, 8aS) -7-phenethyl-1 - ((S) -1-phenyl-ethyl) -decahydro-pyrrolo- [2,3-c] -azepine (G): To a solution (0.02 M) of lactam (1 equivalent) in tetrahydrofuran at -20 ° C, a solution (0.02 M) of LiAIH4 (2 equivalents) in tetrahydrofuran is added slowly. After stirring at room temperature for 1.5 hours, the solution is diluted with ether (1 x 5 times by volume of the solution), and washed with water (2 x 2 times by volume of the solution), dried and concentrated . The crude product is purified by chromatography (CH2Cl2 / MeOH: 97/3), to give the product (yield of about 70 to 90 percent). (NMR and MS confirmed data, U-4117-104). (3aR, 8aS) -7-phenethyl-decahydro-pyrrolo- [2,3-c3-azepine (H): A solution / suspension of the reagent (<1 gram) and 10% Pd on carbon (20%) in weight) in MeOH (10 milliliters, with 2 drops of acetic acid) in a 1000 milliliter round flask, is stirred vigorously at room temperature under hydrogen gas (at atmospheric pressure) from a balloon for about 4 to 8 hours. After it is degassed by a household vacuum for 10 minutes, the reaction mixture is filtered to remove the catalyst, and concentrated. The crude product is diluted with CH 2 Cl 2 / H 2 O (8/2, reasonable amount), and neutralized with 10 percent NH 4 OH to a pH = about 7 to 8. It is then dried and concentrated to give the product (80 percent , approximately quantitative yield) without purification for the reaction of the next step. (NMR and confirmed MS data, U-4117-105).

(S) -N - ((S) -1-cyclohexyl-2-. {(2S, 3R) -2 - [(ethyl-phenethyl-amine) -methyl] -3-methyl-pyrrolidin-1- il.} -2-oxo-ethyl) -2-methyl-amino-propionamide (compound 23): Prepared from compound H following the procedures set forth in Scheme 5.

Example 3 Diagram 6: Difenethylamine (D). To a solution of phenyl-acetaldehyde (6.0 grams, 50 mmol) and 2-phenylethylamine in tetrahydrofuran (200 milliliters), triacetoxy borohydride sodium is added dropwise. The solution is stirred under nitrogen overnight at room temperature. The solution is quenched with saturated aqueous sodium bicarbonate (200 milliliters), and extracted with EtOAc (100 milliliters, 4 times). The organic extracts are combined, dried and concentrated in vacuo. The residue is purified by evaporation chromatography (silica gel; EtOAc / MeOH 9: 1) to provide 1.25 grams (11 percent) of compound D as a clear oil. M + H + = 226.10. Differentnetyl- (S) -1-pyrrolidin-2-yl-methyl-amine (E). To a solution of (S) -2-formyl-pyrrolidine-1-carboxylic acid terbutil ester (1.0 grams, 5.0 mmol) and D (1.125 grams, 5.0 mmol) in tetrahydrofuran (40 milliliters), it is added through Triacetoxy-sodium borohydride drip. The solution is stirred under nitrogen overnight at room temperature. The solution is quenched with saturated aqueous sodium bicarbonate (40 milliliters). The mixture is extracted with EtOAc (50 milliliters, 4 times). The organic extracts are combined, dried and concentrated in vacuo. The residue is purified by evaporation chromatography (silica gel; hexane / EtOAc, 4: 1) to give a yellow oil. The yellow oil is dissolved in dichloromethane (20 milliliters), trifluoroacetic acid (10 milliliters) is added, and the mixture is stirred at room temperature for 3 hours. The mixture is concentrated and the residue is dissolved in dichloromethane (100 milliliters), and neutralized with saturated sodium bicarbonate. The solution is extracted with dichloromethane (50 milliliters, 3 times). The organic extracts are combined, dried, and concentrated in vacuo to provide 1.04 grams (68 percent in two steps) of the title compound E, which is used in the next step without further purification or characterization. Compound (F). To a solution of t-Boc-L-cyclohexyl glycine (0.868 grams, 3.38 mmol) in N, N-dimethylformamide (20 milliliters), di-isopropyl-ethyl-amine (1.83 milliliters, 16.9 mg) was added. millimoles). The mixture is stirred for 20 minutes at room temperature. Then a solution of E, 1-hydroxybenzotriazole (516 milligrams, 3.82 millimoles), and O-benzyltriazol-1-yl-N, N, N \ N'-tetramethyl-uronium hexafluorophosphate (1448 grams, 3.82 millimoles) is added. N, N-dimethyl-formamide (30 milliliters). The mixture is stirred overnight at room temperature, and then diluted with ether (200 milliliters), and washed in sequence with 1 M citric acid (50 milliliters), water (50 milliliters), saturated aqueous NaHCO3 (50 milliliters) , and brine (50 milliliters, 2 times). The organic extract is dried and concentrated in vacuo. The residue is purified by evaporation chromatography (silica gel, hexane / EtOAc, 2: 3) to give a yellow oil. The yellow oil is dissolved in dichloromethane (20 milliliters), trifluoroacetic acid (10 milliliters) is added, and the mixture is stirred at room temperature for 3 hours. The mixture is concentrated, and the residue is dissolved in dichloromethane (100 milliliters), and neutralized with saturated sodium bicarbonate. The solution is extracted with dichloromethane (50 milliliters, 3 times). The organic extracts are combined, dried, and concentrated in vacuo to provide 780 milligrams (52 percent in two steps) of the title compound F, which is used in the next step without further purification or characterization. Compound 26. To a solution of t-Boc-N-methyl-L-alanine (354 milligrams, 1.75 millimoles) in N, N-dimethylformamide (20 milliliters), di-isopropyl-ethyl-amine (0.938) was added. milliliters, 8.75 millimoles). The mixture is stirred for 20 minutes at room temperature. Then add a solution of F, 1-hydroxybenzotriazole (267 milligrams, 1.98 millimoles), and O-benzyl-triazol-1-yl-N, N, N ', N'-tetramethyl-uronium hexafluorophosphate (751 milligrams, 1.98 millimoles) in N, N-dimethyl-formamide (30 milliliters). The mixture is stirred for 3 hours at room temperature, and then diluted with ether (200 milliliters), and washed in sequence with 1 M citric acid (50 milliliters), water (50 milliliters), saturated aqueous NaHCO3 (50 milliliters) , and brine (50 milliliters, 2 times). The organic extract is dried and concentrated in vacuo. The residue is dissolved in dichloromethane (20 milliliters), and trifluoroacetic acid (10 milliliters) is added. The mixture is stirred at room temperature for 3 hours and concentrated. The resulting residue is dissolved in dichloromethane (100 milliliters), and neutralized with saturated sodium bicarbonate. The solution is extracted with dichloromethane (50 milliliters, 3 times). The organic extracts are combined, dried and concentrated in vacuo. A portion of the residue is purified by HPLC (silica gel C-18, 30% CH 3 CN / H 2 O in 0.5 percent trifluoroacetic acid), to provide 120 milligrams of compound 26 as the trifluoroacetic acid salt. M + H + = 533.47.

Example 4 Compound 32 is prepared as follows: Qutral Separation Scheme 7 Compound I. Compounds G (122 milligrams, 1 millimole) and H (226 milligrams, 1 millimole) are dissolved in 5 milliliters of ethylene glycol dimethyl ether. To this, a mixture of 1 milliliter of 2N aqueous Na2CO3 and 50 milligrams of tetrakis- (triphenylphosphine) -palladium (O) is added. The resulting mixture is degassed for 5 minutes, stirred at 90 ° C for 6 hours, cooled to room temperature, and concentrated. The residue is purified by evaporation chromatography (ethyl acetate / hexane) to give the I as an amber oil (204 milligrams, 90 percent). The crude product is used directly in the next reaction without further purification or characterization. Compound J. LAH (38 milligrams) is added to a solution of I (226 milligrams, 1 millimole) in 5 milliliters of tetrahydrofuran at 0 ° C. The temperature of the mixture is allowed to warm to room temperature, and is further stirred overnight. The reaction is quenched following Fisher's method, filtered, and concentrated to give J as a colorless oil (183 milligrams, 92 percent), and used directly in the next reaction without further purification or characterization. Compound K. The suspension of compound J (198 milligrams, 1 millimole) and MnO2 (870 milligrams, 10 millimoles) in 15 milliliters of chloroform is stirred overnight. Filtration and concentration produced the product K as a colorless oil (192 milligrams, 98 percent). 1 H-NMR (CDCl 3) d 9.96 (s, 1H), 7.72 (s, 2H), 7.47 (s, 2H), 7.15-7.35 (m, 5H), 4.07 (s, 2H). Compound L. A mixture of 3-chloro-propyl-amine hydrochloride (140 milligrams, 1.1 millimoles), aldehyde K (196 milligrams, 1.0 millimoles), and sodium carbonate (212 milligrams, 2 millimoles) in water (10 milliliters) ), is stirred overnight at room temperature. The resulting solution is extracted with ethyl acetate (20 milliliters, 3 times), separated, dried over Na2SO4, and evaporated under vacuum (15 Torr), to give an essentially pure oil residue (270 milligrams), which is used for the next reaction without further purification. (M + H + = 272, calculated: 272). Compound Imine L (271 milligrams, 1 millimole) is added to a blue suspension of lithium powder (75 milligrams, 10 millimoles) and a catalytic amount of 4,4'-di-tert-butyl-biphenyl (30 milligrams, 0.10 millimoles; mole percent) in tetrahydrofuran (5 milliliters) at -78 ° C. The resulting mixture is stirred for 2 hours at the same temperature. The reaction is quenched with water (20 milliliters), allowing the temperature to rise to 20 ° C. The resulting solution is purified by successive extraction of acid-base with 2 M hydrochloric acid (15 milliliters, 3 times) and 4 M sodium hydroxide (20 milliliters, 3 times.) The final solution is extracted with ethyl acetate (20 milliliters, 3 times), separated, dried over Na2SO4, and evaporated, to give pure compound M (214 milligrams, 90 percent); (M + H + = 238, calculated: 238) Compound O. A mixture of the compound M (237 milligrams, 1 millimole), compound N (257 milligrams, 1 millimole), O-benzyltriazol-1-yl-N, N, N ', N'-tetramethyl-uronium hexafluorophosphate (460 milligrams, 1.2 millimoles) , 1-hydroxy-benzotriazole (170 milligrams, 1.1 mmol), di-isopropyl-ethyl-amine (512 milligrams, 3 mmol), and 5 milliliters of N, N-dimethyl formamide, is stirred overnight. dilute with ether (25 milliliters), wash with water, brine, dry over MgSO 4, filter, and concentrate The resulting residue is treated with 2 milliliters of CH 2 Cl 2 / trifluoro-ac acid (1/1), stirred for 2 hours, and concentrated to afford the product as an O pale yellow solid (320 mg, 85 percent); (M + H + = 377, calculated: 377). Compound 32. A mixture of compound O (376 milligrams, 1 millimole), t-Boc-N-methyl-alanine P (203 milligrams, 1 millimole), O-benzyltriazole-1-yl-N hexafluorophosphate, N, N ', N'-tetramethyl-uronium (460 milligrams, 1.2 millimoles), 1-hydroxybenzotriazoi (170 milligrams, 1.1 millimoles), di-isopropyl-ethyl-amine (512 milligrams, 3 millimoles), and 5 milliliters of N, N-dimethyl formamide, is stirred overnight. The mixture is diluted with ether (25 milliliters), washed with water, brine, dried over MgSO 4, filtered, and concentrated. The resulting residue is treated with 2 milliliters of CH2Cl2 / trifluoroacetic acid (1/1), stirred for 2 hours, and concentrated in vacuo. Column chromatography afforded compound 32 as a pale yellow solid (397 milligrams, 86 percent). (M + H + = 462, calculated: 462).

Example 5 (S) -N-. { (S) -1-Cycloalkyl-2 - [(S) -2- (i n dan -2-i I oxymethyl) -pyrrole din 1-l] -2-oxo-ethyl} -2-methyl-amino-propionamide (34) (S) -2-Methanesulfonyloxy-methyl-pyrrolidine-1-carboxylic acid terbutyl ester, (P). To a flame-dried flask, charged with (S) -2-hydroxy-methyl-pyrrolidine-1-carboxylic acid terbutil-ester (1 gram, 5 mmol), dichloromethane (DCM) (20 milliliters), and triethyl -amine (0.70 milliliters, 5.2 mmol), cooled to 0 ° C under N2, a solution of methanesulfonyl chloride (0.38 milliliters, 5 mmol) in dichloromethane (5 milliliters) was added dropwise over 10 minutes. The reaction is stirred for 1 hour. After the addition of dichloromethane (100 milliliters), the reaction mixture is washed with brine, dried, and concentrated in vacuo. The residue is purified by chromatography on SiO2 (5 percent EtOAc / hexanes), to give 1.37 grams of the methanesulfonate ester (P) as a clear colorless oil: LCMS (ES) 280.10 (MHM-Terbutil-acid ester (S) ) -2- (indan-2-yloxy-methyl) -pyrrolidine-1-carboxylic acid, (Q) Sodium hydride (60 percent) (0.6 grams, 14.4 mmol) is added to a flame-dried flask, charged with indan-2-ol (0.965 grams, 7.2 mmol) and N, N'-dimethyl formamide (DMF) (20 milliliters), cooled to 0 ° C under N2, and stirred for 30 minutes. The reaction mixture was a solution of (S) -2-methansulfonyloxy-methyl-pyrrolidine-1-carboxylic acid (S) -2- (1 gram, 3.6 mmol) in N, N'-dimethyl-formamide (5). milliliters), so that it is kept at 0 ° C. The reaction is stirred at 60 ° C. for one hour, cooled to 0 ° C., quenched with brine, diluted with EtOAc, washed repeatedly with brine (6). times), dry, and concentrate in vacuum. The residue is purified by chromatography on SiO2 (5 percent EtOAc / hexanes), to give 0.20 grams of indanyl ether (Q) as a clear colorless oil: LCMS (ES) 340.17 (MNa +).

(S) -N-. { (S) -1-cyclohexyl-2 - [(S) -2- (indan-2-yloxy-methyl) -pyrrolidin-1-yl] -2-oxo-ethyl} -2-methyl-amino-propionamide, (34). The ((S) -1-. {(S) -1-cyclohexyl-2 - [(S) -2- (indan-2-yloxymethyl) -pyrrolidin-1-yl] - tert-butyl ester is dissolved. 2-oxo-ethylcarbamoyl.) -ethyl) -methyl-carbamic acid (Q) (0.54 grams, 1 millimole) in dichloromethane (8 milliliters), and treated with trifluoroacetic acid (4 milliliters) for 45 minutes. The reaction mixture is concentrated in vacuo, purified by reverse phase high pressure liquid chromatography of preparation, to give 0.096 grams of methylamine (34) as a clear gum: LCMS (ES) 442.26 (MH +).

Example 6 HOBt, HBTU, DIPEA > O TFA CH2CI2 D - ?? N NHBoc 1-Bromo-3-phenoxy-benzene (A). A mixture of dibromobenzene (3 grams, 12.75 millimoles), phenol (1 gram, 10.6 millimoles), copper oxide (1) (152 milligrams, 1 millimole), and cesium carbonate (3.46 grams, 10.6 millimoles), in 8 milliliters of NMP, is heated at 195 ° C for 20 minutes in a microwave oven. The heterogeneous mixture is filtered through a pad of Celite, and the residue is washed with EtOAc (20 milliliters, 1 time). The filtrate is diluted with 1 N NaOH (200 milliliters), and extracted with EtOAc (100 milliliters, 3 times). The organics are combined, dried over Na2SO, filtered, and concentrated under reduced pressure, to give the crude product as a yellow oil, which is purified by column chromatography (100 percent hexanes), to give the -bromo-3-phenoxy-benzene as a colorless oil (1.4 grams, 53 percent). LCMS m / z 250 (M + 1). 5- (3-phenoxy-phenyl) -3,4-dihydro-2H-pyrrole (B): To a cold solution (-78 ° C) of 1-bromo-3-phenoxy-benzene (10.13 grams, 40.6 millimoles) in anhydrous tetrahydrofuran (100 milliliters) and under nitrogen, n-BuLi (1.6 M, 44.7 mmol, 27 milliliters) is added. The mixture is allowed to stir for 30 minutes before being added to a cold solution (-78 ° C) of 1- (terbutoxy-carbonyl) -2-pyrrolidinone in anhydrous tetrahydrofuran (50 milliliters) under nitrogen via a cannula. The resulting mixture is allowed to warm to room temperature overnight before quenching with water (200 milliliters), and extracted with EtOAc (100 milliliters, 3 times). Organics were collected, dried over Na2SO, filtered and concentrated under reduced pressure. The residue is dissolved in CH2Cl (20 milliliters), and trifluoroacetic acid (10 milliliters) is added with stirring. The mixture is stirred for 30 minutes and quenched over ice-cold saturated NaHCO3, extracted with CH2Cl2 (100 milliliters, 3 times), and the organics combined, dried over Na2SO, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (20 percent EtOAc / hexanes), to give 5- (3-phenoxy-phenyl) -3,4-dihydro-2H-pyrrole as a light yellow oil ( 6.1 grams, 63 percent). LCMS m / z 238 (M + 1). (S) -2- (3-phenoxy-phenyl) -pyrrolidine (C): To an oven-dried round bottom flask, add S, S-EBTHITF2 (100 milligrams, 0.3 mmol), and dilute with tetrahydrofuran (5 milliliters). The flask is sealed and purged with argon. To the yellow solution is added phenylsilane (4.6 milliliters, 37.5 millimoles), pyrrolidine (100 microliters, 1.1 millimoles), and anhydrous methanol (100 microliters, 1.1 millimoles). The resulting yellow mixture is stirred for 45 minutes until the green color persists. To the catalyst is added a solution of 5- (3-phenoxy-phenyl) -3,4-dihydro-2H-pyrrole (1.2 grams, 5.05 mmol) in tetrahydrofuran (2 milliliters), and the mixture is stirred for 8 hours. The reaction is carefully quenched with 10 percent HCl ai (100 milliliters) until the evolution of gas ceases and until the pH is about 2. The mixture is diluted with EtOAc (100 milliliters), and the aqueous layer is removed, neutralize with 3 M NaOH (50 milliliters) until basic, and extract with EtOAc (100 milliliters, 3 times). The organics were combined, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The solid residue is purified by silica gel column chromatography (100 percent EtOAc) to give (S) -2- (3-phenoxy-phenyl) -pyrrolidone as a yellow solid (580 milligrams, 48%). hundred). LCMS m / z 240.1 (M + 1).

Terbutil-acid ester. { (S) -1-cyclohexyl-2-oxo-2 - [(S) -2- (3-phenoxy-phenyl) -pyrrolidin-1-yl] -ethyl} -carbamic (D): (S) -2- (3-phenoxy-phenyl) -pyrrolidine (1.2 grams, 5.02 mmol) is added to a solution of Boc-La-cyclohexyl-glycine (1.42 grams, 5.2 mmol), 1 -hydroxybenzotriazole (1.0 grams, 7.53 millimoles), and O-benzyltriazol-1-yl-N, N, N ', N'-tetramethyl-uronium hexafluorophosphate (2.86 grams, 7.53 millimoles) in 10 milliliters of N, N-dimethyl -formamide. Hunig's base (3.6 Ml, 20 mmol) is added, and the mixture is stirred for 30 minutes. The mixture is diluted with brine (20 milliliters), and extracted with EtOAc (10 milliliters, 3 times). The organics were combined, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (20 percent EtOAc / hexanes), to give the terbutilus acid ester. { (S) -l-cyclohexyl-2-oxo-2 - [(S) -2- (3-phenoxy-phenyl) -pyrrolidin-1-yl] -ethyl} -carbamic as a white powder (1.65 grams, 66 percent). LCMS m / z 479.2 (M + 1). (S) -2-amino-2-cyclohexyl-1 - [(S) -2- (3-phenoxy-phenyl) -pyrrolidin-1-yl] -ethanone (E): To a solution of terbutyl ester of the acid . { (S) -1-Cyclohexyl-2-oxo-2 - [(S) -2- (3-phenoxy-phenyl) -pyrrolidin-1-yl] -ethyl} -carbámico in CH2Ci2 (20 milliliters), add trifluoroacetic acid (10 milliliters), and the mixture is stirred for 30 minutes. The mixture is concentrated under reduced pressure, to give (S) -2-amino-2-cyclohexyl-1 - [(S) -2- (3-phenoxy-phenyl) -pyrrolidin-1-yl] -ethanone as a quantitatively salt of trifluoroacetic acid (1.65 grams). LCMS m / z 379 (M + 1).

TerbutH-acid ester ((S) -1- { (S) -1-cyclohexyl-2-oxo-2 - [(S) -2- (3-phenoxy-phenyl) -pyrrolidin-1-yl] -ethyl-carbamoyl.} -ethyl) -methyl-carbamic acid (F): To a solution of Boc-N-methyl-L-alanine (771 milligrams, 3.79 mmol), 1-hydroxybenzotriazole (700 milligrams, 5.17 mmol), and O-benzyltriazol-1-yl-N, N, N ', N'-tetramethyl-uronium hexafluorophosphate (2.0 grams, 5.17 mmol) in N, N-dimethylformamide (10 milliliters) is added (S) -2-amino-2-cyclohexyl-1 - [(S) -2- (3-phenoxy-phenyl) -pyrrolidin-1-yl] -et -one and di-isopropyl-ethyl-amine (3 milliliters, 17.25 mmol) . The mixture is stirred for 30 minutes and diluted with brine (20 milliliters), and extracted with EtOAc (10 milliliters, 3 times). The organics were combined, dried over Na 2 SO 4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (50 percent EtOAc / hexanes), to give the terbuthyl ester product ((S) -1 - { (S) -1-cyclohexyl-2-oxo-2 - [(S) -2- (3-phenoxy-phenyl) -pyrrolidin-1-yl] -ethyl-carbamoyl} -ethyl) -methylcarbamic acid as a white powder (1.3 grams, 84 percent). LCMS m / z 564 (M + 1). (S) -N-. { (S) -1-cyclohexyl-2-oxo-2 - [(S) -2- (3-phenoxy-phenyl) -pyrrolidin-1-yl] -ethyl} -2-Methyl-amino-propionamide (45): To a solution of ((S) -1-. {(S) -1-cyclohexyl-2-oxo-2- ((S) -) terbutyl ester 2- (3-phenoxy-phenyl) -pyrrolidin-1-yl] -ethyl-carbamoyl.] -ethyl) -methyl-carbamic acid (450 milligrams, 0.79 mmol) in CH2Cl2 (20 milliliters), trifluoroacetic acid ( 10 milliliters), and stirred for 30 minutes. The mixture is concentrated under reduced pressure, and purified by reverse phase column chromatography, to give the product as a trifluoroacetic acid salt (370 milligrams, 82 percent). LCMS m / z 464.1 (M + 1).

Example 7 Terbutil-ester of (S) -2- (1 H-tetrazol-5-yl) -pyrrolidine-1-carboxylic acid (A). To a solution of (S) -2-cyano-pyrrolidin-1-carboxylic acid terbutyl ester (500 milligrams, 2.55 millimoles) in N, N-dimethylformamide (20 milliliters), sodium azide (174 mg) is added. milligrams, 2.68 millimoles) and ammonium chloride (150 milligrams, 2.81 millimoles). The solution is stirred at 93 ° C overnight. The solution is poured into a 5 percent citric acid solution with ice, and the mixture is extracted with EtOAc. The organic extract is washed with brine, dried, and concentrated in vacuo. The crude oil is used directly in the next step without further purification. M + H + = 240. (S) -2- (2-Benzyl-2H-tetrazol-5-yl) -pyrrolidine-1-carboxylic acid ester (B). To a solution of the crude compound A in N, N-dimethylformamide (5 milliliters) is added K2CO3 (1.16 grams, 8.4 millimoles) and benzyl bromide (665 microliters, 5.6 millimoles). The solution is stirred at room temperature for 1 hour. The mixture is diluted with EtOAc and washed with brine. The organic layer is dried and concentrated in vacuo. The residue is purified by column chromatography by evaporation (hexanes / EtOAc), to provide 404 milligrams of the title compound, M + H + = 330, and 401 milligrams of the other regio-isomer, (S) -2- (1-benzyl-1 H-tetrazole) terbutyl ester -5-yl) -pyrrolidine-1-carboxylic acid (C). M + H + = 330. The combined yield is 87 percent for the 2 steps. 2-benzyl-5- (S) -pyrrolidin-2-yl-2H-tetrazole (D). To a solution of compound B in dichloromethane (5 milliliters), triethylsilane (479 microliters, 3.0 mmol), and then trifluoroacetic acid (5 milliliters) is added. The solution is stirred at room temperature for 1 hour and dried under vacuum. The crude oil is used directly in the next step without further purification. M + H + = 230.

Terbutil-acid ester. { 2 - [(S) -2- (2-Benzyl-2H-tetrazol-5-yl) -pyrrolidin-1 -yl] -1-cyclohexyl-2-oxo-ethyl} -carbámíco (E). To a solution of (S) -tertbutoxy-carbonyl-amino-cyclohexyl-acetic acid (123.8 milligrams, 0.48 mmol) in DMA (5 milliliters), hexafluoro-phosphate of O-benzyltriazol-1 -yl-N, N is added. , N ', N'-tetramethyl-uronium (248.8 milligrams, 0.656 millimoles), 1-hydroxybenzotriazole (88.6 milligrams, 0.656 millimoles), and di-isopropyl-ethyl-amine (305 microliters, 1.75 millimoles). The mixture is stirred at room temperature for 5 minutes. To the above mixture is added a solution of compound D in dichloromethane (5 milliliters) at 0 ° C. The reaction mixture is stirred at room temperature for 1 hour, and concentrated in vacuo. The residue is diluted with EtOAc. The organic is washed with brine, citric acid (5 percent), brine, NaHCO3 (saturated), and brine. Then the organic layer is dried and concentrated in vacuo. The residue is purified by column chromatography by evaporation (hexanes / EtOAc) to give the title compound (190 milligrams, 92 percent). M + H + = 369. 2-amino-1 - [(S) -2- (2-benzyl-2H-tetrazol-5-yl] -pyrrolidin-1-yl] -2-cyclohexyl-ethanone; compound with trifluoric acid -acetic (F) To a solution of compound E in dichloromethane (4 milliliters), trifluoroacetic acid (4 milliliters) is added at 0 ° C. The solution is stirred at room temperature for 1 hour, and dried at room temperature. empty The crude oil is used directly in the next step without further purification M + H + = 369.

Terbutil-ester of the acid ((S) -1- { 2 - [(S) -2- (2-benzyl-2H-tetrazol-5-yl) -pyrrolidin-1-yl] -1-cidohexyl-2 -oxo-ethyl-carbamoyl.}. propyl) -methyl-carbamic acid (G). To a solution of (S) -2- (terbutoxy-carbonyl-methyl-amino) -butyric acid (53.0 milligrams, 0.24 millimoles) in DMA (2 milliliters), hexafluorophosphate is added.

O-benzyltriazol-1-yl-N, N, N ', N'-tetramethyl-uronium (125.0 milligrams, 0.33 mmol), 1-hydroxybenzotriazole (44.6 milligrams, 0.33 mmol), and di-isopropyl-ethyl-amine (192 microliters, 1.1 mmol). The mixture is stirred at room temperature for 5 minutes. A solution of compound F in dichloromethane (2 milliliters) is added to the above mixture at 0 ° C. The reaction mixture is stirred at room temperature for 1 hour, and concentrated in vacuo. The residue is diluted with EtOAc. The organic is washed with brine, citric acid (5 percent), brine, NaHCO3 (saturated), and brine. The organic layer is then dried and concentrated in vacuo. The crude oil is used directly in the next step without further purification. M + H + = 554. (S) -N-. { 2 - [(S) -2- (2-Benzyl-2H-tetrazol-5-yl) -pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-ethyl} -2-methyl-amino-butyramide; compound with trifluoroacetic acid (50). To a solution of compound G in dichloromethane (2 milliliters), trifluoroacetic acid (2 milliliters) is added at 0 ° C. The solution is stirred at room temperature for 1 hour, and dried in vacuo. The crude oil is purified by high pressure liquid chromatography to provide the title compound. M + H + = 467.

Example 8 cx ° -O ^ h pyridine H, N 'v. Ph boc 9 AA h TFA? A? > - '8% boc B DIPEA, HOBt, HBTU Boc-N-methyl-L-alanine 2- (Benzyloxy-imino-methyl) pyrrolidine-1-carboxylic acid terbutil-ester (A). To a solution of benzyl-hydroxylamine (2.64 grams), 16.56 millimoles) in dry pyridine (20 milliliters), is added 2-formyl-pyrrolidine-1-carboxylic acid terbutyl ester (3.30 grams, 16.56 millimoles). The solution is stirred for three hours at room temperature. The reaction solution is quenched with water and extracted with dichloromethane. The organic layer is combined, dried, and concentrated in vacuo. The residue is purified by evaporation chromatography (silica gel; 50 percent to 50 percent ethyl acetate in hexane), to provide 4.9 grams (98 percent) of the title compound. M + H + -Boc = 205.1. Pyrrolidine-2-carbaldehyde-O-benzyl oxime (B). The solution of 2 ~ (benzyloxy-imino-methyl) -pyrrolidine-1-carboxylic acid terbutyl ester (1.50 grams, 4.92 mmol) and trifluoroacetic acid (10 milliliters) in dichloromethane (10 milliliters) is stirred for 2 hours at room temperature. The solvent is removed. The crproduct is taken to the next step without further purification. M + H + = 205.1. Terbutil-acid ester. { (S) -2- [benzyloxy-imino-methyl-pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-ethyl} -carbámico (C). The solution of Boc-L-a-cyclohexyl-glycine (1.27 grams, 4.93 millimoles), 1-hydroxybenzotriazole (0.99 grams, 7.38 millimoles), di-isopropyl-ethyl-amine (2.54 grams, 19.68 millimoles), and O-benzotriazole hexafluorophosphate-N, N, N ', N'-tetramethyl-uronium (2.80 grams, 7.38 mmol) in dichloromethane (30 milliliters), is stirred for 15 minutes at room temperature. A solution of pyrrolidin-2-carbaldehyde-O-benzyl oxime (approximately 1.00 grams, 0.49 mmol) in dichloromethane is added. The reaction solution is stirred for three hours at room temperature, then quenched with saturated aqueous NaHCO3, and extracted with dichloromethane. The organic layer is combined, dried, and concentrated in vacuo. The residue is purified by evaporation chromatography (silica gel, 20 percent to 70 percent ethyl acetate in hexane), to give 1.81 grams (83 percent over 2 steps) of the title compound. M + H + = 444.2. 1 - ((S) -2-amino-2-cyclohexyl-acetyl) -pyrrolidin-2-carbaldehyde-O-benzyl oxime (D). The solution of terbutil-ester of the acid. { (S) -2- [benzyloxy-imino-methyl-pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-ethyl} -carbamic (1.76 grams, 3.97 mmol) and trifluoroacetic acid (10 milliliters) in dichloromethane (20 milliliters), is stirred for one hour. The solvent is removed in vacuo. The residue is taken to the next step without further purification. M + H + = 344.2. Terbutil-ester of ((S) -1- { (S) -2- [2- (benzyl-oxy-imino-methyl) -pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-ethyl acid -carbamoyl.} -ethyl) -methyl-carbamic (E). The solution of Boc-La-cyclohexyl-glycine (0.81 grams, 3.87 millimoles), 1-hydroxy-benzotriazole (0.81 grams, 5.95 millimoles), di-isopropyl-ethyl-amine (2.05 grams, 15.88 millimoles), and O-hexafluorophosphate -benzotriazole-NNN'.N'-tetramethyl-uronium (2.35 grams, 5.95 mmol) in dichloromethane, is stirred for 15 minutes at room temperature. A solution of 1 - ((S) -2-amino-2-cyclohexyl-acetyl) -pyrrolidine-2-carbaldehyde-O-benzyl oxime (approximately 1.40 grams, 3.97 mmol) in dichloromethane is added. The reaction solution is stirred for three hours at room temperature, and then quenched with saturated aqueous NaHCO3, and extracted with dichloromethane. The organic layer is combined, dried, and concentrated in vacuo. The residue is taken to the next step without further purification. M + H + = 529.4. (S) -N-. { 2- [2- (benzyloxy-imino-methyl-pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-ethyl} -2-methyl-amino-propionamide (8). ((S) -1 - { (S) -2- [2- (benzyl-oxy-imino-methyl) -pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-etii-carbamoyl acid} .-ethyl) -methyl-carbamic acid (approximately 2.10 grams, 3.97 mmol) and trifluoroacetic acid (20 milliliters) in dichloromethane (40 milliliters), stir for one hour, remove the solvent in vacuo to obtain 1.36 grams of crude product. The crude product is purified (0.66 grams) by high pressure liquid chromatography (silica gel C-18, 10 percent to 70 percent CH3CN / H2O in 0.1 percent trifluoroacetic acid), to provide 0.058 grams of the title compound as the trifluoroacetic acid salt of isomeric mixtures M + H + = 429.4.

Examples 9 to 78 The following compounds are prepared by analogous methods to those described herein, using analogous starting materials: fifteen twenty Additional compounds within the scope of the Formula include: Example 195 (S) -N - [(S) -1-cyclohexyl-2 - ((R) -2-. {6 - [(2-fluoro-phenyl) -methyl-amino] -pyridin-2- il.} - pyrrolidin-1-yl) -2-oxo-ethyl] -2-methyl-amino-propionamide (78) 4,4, N-trimethoxy-N-methyl-butyramide (1). To a solution of methyl 4,4-dimethoxybutyrate (4.99 grams, 30.8 millimoles) and N, O-dimethylhydroxylamine hydrochloride (4.65 grams, 47.68 millimoles) in 60 milliliters of tetrahydrofuran at -20 ° C. add iso-propylmagnesium chloride (46 milliliters, 92.28 millimoles, 2.0M in tetrahydrofuran), keeping the temperature below -20 ° C. After stirring at -10 ° C for 30 minutes, the reaction mixture is quenched with 50 milliliters of water, and extracted with 80 milliliters of EtOAc, 3 times. The combined organic layers are dried over Na2SO, and filtered through a plug of short silica gel. The solution is concentrated to give 4.4, N-trimethoxy-N-methyl-butyramide (5.9 grams, 99 percent) as a pale liquid. M / Z = 191.0. N- [1-et- (Z) -ylidene-5,5-dimethoxy-2-oxo-pentyl] -ac-undiolyl bromide (2). To a suspension of 2,6-dibromo-pyridine (8.1 grams, 34.03 mmol) in 80 milliliters of ether at -70 ° C, BuLi (12.3 milliliters, 26.17 mmol, 2.5 M in hexane) is added in one portion. After stirring at -70 ° C for 5 minutes, 4.4, N-trimethoxy-N-methyl-butyramide (5.0 grams, 26.17 mmol) is added dropwise to the solution. After stirring at -70 ° C for 1.5 hours, the reaction mixture is quenched with 120 milliliters of water and extracted with 130 milliliters of EtOAc, 3 times. The combined organic layers are concentrated and purified by chromatography (hexane / EtOAc: 70/30) to give N- [1-et- (Z) -ylidene-5,5-dimethoxy-2-oxo-pentyl bromide. ] -acrilimidoyl (5.96 grams, 60.5 percent) as a light yellow liquid. M / Z = 288.0. N- [1-et- (Z) -ylidene-2,5-dioxo-pentyl] -acyl-imidoyl bromide (3). To a solution of N- [1-et- (Z) -ylidene-5,5-dimethoxy-2-oxo-pentyl] -acrylimidoyl bromide (7.0 grams, 28.9 mmol) in an acetone solution (30 milliliters) and water (1.5 milliliters) at room temperature, Amberlyse-15 (20 grams) is added.

After mechanical stirring for 3 hours at room temperature, the reaction mixture is filtered. The resin beads are washed with acetone (contain 10 percent Et3N). The combined organic layers are concentrated and purified by chromatography (hexane / EtOAc: 70/30) to yield N- [1-et- (Z) -ylidene-2,5-dioxo-pentyl] -acryl bromide. imidoyl (5.18 grams, 88.1 percent) as a light yellow liquid. M / Z = 421, 243.9 [M + 1]. 2-Bromo-6 - [(S) -1 - ((R) -1-phenyl-ethyl) -pyrrolidin-ethyl) -pyrrolidin-2-yl] -pyridine (4). To a solution of N- [1-et- (Z) -ylidene-2,5-dioxo-pentyl-acryl-imidoyl bromide (1.0 grams, 4.1 mmol) and R (+) -a-methyl-benzyl-amine (0.5 grams, 4.1 millimoles) in 17 milliliters of CH2Cl2 at -70 ° C, are added acetic acid (0.6 mL) and sodium triacetoxyborohydride (1.74 g, 8.2 mmol). After stirring at -70 ° C for 40 minutes, the dry ice bath is removed, and the reaction solution is warmed to room temperature. After stirring at room temperature overnight, the reaction mixture is quenched with 20 milliliters of water, and extracted with 30 milliliters of CH 2 Cl 2, 3 times. The combined organic layers are concentrated and purified by chromatography (hexane / EtOAc: 70/30), to yield 2-bromo-6 - [(S) -1 - ((R) -1-phenyl-ethyl) -pyrrolidine. -2-i I] -pyrid ina (0.86 grams, 62.9 percent) as a light yellow liquid. M / Z = 332.7 [M + 1]. (Z) -N- (2-fluoro-phenyl) -N-methyl-N '- [1 - [(S) -1 - ((R) -1-phenyl-ethyl) -pyrrolidin-2-yl] - prop-2-en- (E) -ylidene] -propenamidine (5).

To a solution of 2-bromo-6 - [(S) -1 - ((R) -1-phenyl-ethyl) -pyrrolidin-2-yl] -pyridine (86.5 milligrams, 2.57 mmol), 2-fluoro- methyl-aniline (64.7 mg, 5.14 mmol) and 2- (dicyclohexyl-phosphino) -bi-phenyl (38.5 mg, 0.13 mmol) in 20 mL of toluene at room temperature was added Pd2 (dba) 3 ( 117.6 milligrams, 0. 13 millimoles). The reaction mixture is stirred at 80 ° C for 2 hours, and then cooled to room temperature. The reaction mixture is filtered through Celite, and the filtrate is diluted with 50 milliliters of EtOAc, and washed with 50 milliliters of water, 2 times. The combined organic layers are concentrated and purified by chromatography (CH2Cl2 / MeOH: 97/3) to give (Z) -N- (2-fluoro-phenyl) -N-methyl-N, - [1 - [( S) -1 - ((R) -1-phenyl-etii) -pyrrolidin-2-yl] -prop-2-en- (E) -ylidene] -propenamidine (870 milligrams, 90.3 percent) as a pale solid . M / Z = 376.0 [M + 1], (Z) -N- (2-fluoro-phenyl) -N-methyl-N '- [1 - [(S) -1- (< R) -1- phenyl-ethyl) -pyrrolidin-2-yl] -prop-2-en- (E) -ylidene] -propenamidine (6). The (Z) -N- (2-fluoro-phenyl) -N-methyl-N '- [1 - [(S) -1 - ((R) -1-phenyl-ethyl) -pyrrolidin-2- is dissolved yl] -prop-2-en- (E) -ylidene] -propenamidina (500 milligrams, 1.33 millimoles) in 10 milliliters of MeOH into a round bottom flask 500 ml, with 300 mg of Pd / C. The reaction mixture is stirred under H2 gas (1 atmosphere) from a balloon for 24 hours. After degassing in vacuo, the reaction mixture is filtered to remove the catalyst. The crude product is purified by reverse phase high pressure liquid chromatography to give (Z) -N- (2-fluoro-phenyl) -N-methyl-N '- [1 - [(S) -1- ((R) -1- phenyl-ethyl) -pyrrolidin-2-yl] -prop-2-en- (E) -ylidene] -propenamidine (200 milligrams, 55.4 percent) as a yellow oil. M / Z = 272.07 [M + 1]. [(S) -1-cyclohexyl-2 - ((S) -2- { 1 - [(E) - (Z) -N- (2-fluoro-phenyl) -N-methyl] tert-butyl ester -1-ioxoxo-propenyl-imino] -alyl.} Pyrrolidin-1-yl) -2-oxo-ethyl] -carbamic acid (7). To a solution of Boc-La-cicIohexil-glycine (204 mg, 0.79 mmol) in 5 mL of N, N-dimethylformamide at room temperature was slowly added diisopropyl-ethylamine (0.58 milliliters, 3.3 millimoles ). After stirring at room temperature for 20 minutes, a solution of 1-hydroxybenzotriazole (116 mg, 0.86 mmol) and O-benzyltriazole-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate is added ( 325 milligrams, 0.86 millimoles) in N, N-dimethylformamide (5 milliliters) to the reaction mixture, and the solution is transferred to another flask containing (Z) -N- (2-fluorophenyl) -N-methyl-N '- [(S) - 1-pyrrolidin-2-yl-prop-2-en- (E) -ylidene] -propenamidine (180 milligrams, 0.66 millimoles). After stirring for 1 hour, the reaction solution is diluted with EtOAc (50 milliliters), and washed with water (20 milliliters, 3 times). The combined organic layers are concentrated. The crude product is diluted with CH2Cl2 (10 milliliters), dried over Na2SO4, and purified by chromatography (CH2Cl2 / MeOH: 97/3), to give the terbutilic acid ester [(S)]. { 1-cyclohexyl-2 - ((S) -2- { 1 - [(E) - (Z) -N- (2-fluoro-phenyl) -N-methyl-1-imioxo-propeni! -imino] -alyl.} - pyrrolidin-1-yl) -2-oxo-ethyl] -carbamic acid (320 milligrams, 94.5 percent) as a pale gum. M / Z = 511.14 [M + 1]. (Z) -N'- |; i - [(S) -1 - ((S) -2-amino-2-cyclohexyl-acetyl) -pyrrolidin-2-yl] -prop-2-en- (E) -ylidene] -N- (2 -fluoro-phenyl) -N-methyl-propenamidine (8). To a solution of terbutil-ester of acid [(S). { 1-cyclohexyl-2 - ((S) -2- { 1 - [(E) - (Z) -N- (2-fluoro-phenyl) -N-methyl-1-imioxo-propenyl-imino] - allyl} - pyrrolidin-1-yl) -2-oxo-ethyl] -carbamic acid (320 milligrams, 0.63 mmol) in CH2Cl2 (3 milliliters) at -20 ° C, trifluoroacetic acid (5 milliliters, previously cooled to -20 ° C). After stirring at 0 ° C for 30 minutes, the reaction mixture is concentrated to remove most of the trifluoroacetic acid.

The residue is dissolved in 20 milliliters of CH2Cl2, and neutralized with 10 percent NH4OH to pH = 8. The solution is dried over Na2SO4, and concentrated, to give the (Z) -N '- [1- [ (S) -1 - ((S) -2-amino-2-cyclohexyl-acetyl) -pyrrolidin-2-yl] -prop-2-en- (E) -ylidene] -N- (2-fluoro-phenyl) ) -N-methyl-propenamidine (260 milligrams, quantitative) as a pale gum without further purification for the next step reaction. M / Z = 411.2 [M + 1]. Terbutil-acid ester. { (S) -1 - [(S) -1-cyclohexyl-2 - ((S) -2-. {6 - [(2-fIuoro-phenyl) -methyl-amino] -pyridin-2-yl} .pyrrolidin-1-yl) -2-oxo-ethyl-carbamoyl] -ethyl} -methyl-carbamic (9). To a solution of Boc-N-metii-La-alanine (155 milligrams, 0.76 millimoles) in 5 milliliters of N, N-dimethyl formamide at room temperature, di-isopropyl-ethyl-amine (0.58 milliliters, 3.3 millimoles). After stirring at room temperature for 20 minutes, a solution of 1-hydroxybenzotriazole (111 milligrams, 0.82 millimole) and O-benzyltriazol-1-yl-N, N, N ', N' hexafluorophosphate is added to the reaction mixture. -tetramethyl-uronium (311 milligrams, 0.82 mmol) in N, N-dimethyl-formamide (5 milliliters), and the solution is transferred to another flask containing (Z) -N '- [1 - [(S) -1 - ((S) -2-amino-2-cyclohexyl-acetyl) -pyrrolidin-2-yl] -prop-2-en- (E) -ylidene] -N- (2-fluoro-phenyl) -N -methyl-propenamidine (260 milligrams, 0.63 millimoles). After stirring for 1 hour, the reaction solution is diluted with EtOAc (50 milliliters), and washed with water (20 milliliters, 3 times). The combined organic layers are concentrated. The crude product is diluted with CH2Cl2 (10 milliliters), dried over Na2SO4, and purified by chromatography (CH2Cl2 / MeOH: 97/3), to give the terbutyl ester of the acid. { (S) -1 - [(S) -1-cyclohexyl-2 - ((S) -2-. {6 - [(2-fluoro-phenyl) -methyl-amino] -pyridin-2-yl} .pyrrolidin-1-yl) -2-oxo-ethyl-carbamoyl] -ethyl} -methyl-carbamic (300 milligrams, 79.5 percent) as a pale gum. M / Z = 596.2 [M + 1]. (S) -N - [(S) -1-cyclohexyl-2 - ((S) -2-. {6 - [(2-fluoro-phenyl) -methyl-aminoj-pyridin-2-yl}. -pyrrolidin-1-yl) -2-oxo-ethyl] -2-methyl-amino-propionamide (78). To a solution of the terbutil-ester of the acid. { (S) -1 - [(S) -1-cyclohexyl-2 - ((S) -2-. {6 - [(2-fluoro-phenyl) -methyl-amino] -pyridin-2-yl} .pyrrolidin-1-yl) -2-oxo-ethyl-carbamoyl] -ethyl} -methyl-carbamic (300 milligrams), 0.50 millimoles) in CH2CI2 (1 milliliter) at -20 ° C, trifluoroacetic acid (5 milliliters, previously cooled to -20 ° C) is added slowly. After stirring at 0 ° C for 30 minutes, the reaction mixture is concentrated and purified by preparative high pressure liquid chromatography (Column: Waters Sunfire prep C18, 30 x 100 millimeters; Mobile phase: isocratic condition, CH3CN al 28 percent / 72 percent H2O with 0.1 percent tri-fluoroacetic acid; Flow rate: 45 milliliters / minute), to give (S) -N - [(S) -1-cyclohexyl-2- ( (S) -2- {6 - [(2-fluoro-phenyl) -methyl-amino] -pyridin-2-yl}. -pyrrolidin-1-ii) -2-oxo-ethyl] -2- methyl-amino-propionamide (206 milligrams, 67.0 percent) as a white solid of the trifluoroacetic acid salt. (HR Masas M / Z = 496.3069 [M + 1]).

In order to measure the ability of the compounds of the invention to bind to the binding pocket of BIR3 peptide, an ELISA and cell-based assays are used. ELISA Compounds are incubated with GST-BIR3 fusion protein and biotinylated SMAC peptide (AVPFAQK) in streptavidin-coated 96-well plates. For the XIAP BIR3 Smac ELISA, a fusion of GST-BIR3 containing amino acids 248-358 from XIAP is used. For the CIAP1 BIR3 Smac ELISA, a fusion of GST-BIR3 containing amino acids 259-364 from C1AP1 is used. Following a 30 minute incubation, wells are washed extensively. The remaining GST-BIR3 fusion protein is monitored by an ELISA assay which first involves incubation with goat anti-GST antibodies, followed by washing and incubation with goat anti-alkaline phosphatase conjugated antibodies. The signal is amplified using Attophos (Promega), and read with Cytoflour Ex 450 nm / 40 and Em 580 nm. The IC50s correspond to the concentration of the compound that displaces half of the GST-BIR3 signal. The IC 50 for the non-biotinylated Smac is 400 nM. The IC 50 values of the compounds listed in Table 1 in the ELISA assays described were in the range of 0.005 to 10 μM. Cell Proliferation Assay. The ability of the compounds to inhibit the growth of tumor cells in vitro is monitored, using CelITiter 96® AQue0US Non-Radioactive Cell Proliferation Assay (Promega). This test is composed of solutions of a novel tetrazolium compound [3, (4,5-dimethyl-thiazol-2-yl) -5- (3-carboxy-methoxy-phenyl) -2- (4-sulfophenyl) - 2H-tetrazolium, internal salt; MTS] and an electron coupling reagent (phenazine methosulfate) PMS. The MTS is bio-reduced by the cells in a formazan product, whose absorbance is measured at 490 nanometers. The conversion of MTS into the water-soluble formazan product is carried out by the dehydrogenase enzymes found in the metabolically active cells. The amount of formazan product measured by the amount of absorbance at 490 nanometers is directly proportional to the number of living cells in the culture. The IC5o values of the compounds listed in Table 1 in the cell assays described were in the range of 0.005 to 50 μl Example 196 Tablets 1 comprising compounds of the formula (I) Tablets comprising, as an active ingredient, 50 milligrams of any of the compounds of the formula (I) mentioned in the preceding Examples 9-194, of the following composition are prepared, using routine methods: Composition Active ingredient 50 mg Wheat starch 60 mg Lactose 50 mg Colloidal silica 5 mg Talc 9 mg Magnesium stearate 1 mg Total 175 mg Manufacturing: The active ingredient is combined with part of the wheat starch, the lactose, and the colloidal silica, and the mixture is compressed through a sieve. An additional part of the wheat starch is mixed with 5 times the amount of water, in a water bath, to form a paste, and the mixture made first is kneaded with this paste until a weakly plastic mass is formed. The dried granules are compressed through a sieve having a mesh size of 3 millimeters, mixed with a previously sieved mixture (1 millimeter sieve) of the remaining corn starch, magnesium stearate, and talc, and compressed to form slightly biconvex tablets.

Example 197 Tablets 2 comprising compounds of the formula (I) Tablets are prepared which comprise, as an active ingredient, 100 milligrams of any of the compounds of the formula (I) mentioned in Examples 9-194, with the following composition, employing conventional procedures: Composition Active Ingredient 100 mg Crystalline lactose 240 mg Avicel 80 mg PVPPXL 20 mg Aerosil 2 mg Magnesium stearate 5 mg Total 447 mg Manufacturing: The active ingredient is mixed with the carrier materials and compressed by means of a tablet-forming machine (Korsch EKO, Stempeldurchmesser, 10 millimeters).

Example 198 Capsules Capsules are prepared which comprise, as an active ingredient, 100 milligrams of any of the compounds of the formula (I) given in Examples 9-194, of the following composition, according to the conventional procedures: Composition Active Ingredient 100 mg Avicel 200 mg PVPPXL 15 mg Aerosil 2 mg Magnesium stearate 1.5 mg Total 318.5 mg The manufacturing is done by mixing the components and filling them in hard gelatin capsules, size 1.

Claims (26)

1. A compound according to formula I: where: R-i is H; alkyl of 1 to 4 carbon atoms; alkenyl of 1 to 4 carbon atoms; alkynyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 10 carbon atoms, which are unsubstituted or substituted; R2 is H; alkyl of 1 to 4 carbon atoms; alkenyl of 1 to 4 carbon atoms; alkynyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 10 carbon atoms, which are unsubstituted or substituted; R3 is H; -CF3; -C2F5; alkyl of 1 to 4 carbon atoms; alkenyl of 1 to 4 carbon atoms; alkynyl of 1 to 4 carbon atoms; -CH2-Z; or R2 and R3, together with nitrogen, form a ring het; Z is H; -OH; F; Cl; -CH3; -CH2CI; -CH2F, or -CH2OH; R 4 is straight or branched alkyl of 1 to 16 carbon atoms; alkenyl of 1 to 16 carbon atoms; alkynyl of 1 to 16 carbon atoms; or cycloalkyl of 3 to 10 carbon atoms; - (CH2) 1.6-Z1; -CH2) or -6-aryl; and - (CH2) or ~ e-het; wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted; ZT is -N (R8) -C (O) -alkyl of 1 to 10 carbon atoms; -N (R8) -C (O) - (CH2)? -6-cycloalkyl of 3 to 7 carbon atoms; -N (R8) -C (O) - (CH2) o -6-phenyl; -N (R8) -C (O) - (CH2) 1.6-het; -C (O) -N (Rg) (R10); - C (O) -O-alkyl of 1 to 10 carbon atoms; -C (O) -O- (CH 2) 1,6-cycloalkyl of 3 to 7 carbon atoms; -C (O) -O- (CH 2) o-6-phenyl; -C (O) -O- (CH2) 1.6-het; -O-C (O) -alkyl of 1 to 10 carbon atoms; -O-C (O) - (CH 2)? - 6-cycloalkyl of 3 to 7 carbon atoms; -O-C (O) - (CH2) 0_6-phenyl; -O-C (O) - (CH2) 1.6-het; wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted; het is a 5 to 7 membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, and S, or a fused ring system of 8 to 12 members, including at least one heterocyclic ring of 5 to 7 members containing 1, 2, or 3 heteroatoms selected from N, O, and S, whose heterocyclic ring or fused ring system is unsubstituted or substituted on a carbon or nitrogen atom; R8 is H; -CH3; -CF3; -CH2OH, or -CH2CI; R9 and R10 are each independently H; alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms; - (CH 2)? - β-cycloalkyl of 3 to 7 carbon atoms; - (CH2) 0.6-phenyl; wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted, or R9 and R-io, together with nitrogen, form het; R5 is H; alkyl of 1 to 10 carbon atoms; aril; phenyl; cycloalkyl of 3 to 7 carbon atoms; - (CH2) 0-6-phenyl; - (CH2) o- CH - ((CH2) 1.4-phenyl) 2; - (CH2) o -6-CH (phenyl) 2; -indanilo; -C (O) -alkyl of 1 to 10 carbon atoms; -C (O) - (CH 2) 1,6-cycloalkyl of 3 to 7 carbon atoms; -C (O) - (CH2) 0_6-phenyl; - (CH2) 0.e-C (O) -phenyl; - (CH2) 0-6-het; -C (O) - (CH2) 1.6-het; or R5 is a residue of an amino acid, wherein the substituents of alkyl, cycloalkyl, phenyl, and aryl are unsubstituted or substituted; U is as shown in structure II: where: n = 0 to 5; X is -CH or N; Ra and Rb are independently an atom of O, S, or N, or alkyl of 0 to 8 carbon atoms, wherein one or more of the carbon atoms in the alkyl chain can be replaced by a heteroatom selected from O, S, or N, and wherein the alkyl may be unsubstituted or substituted; Rd is selected from: (a) -Re-Q - (Rf) p (Rg) q; or (b) AGÍ-D-Ar2; Rc is H, or Rc and Rd can together form a cycloalkyl or het; wherein, if Rd and Rc form a cycloalkyl or het, R5 is attached to the ring formed at a C or N atom; p and q are independently 0 or 1; Re is alkyl of 1 to 8 carbon atoms or alkylidene, and Re may be unsubstituted or substituted; Q is N, O, S, S (O), or S (O) 2; Ar-i and Ar2 are substituted or unsubstituted aryl, or het; Rf and Rg are each independently H; alkyl of 1 to 10 carbon atoms; alkyl of 1 to 10 carbon atoms-aryl; -OH; -O-alkyl of 1 to 10 carbon atoms; - (CH2) 0.6-cycloalkyl of 3 to 7 carbon atoms; -O- (CH2) 0-6-aryl; phenyl; aril; phenyl-phenyl; - (CH2) 1.6-het; -O- (CH2) 1.6-het; -OR? -C (0) -R11; -C (O) -N (R11) (R12); - N (Rn) (R12); -S-RY -S (O) -R? -S (0) 2R11; -S (O) 2-NR 11 R 12; -NR? R S (O) 2 -R12; S-alkyl of 1 to 10 carbon atoms; aryl-alkyl of 1 to 4 carbon atoms; het-alkyl of 1 to 4 carbon atoms, wherein alkyl, cycloalkyl, het, and aryl are unsubstituted or substituted; -SO 2 -alkyl of 1 to 2 carbon atoms; -SO2-alkyl of 1 to 2 carbon atoms-phenyl; -O-alkyl of 1 to 4 carbon atoms; or Rg and Rf form a ring selected from het or aryl; D is -CO-; -C (O) -alkylene of 1 to 7 carbon atoms or arylene; -CF2-; -OR-; -S (O) r, where r is from 0 to 2; 1,3-dioxolane; or alkyl of 1 to 7 carbon atoms-OH; where alkyl, alkylene,

Or arylene can be unsubstituted or substituted with one or more halogens, OH, -O-alkyl of 1 to 6 carbon atoms, -S-alkyl of 1 to 6 carbon atoms, or -CF3; or D is -N (Rh), where Rh is H; alkyl of 1 to 7 carbon atoms (unsubstituted or substituted); aril; - O- (cycloalkyl of 1 to 7 carbon atoms) (unsubstituted or substituted); C (O) -alkyl of 1 to 10 carbon atoms; C (O) -alkyl of 0 to 10 carbon atoms-aryl; C-O-alkyl of 1 to 10 carbon atoms; C-O-alkyl of 0 to 10 carbon atoms-aryl, or SO 2 -alkyl of 1 to 10 carbon atoms; SO2- (alkyl of 0 to 10 carbon atoms-aryl); R6, R, R ', and R7 are each independently H; -alkyl of 1 to 10 carbon atoms; -alkoxyl of 1 to 10 carbon atoms; aryl-alkoxy of 1 to 10 carbon atoms; -OH; -O-alkyl of 1 to 10 carbon atoms; - (CH2) 0.6-cycloalkyl of 3 to 7 carbon atoms; -O- (CH2) 0.e-aryl; feniio; - (CH2) 1.6-het; -O- (CH2) 1.6-het; -ORn; -C (O) R1 ?; -C (O) -N (R11) (R12); -N (R11) (R12); -MR? -S (O) -R? -S (O) 2 -R11; -S (O) 2-NR 11 R 12; -NR11-S (O) 2-R12; wherein alkyl, cycloalkyl, and aryl are unsubstituted or substituted; and R6, R7, R'e, and R'7 can be joined to form a ring system; R11 and R-? 2 are independently H; alkyl of 1 to 10 carbon atoms; - (CH2) 0-6-cycloalkyl of 3 to 7 carbon atoms; - (CH2) 0-6- (CH0.? (Aryl) 1.2; -C (O) -alkyl of 1 to 10 carbon atoms; -C (O) - (CH2) 1,6-cycloalkyl of 3 to 7 carbon atoms carbon; -C (O) -O- (CH2) 0-6-aryl; -C (O) - (CH2) 0-6-O-fluorenyl; -C (O) -NH- (CH2) 0-6 -aryl-C (O) - (CH2) o-β-aryl; -C (O) - (CH2) 1.6-het; -C (S) -alkyl of 1 to 10 carbon atoms; -C (S) ) - (CH2) 1,6-cycloalkyl of 3 to 7 carbon atoms: -C (S) -O- (CH2) o-β-aryl; -C (S) - (CH2) 0-6-O-fluorenyl; -C (S) -NH- (CH2) 0-6-aryl; -C (S) - (CH2) 0.β-aryl; -C (S) - (CH2) 1.6-het; wherein alkyl, cycloalkyl , and aryl are unsubstituted or substituted, or Rn and R12 are a substituent that facilitates the transport of the molecule through a cell membrane, or Rn and R12, together with the nitrogen atom, form het; wherein the alkyl substituents of Rn and R12 may be unsubstituted or substituted by one or more substituents selected from alkyl of 1 to 10 carbon atoms, halogen, OH, -O-alkyl of 1 to 6 carbon atoms, -S-alkyl of 1 to 6 carbon atoms, or -CF3: the substituted cycloalkyl substituents of R-n and R-? 2 are substituted by one or more substituents selected from aiken of 1 to 10 carbon atoms; alkyl of 1 to 6 carbon atoms; halogen; OH; -O-alkyl of 1 to 6 carbon atoms; -S-alkyl of 1 to 6 carbon atoms, or -CF3; and substituted phenyl or aryl of R ^ and R12 are substituted by one or more substituents selected from halogen; hydroxyl; alkyl of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; nitro; -CN; -O-C (O) -alkyl of 1 to 4 carbon atoms, and -C (O) -O-aryl of 1 to 4 carbon atoms; or pharmaceutically acceptable salts thereof. 2. A compound of the formula (I), according to claim 1, wherein: R-] is H; alkyl of 1 to 4 carbon atoms; alkenyl of 1 to 4 carbon atoms; alkynyl of 1 to 4 carbon atoms, or cycloalkyl, which are unsubstituted or substituted by one or more substituents selected from halogen, -OH, -SH, -OCH3, -SCH3, -CH, -SCN, and nitro; R2 is H; alkyl of 1 to 4 carbon atoms; alkenyl of 1 to 4 carbon atoms; alkynyl of 1 to 4 carbon atoms, or cycloalkyl, which are unsubstituted or substituted by one or more substituents selected from halogen, -OH, -SH, -OCH3, -SCH3, -CH, -SCN, and nitro; R3 is H; -CF3; -C2F5; alkyl of 1 to 4 carbon atoms; alkenyl of 1 to 4 carbon atoms; alkynyl of 1 to 4 carbon atoms; -CH2-Z; or R2 and R3, together with nitrogen, form a het; Z is H; -OH; F; Cl; -CH3; -CF3, -CH2C1; -CH2F, or

CH2OH; R 4 is straight or branched alkyl of 1 to 16 carbon atoms; alkenyl of 1 to 16 carbon atoms; alkynyl of 1 to 16 carbon atoms; or cycloalkyl; - (CH2) 1.6-Z ?; -CH2) or -6-phenyl; and - (CH2) o-6-het; wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted; Z-i is -N (R8) -C (O) -alkyl of 1 to 10 carbon atoms; -N (R8) -C (O) - (CH2)? -6-cycloalkyl of 3 to 7 carbon atoms; -N (R8) -C (O) - (CH2) 0-6-phenyl; -N (R8) -C (O) - (CH2) 1.6-het; -C (O) -N (R9) (R10); -C (O) -O-alkyl of 1 to 10 carbon atoms; -C (O) -O- (CH 2) 1,6-cycloalkyl of 3 to 7 carbon atoms; -C (O) -O- (CH 2) o-6-phenyl; -C (O) -O- (CH2) 1.6-het; -O-C (O) -alkyl of 1 to 10 carbon atoms; -O-C (O) - (CH2)? _6-cycloalkyl of 3 to 7 carbon atoms; -O-C (O) - (CH2) 0.6-phenyl; -O-C (O) - (CH2)? 6-het; wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted; het is a 5 to 7 membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, and S, or a fused ring system of 8 to 12 members, including at least one heterocyclic ring of 5 to 7 members containing 1, 2, or 3 heteroatoms selected from N, O, and S, whose heterocyclic ring or fused ring system is unsubstituted or substituted on a carbon atom by halogen, hydroxyl, alkyl of 1 to 4 carbon atoms carbon, alkoxy of 1 to 4 carbon atoms, nitro, -OC (O) -alkyl of 1 to 4 carbon atoms, or -C (O) -O-alkyl of 1 to 4 carbon atoms, or on a nitrogen for alkyl of 1 to 4 carbon atoms, -O-C (O) -alkyl of 1 to 4 carbon atoms, or -C (O) -O-alkyl of 1 to 4 carbon atoms; R8 is H; -CH3; -CF3; -CH2OH, or -CH2CI; Rg and R10 are each independently H; alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms; - (CH2)? 6-cycloalkyl of 3 to 7 carbon atoms; - (CH2) 0.6-phenyl; wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted, or R9 and R10, together with nitrogen, form het; R5 is H; alkyl of 1 to 10 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; - (CH2) 1,6-cycloalkyl of 3 to 7 carbon atoms; -alkyl of 1 to 10 carbon atoms-aryl; (CH2) 0-e-cycloalkyl of 3 to 7 carbon atoms- (CH2) 0-6-phenyl; - (CH2) 0.4CH - ((CH2) 1.4-phenyl) 2; - (CH2) o.6-CH (phenyl) 2; - (CH2) 0-6C (O) -phenyl-indanyl; aryl-C (O) -alkyl of 1 to 10 carbon atoms; -C (O) - (CH2)? _6-cycloalkyl of 3 to 7 carbon atoms; -C (O) - (CH2) o -6-phenyl; - (CH2) 0-6-het; -C (O) - (CH2) 1.6-het; or R5 is a residue of an amino acid, wherein alkyl, cycloalkyl, phenyl, and aryl are unsubstituted or substituted; U is as shown in structure II: where: n = 0 to 5; X is -CH or N; Ra and Rb are independently an atom of O, S, or N, or alkyl of 0 to 8 carbon atoms, wherein one or more of the carbon atoms in the alkyl chain can be replaced by a heteroatom selected from O, S, or N, and wherein the alkyl may be unsubstituted or substituted; Rd is selected from: (a) -Re-Q - (Rf) p (Rg) q; or (b) Ar! - D - Ar2; P and q are independently 0 or 1; Rc is H, or Rc and Rd together form cycloalkyl or het; wherein, if Rd and Rc form a cycloalkyl or hetero ring, R 5 is attached to the ring formed on a C or N atom; Re is alkyl of 1 to 8 carbon atoms which may be unsubstituted or substituted;

Q is N, O, S, S (O), or S (O) 2; Ar! and Ar2 are substituted or unsubstituted aryl, or het; Rf and Rg are each independently H; alkyl of 0 to 10 carbon atoms unsubstituted or substituted, or alkyl of 1 to 10 carbon atoms-aryl; D is -CO-; -C (O) -alkylene of 1 to 7 carbon atoms or aryiene; -CF2-; -OR-; -S (O) r, where r is from 0 to 2; 1,3-dioxolane; or alkyl of 1 to 7 carbon atoms-OH; where alkyl, alkylene,

Or arylene can be unsubstituted or substituted with one or more halogens, OH, -O-alkyl of 1 to 6 carbon atoms, -S-alkyl of 1 to 6 carbon atoms, or -CF3; or D is -N (Rh), where Rh is H; alkyl of 1 to 7 carbon atoms (unsubstituted or substituted); aril; -O- (cycloalkyl of 1 to 7 carbon atoms) (unsubstituted or substituted); C (O) -alkyl of 1 to 10 carbon atoms; C (O) -alkyl of 0 to 10 carbon atoms-aryl; C-O-alkyl of 1 to 10 carbon atoms; C-O-alkyl of 0 to 10 carbon atoms-aryl, or SO 2 -alkyl of 1 to 10 carbon atoms; SO2- (alkyl of 0 to 10 carbon atoms-aryl); and R6, R, R ', and R' are each independently H; -alkyl of 1 to 10 carbon atoms; -OH; -O-alkyl of 1 to 10 carbon atoms; - (CH2) 0.6-cycloalkyl of 3 to 7 carbon atoms; -O- (CH2) 0-6-aryl; phenyl; - (CH2)? - 6-het; -O- (CH2) 1.6-het; -ORn; -C (O) RÜ; -C (O) -N (R!) (R? 2); -N (R,?) (R12); -MR"; -S (0) -R?,; -S (O) 2 -Rn; -S (0) 2-NR 11 R 12; -NR11-S (O) 2-R12; wherein alkyl, cycloalkyl, and aryl are unsubstituted or substituted; or any of R6, R, R'ß, and R * 7 can be joined to form a ring system; R11 and R12 are independently H; alkyl of 1 to 10 carbon atoms; - (CH2) 0-6-cycloalkyl of 3 to 7 carbon atoms; - (CH2) 0-6- (CHo -? (Aryl)! _ 2; -C (O) -alkyl of 1 to 10 carbon atoms; -C (O) - (CH2)? 6-cycloalkyl of 3 to 7 carbon atoms: -C (O) -O- (CH2) 0-6-aryl; -C (O) - (CH2) 0-6-O-fluorenyl; -C (O) -NH- ( CH2) 0.6-aryl; -C (O) - (CH2) 0-e-aryl; -C (O) - (CH2) 1.β-het; -C (S) -alkyl of 1 to 10 carbon atoms; -C (S) - (CH2)? 6-cycloalkyl of 3 to 7 carbon atoms; -C (S) -O- (CH2) 0.β-aryl; -C (S) - (CH2) or -6-O-fluorenyl; -C (S) -NH- (CH2) 0-6-aryl; -C (S) - (CH2) 0.6-aryl; -C (S) - (CH2) 1.- et, wherein alkyl, cycloalkyl, and aryl are unsubstituted or substituted, or Rn and R 2 are a substituent that facilitates the transport of the molecule through a cell membrane, or R11 and i2, together with the nitrogen atom, are he aryl of RÜ and R 12 may be phenyl, naphthyl, or indanyl which is unsubstituted or substituted, alkyl of R n and R 12 may be unsubstituted or substituted by one or more substituents selected from alkene of 1 to 10 carbon atoms, halogen , OH, -O-alkyl from 1 to 6 carbon volumes, -S-alkyl of 1 to 6 carbon atoms, and -CF3; cycloalkyl of Rn and R12 may be unsubstituted or substituted by one or more selected from alkene of 1 to 10 carbon atoms, one or more halogens, alkyl of 1 to 6 carbon atoms, halogen, OH, -O-alkyl of 1 to 6 carbon atoms, -S-alkyl of 1 to 6 carbon atoms, or -CF3; and phenyl or aryl of R ,, and Ri2 may be unsubstituted or substituted by one or more substituents selected from halogen; hydroxyl; alkyl of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; nitro; -CN; -O-C (O) -alkyl of 1 to 4 carbon atoms, and -C (O) -O-aryl of 1 to 4 carbon atoms; or pharmaceutically acceptable salts thereof. 3. A compound according to claim 1, wherein: Ri and R2 are independently H, or substituted or unsubstituted alkyl of 1 to 4 carbon atoms; R 4 is straight or branched alkyl of 1 to 16 carbon atoms; alkenyl of 1 to 16 carbon atoms, or cycloalkyl of 3 to 10 carbon atoms, wherein alkyl or cycloalkyl may be unsubstituted or substituted; R5 is H; alkyl of 1 to 10 carbon atoms; alkyl of 1 to 10 carbon atoms-aryl; -C (O) - (CH2) 0.6-phenyl; - (CH2) 0-eC (O) -phenyl; aryl, indanyl; naphthyl; or R5 is a residue of an amino acid, wherein the alkyl or aryl substituents are unsubstituted or substituted; U is as shown in the structure where: n = 0 to 5; X is -CH or N; Ra and Rb are independently an atom of O, S, or N, or alkyl of 0 to 8 carbon atoms, wherein one or more of the carbon atoms in the alkyl chain can be replaced by a heteroatom selected from O, S, or N, and wherein the alkyl may be unsubstituted or substituted; Rd is selected from: (a) -Re-Q - (Rf) p (Rg) q; or (b) AGT-D-Ar2; Rc is H, or Rc and Rd together form cycloalkyl or het; wherein, if Rd and Rc form a cycloalkyl or hetero ring, R 5 is attached to the ring formed on a C or N atom; p and q are independently 0 or 1; Re is alkyl of 1 to 8 carbon atoms or methylidene, which may be unsubstituted or substituted; Q is N, O, S, S (O), or S (O) 2; Ar! and Ar2 are substituted or unsubstituted aryl, or het; Rf and Rg are each independently H, or alkyl of 0 to 10 carbon atoms; alkyl of 1 to 10 carbon atoms-aryl; aryl-alkyl of 1 to 10 carbon atoms; het-alkyl of 1 to 10 carbon atoms; -C (O) -alkyl of 1 to 4 carbon atoms-phenyl; -C (O) -alkyl of 1 to 4 carbon atoms; -SO 2 -alkyl of 1 to 2 carbon atoms; -SO 2 -alkyl of 1 to 2 carbon atoms-phenyl; -O-alkyl of 1 to 4 carbon atoms;

D is -C (O) -; alkylene of 1 to 7 carbon atoms or arylene; -OR-; -S (O) r, where r is from 0 to 2; wherein alkyl, alkylene, or arylene may be unsubstituted or substituted with one or more halogens; -OH, -O-alkyl of 1 to 6 carbon atoms, -S-alkyl of 1 to 6 carbon atoms, or -CF3; or D is -NRh, where Rh is H; alkyl of 1 to 7 carbon atoms (unsubstituted or substituted); aril; -O-cycloalkyl of 1 to 7 carbon atoms (unsubstituted or substituted); CO-alkyl of 0 to 10 carbon atoms, or aryl, or SO 2 -alkyl of 0 to 10 carbon atoms, or aryl; and R6, R7, R'ß, and R 'are each independently H; -alkyl of 1 to 10 carbon atoms; u -OH, -alkoxy, or aryloxy; or pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein: U is a saturated or unsaturated bicyclic ring system, which consists of the entire carbon skeleton, or with one or more heteroatoms, such as O, N, S, but preferably as shown in structure III: wherein: any of the ring carbon atoms may be unsubstituted or substituted with any of the substituents defined above for R6, R7, R'6, and R'7; X is CH or N; V is O, F2, Cl2, Br2, I2, S, YH, H2, NH, or alkyl of 1 to 4 carbon atoms; W is -CH or -N; n is from 0 to 3; and m is from 0 to 3. A compound according to claim 1, wherein the ring carbon atoms on U are substituted with substituents independently selected from halogen, H, OH, lower alkyl, or lower alkoxy, wherein alkyl or alkoxy are unsubstituted or substituted by halogen, OH, lower alkyl, or lower alkoxy. 6. A compound according to claim 1, wherein: R! and R3 are preferably methyl or ethyl; R2 is especially H; methyl; ethyl; chloro-methyl; dichloro-methyl, or trifluoromethyl; R 4 is -alkyl of 1 to 4 carbon atoms; -Cycloalkyl of 3 to 7 carbon atoms; - (CH2)? 6-cycloalkyl; or - (CH2) 0-6-aryl; R5 is -alkyl of 1 to 4 carbon atoms-phenyl; -C (O) -alkyl of 1 to 4 carbon atoms-fenium; -alkyl of 1 to 4 carbon atoms-C (O) -phenyl, or aryl; R5 is in particular phenyl-methyl, f in i-ethyl, and phenyl-propyl; indanyl, naphthyl; -C (O) -CH2-phenyl, or -CH2-C (O) -phenyl; R6 and R7 are H or methyl; U has the structure of formula III: wherein: any of the ring carbon atoms may be unsubstituted or substituted with any of the substituents defined above for R6, R7, R'e, and RM X is N; V is O or H2; W is -N; n is 1; and m is 1 or 2. 7. A compound according to claim 1, wherein: R and R3 are preferably methyl or ethyl; R2 is H; R4 is alkyl of 1 to 4 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkyl of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms; phenyl-alkyl of 1 to 7 carbon atoms, or aryl. R 4 is in particular methyl; ethyl; butyl; isopropyl; tertiary butyl; or cyclohexyl; -CH2-cyclopentyl; -CH2-cyclohexyl; - CH2-cyclopropyl; phenyl, or -CH2-phenyl; R5 is -alkyl of 1 to 4 carbon atoms-phenyl; -C (O) -alkyl of 1 to 4 carbon atoms-phenyl; -alkyl of 1 to 4 carbon atoms-C (O) -phenyl, or aryl. R5 is in particular phenyl-ethyl; indanium, naphthyl; -C (O) -CH2-phenyl; -CH2-C (O) -phenyl, or

(CF3O) phenyl-ethyl; U has the structure of formula III wherein: any of the ring carbon atoms may be unsubstituted or substituted with any of the substituents defined above for R6, R7, R'6, and R'7; X is N; V is O or H2; W is -N; n is 1; and m is 1 or 2. 8. A compound according to claim 1, wherein: Ri and R3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is H;

U has the structure of formula II where: X is N; n is O; Rc is H; Ari and Ar2 are substituted or unsubstituted phenyl or het, in particular tetrazolyl, 1,2,3-triazole, pyrazole, oxazole, pyrrolyl, triazine, pyrimidine, imidazole, oxadiazole; and D is alkyl of 1 carbon atom, which may be optionally substituted with halogen, especially F. 9. A compound according to claim 1, wherein: R-i and R3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkyl of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms; phenyl-alkyl of 1 to 7 carbon atoms, or aryl; R5 is H; U has the structure of formula II where: X is N; Re, R'e, R7, and R'7 are H; or R6 is -C (O) -alkyl of 1 to 4 carbon atoms-phenyl, and R'6, R7, and R'7 are H; n is O;

Rc is H; Ari and Ar2 are substituted or unsubstituted phenyl or het, in particular triazine, pyrimidine, pyridine, oxazole, 2,4-difluoro-phenyl, Cl-phenyl, or fluoro-phenyl; and D is N (Rh), where Rh is H, Me, -CHO, -SO2, -C (O), -CHOH, -CF3, or -SO2CH3.

10. A compound according to claim 1, wherein: Ri and R3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkyl of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms; phenyl-alkyl of 1 to 7 carbon atoms, or aryl. R is in particular methyl, ethyl, butyl, isopropyl, tertiary butyl, or cyclohexyl; -CH2-cyclopentyl, -CH2-cyclohexyl; -CH2-cyclopropyl; phenyl, or -CH2-phenyl; R5 is H; U has the structure of formula II where: X is N; Re, R'e, R7, and R'7 are H; n is O; Rc is H; Ar! and Ar2 are substituted or unsubstituted phenyl or het, in particular pyrimidine, pyridine, oxazole, 2-methyl-oxazoi; and D is -O-.

11. A compound according to claim 1, wherein: Ri and R3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyium; R5 is H; U has the structure of formula II where: X is N; n is O; Rc is H; Ari and Ar2 are substituted or unsubstituted phenyl or het; and D is S, S (O), or S (O) 2.

12. A compound according to claim 1, wherein: Ri and R3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is H; U has the structure of formula II where: X is N; Re, R'e, R7, and R'7 are H; n is O; Rc is H; Ar! and Ar2 are substituted or unsubstituted phenyl or het, in particular oxazole, thiazole, and oxadiazole; and D is C (O), or 1,3-dioxolane.

13. A compound according to claim 1, wherein: Ri and R3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is H or phenyl-alkyl of 1 to 10 carbon atoms, such as phenyl-ethyl; U has the structure of formula II where: X is N; Re, R'e, R7, and R '? they are H; n is O; Rc and Rd are het, in particular pyrrolidine; pyrrolidin-2-one; or pyrrolidin-3-one.

14. A compound according to claim 1, wherein: Ri and R3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is H, indanyl, or phenyl; U has the structure of formula II where: X is N; Q is O; n is O; Re is alkyl of 1 carbon atom; and p and q are 0. 15. A compound according to claim 1, wherein: Ri and R3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is H, indanyl, or phenyl;

U has the structure of formula II where: X is N; Q is N; n is O; Re is alkyl of 1 carbon atom; and Rg is H, alkyl of 1 to 8 carbon atoms, methyl, ethyl, hexyl, heptyl, octyl; or CH2CF3; or aryl-alkyl of 1 to 4 carbon atoms, in particular phenyl-ethyl, furanyl-ethyl; cycloalkyl of 3 to 7 carbon atoms, in particular cyclohexyl; etyl-fyl; -C (O) -alkyl of 1 to 4 carbon atoms-phenyl; -C (O) -alkyl of 1 to 4 carbon atoms, -alkyl of 1 to 4 carbon atoms-aryl, in particular -CH2-phenyl; -CH2-thiophene, -CH2-furan, -CH2-pyrrolidinyl, -CH2-imidazole, -CH2-triazole, -CH2-imidazole; and Rf is alkyl of 1 to 2 carbon atoms; alkyl from 1 to 2 carbon atoms-phenyl; -SO 2 -alkyl of 1 to 2 carbon atoms; -SO 2 -alkyl of 1 to 2 carbon atoms-phenyl; -O-alkyl of 1 to 4 carbon atoms, in particular O-ethyl; phenyl-phenyl 1, 2,3,4-tetrahydro-naphthalene, and indanyl.

16. A compound according to claim 1, wherein: Ri and R3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R5 is H, indanyl, or phenyl; U has the structure of formula II where: X is N; Q is N; n is O; Re is alkyl of 1 carbon atom; and Rg and Rf form a ring selected from het or ary, in particular 2,3,4,5-tetra-hydro-benzo- [c] -azepine; 1,2,3,4-tetrahydroquinoline; indanyl which may be substituted with alkyl of 1 to 4 carbon atoms-phenyl.

17. A compound according to claim 1, wherein: Ri and R3 are preferably methyl or ethyl; R 2 is in particular H, methyl, ethyl, chloro-methyl, dichloro-methyl, or trifluoromethyl; R 4 is alkyl of 1 to 4 carbon atoms; or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl; R is phenyl; U has the structure of formula II where: X is N; Q is O, S, S (O), or S (O) 2; n is O; Re is alkyl of 1 carbon atom; q is 0; Rc is H; and Rf.es alkyl of 2 carbon atoms.

18. A compound according to claim 1, wherein: R3 and R have the stereochemistry indicated in formula IV, the definitions of the variable substituents and the preferences described hereinbefore also being applied to the compounds having the stereochemistry indicated in formula IV:

19. A compound according to claim 18, which is a compound with the stereochemistry of the formula (IV), wherein: Ri and R3 are preferably methyl or ethyl; R2 is H, methyl, ethyl, or substituted methyl, especially chloro-methyl, dichloro-methyl, and trifluoromethyl; preferably R2 is H or unsubstituted methyl; R 4 is alkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms, in particular isopropyl, tertiary butyl, cyclopentyl, or cyclohexyl;

R is -alkyl of 1 to 4 carbon atoms-phenyl, in particular phenyl-methyl, phenyl-ethyl, and phenyl-propyl, indanyl, naphthyl; and R6 and Ry are H or methyl. 20. A compound according to claim 1, wherein the stereochemistry for U is as shown in Figure V:

21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the formula I according to claim 1.

22. A method for the treatment of a proliferative disease, which comprises administering a therapeutically effective amount of a composed of the formula I according to claim 1, to a mammal in need of said treatment.

23. A method of claim 22, wherein the mammal is a human being.

24. A compound selected from: N - [1-cyclohexy l-2-oxo-2- (6-phenethyl-octah id ro-pyrrole or- [2,3-c] -pyridin-1-yl) - ethyl] -2-methyl-amino-acetamide; 2-Methyl-amino-N- [2-methyl-1- (7-oxo-6-phenethyl-octahydro-pyrrolo- [2,3-c] -pyridin-1-carbonyl) -propyl] -propionamide; 2-Methyl-amino-N- [2-methyl-1- (7-oxo-6-phenethyl-octahydro-pyrrolo- [2,3-c] -pyridin-1-carbonyl) -propyl] -propionamide; 2-Methyl-amino-N- [2-methyl-1- (8-oxo-7-phenethyl-octah, idro-pyrrolo- [2,3-c] -azepin-1-carbonyl) -propyl] -propionamide; 2-Methyl-amino-N- [2-methyl-1- (7-oxo-6-phenethyl-octahydro-pyrrolo- [2,3-c] -pyridin-1-carbonyl) -propyl] -butyramide; 2-Methyl-amino-N- [2-methyl-1- (7-oxo-6-phenethyl-octahydro-pyrrolo- [2,3-c] -pyridin-1-carbonyl) -propyl] -butyramide; 2-Methyl-amino-N- [2-methyl-1- (8-oxo-7-phenethyl-octahydro-pyrrolo- [2,3-c] -azepin-1-carbonyl) -propyl] -butyramide; N- [1-hexyl-2-oxo-2- (7-oxo-6-phenethyl-octah idro-pyrro I or- [2, 3-c] -pyridin-1-yl) -ethyl] -2 -methyl-amino-propionamide; 2-methyl-amino-N-. { 2-methyl-1- [5- (3-methyl-hexa-3,5-dienyl) -6-oxo-hexahydro-pyrrolo- [3,4-b] -pyrrole-1-carbonyl] -propyl} -propionamide; 2-Methyl-amino-N- [2-methyl-1- (3-methyl-7-oxo-6-phenethyl-octahydro-pyrrolo- [2,3-c] -pyridin-1, -carbonyl) -propyl] -propionamide; 2-Methyl-amino-N- [2-methyl-1- (3-methyl-7-oxo-6-phenethyl-octahydro-pyrrolo- [2,3-c] -pyridin-1-carbonyl) -propyl] - propionamide; N- [1- (4-benzyl) oxy-7-oxo-6-phenethyl-octahydro-pyrrolo- [2,3-c] pyridine-1-carbonyl) -2-methyl-propyl] -2-methyl- amino-propionamide; N- [1-cyclohexyl-2-oxo-2- (8-oxo-7-phenethyl-octahydro-pyrrolo- [2,3-c] -azepin-1-yl) -ethyl] -2-methyl-amino- Butyramide; N- [1-cyclohexyl-2-oxo-2- (8-oxo-7-phenethyl-octahydro-pyrrolo- [2,3-c] -azepin-1-yl) -ethyl] -2-methyl-amino- Butyramide; N- [1-cyclohexyl-2-oxo-2- (7-phenethyl-octahydro-pyrrolo- [2,3-c] -azepin-1-yl) -ethyl] -2-methyl-amino-propionamide; 2-Methyl-amino-N- [2-methyl-1- (8-oxo-7-phenethyl-octahydro-pyrrolo- [2,3-c] -azepin-1-carbonyl) -propyl] -butyramide; (S) -N-. { (S) -2 - [(R) -2- (3-benzyl-phenyl) -pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-ethyl} -2-methyl-amino-propionamide; (S) -N-. { (S) -2 - [(S) -2- (3-benzyl-phenyl) -pyrrolidin-1-yl] -1-cyclohexyl 2-oxo-ethyl} -2-methyl-amino-propionamide; (S) -2-methyl-amino-N - ((S) -2-methyl-1- { (S) -2- [3- (methyI-phenyl-amino) -phenyl] -pyrrolidin-1- carbonyl.}. propyl) -propionamide; (S) -N - ((S) -1-cyclohexyl-2- { (S) -2- [3- (methyl-phenyl-amino) -phenyl] -pyrroline-1-yl.} -2 -oxo-ethyl) -2-methyl-amino-propionamide; (S) -N - ((S) -1-cyclohexyl-2- { (R) -2- [3- (methyl-phenyl-amino) -phenyl] -pyrrolidin-1-yl.} -2 -oxo-ethyl) -2-methyl-amino-propionamide; (S) -N-. { (S) -1-cyclohexyl-2-oxo-2 - [(R) -2- (3-phenoxy-phenyl) -pyrrolidin-1-yl] -ethyl} -2-methyl-amino-propionamide; (S) -N-. { (S) -1-cyclohexyl-2-oxo-2 - [(S) -2- (3-phenoxy-phenyl) -pyrrolidin-1-yl] -ethyl} -2-methyl-amino-propionamide; (S) -N-. { (S) -1-cyclohexyl-2-oxo-2 - [(R) -2- (3-phenyl-sulfanyl-phenyl) -pyrrolidin-1-yl] -ethyl} -2-methyl-amino-propionamide; (S) -N-. { (S) -1-cyclohexyl-2-oxo-2 - [(S) -2- (3-phenyl-sulfani-phenyl) -pyrrolidin-1-yl] -ethyl} -2-methyl-amino-propionamide; (S) -N-. { (S) -2 - [(R) -2- (3-benzenesulfonyl-phenyl) -pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-ethyl} -2-methyl-amino-propionamide; (S) -N-. { (S) -2 - [(S) -2- (2-Benzyl-2H-tetrazol-5-ll) -pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-ethyl} -2-methyl-amino-propionamide; (S) -N-. { (S) -2 - [(S) -2- (2-Benzyl-2 H -tetrazol-5-yl) -pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-ethyl} -2-methyl-amino-butyramide; (S) -N-. { (S) -2 - [(S) -2- (1-Benzyl-1 H-tetrazol-5-yl) -pyrrole id in-1-yl] -1-cyclohexyl-2-oxo-ethyl} -2-methyl-amino-propionamide; (S) -N-. { (S) -2 - [(S) -2- (1-Benzyl-1H-tetrazol-5-yl) -pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-ethyl} -2-methyl-amino-butyramide; (S) -N-. { (S) -2- [2-benzyloxy-imino-yl) -pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-ethyl} -2-methyl-amino-propionamide; (S) -2-methyl-amino-N-. { (S) -2-methyl-1- [2 - ((S) -phenyl-methanesulfonyl-amino-methyI) -pyrrolidine-1-carbonyl] -propyl} -propionamide; (S) -2-methyl-amino-N-. { (S) -2-methyl-1- [2 - ((S) -phenyl-methan-sulfonyl-amino-methyl) -pyrrolidine-1-carbonyl] -propyl} -butyramide; N- (1-cyclohexyl-2 { (S) -2 - [(ethyl-indan-2-yl-amino) -methyl] -pyrrolidin-1-yl.} -2-oxo-ethyl) - 2 - ((S) -methyl-amino) -propionamide; (S) -N - [(S) -1-cyclohexyI-2- (2- { [(S) -indan-2-yl- (2,2,2-trifluoro-ethyl) -amino] -methyl .} - pyrrolidin-1-yl) -2-oxo-ethyl] -2-methyl-amino-propionamide; (S) -N - [(S) -1-cyclohexyl-2- (2-. {[[(S) -cyclohexyl-phenethyl-amino) -methyl] -pyrrolidin-1-yl} -2-oxo-etiI) -2-methyl-amino-propionamide; (S) -N - ((S) -2- {2 - [((S) -terbutyl-phenethyl-amino) -methyl] -pyrrolidin-1-yl.} -1-cyclohexyl-2-oxo ethyl) -2-methyl-amino-propionamide; (S) -N - ((S) -1-cyclohexyl-2- { 2 - [((S) -furan-2-yl-metii-phenethyl-amino) -methyl] -pyr-olidin-1-yl .} -2-oxo-ethyl) -2-methyl-amino-propionamide; (S) -N - [(S) -1-cyclohexyl-2-oxo-2- (2 { [(S) -phenethyl- (4-phenyl-butyl) -amino] -methyl}. pyrrolidin-1-yl) -ethyl] -2-methyl-amino-propionamide; (S) -N - [(S) -1-cyclohexyl-2- (2- { [(S) -methyl- (4-phenyl-butyl) -amino] -methyl} - pyrrolidin-1- il) -2-oxo-ethyl] -2-methyl-amino-propionamide; N - [(S) -1- (S) -cyclohexyl-2-oxo-2 - ((R) -6-phenethyl-octahydro-pyrrolo- [2,3-c] -pyridin-1-yl) -ethyl ] -acetamide; (S) -N - [(S) -1- (S) -cyclohexyl-2-oxo-2 - ((R) -6-phenethyl-octahydro-pyrrolo- [2,3-c] -pyridin-1- il) -ethyl] -2-methyl-amino-butyramide; (S) -2-methyl-amino-N - [(S) -2-meti.l-1 - ((R) -6-phenethi-octahydro-pyrrolo- [2,3-c] pyridin-1- carbonyl) -propyl] -propionamide; (S) -N - [(S) -2,2-dimethyl-1 - ((R) -6-phenethyl-octahydro-pyrrolo- [2,3-c] -pyridine-1-carbonyl) -propyl] - 2-methyl-amino-propionamide; (S) -2-methyl-amino-N - [(S) -2-methyl-1 - ((R) -6-phenethyl-octahydro-pyrrolo- [2,3-c] -pyridine-1-carbonyl) -propyl] -butyramide; (S) -N - [(S) -2,2-dimethyl-1 - ((3aR, 7aS) -6-phenethi-octahydro-pyrrolo- [2,3-c] -pyridine-1-carbonyl) -propyl ] -2-methyl-amino-propionamide; (S) -N - ((S) -1-cyclohexyl-2-oxo-2-. {(3aR, 7aS) -6- [2- (2-trifiuoromethoxy-phenyl) -ethyl] -octahydro- pyrrolo- [2,3-c] -pyridin-1-yl.}. -ethyl) -2-methyl-amino-propionamide; (S) -N - ((S) -1-cyclohexyl-2-oxo-2-. {(3aR, 7aS) -6- [2- (3-trifluoro-methoxy -phe nyl) -ethyl] -octahydro -pyrro- [2, 3-c] -pyridin-1-yl]. -ethyl) -2-methyl-amino-propionamide; (S) -N - [(S) -1-cyclohexyl-2-oxo-2 - ((3aR, 6aR) -5-phenethyl-hexahydro-pyrrolo- [3,4-b] -pyrrol-1-yl) ethyl) -2-methyl-amino-butyramide; (S) -N - [(S) -1-cyclohexyl-2-oxo-2 - ((3aS, 6aS) -5-phenethyl-hexahydro-pyrrolo- [3,4-b] -pyrrol-1-yl) ethyl) -2-methyl-amino-butyramide; (S) -N - [(S) -1-cyclohexyl-2-oxo-2 - ((3aS, 6aS) -5-phenethyl-hexahydro-pyrrolo- [3,4-b] -pyrrol-1-yl) -ethyl] -2-methyl-amino-propionamide; (S) -N - [(S) - 1 -hexyl-2-oxo-2 - ((3aS, 6a S) -6-oxo-5-f eneti I-hexahydro-pyrrolo- [3,4-b] ] -pyrrol-1-yl) -ethyl] -2-methyl-amino-butyramide; (S) -N - [(R) - -cyclohexyl-2-oxo-2 - ((3aS, 6aS) -6-oxo-5-f eneti I-hexahydro-pyrrolo- [3,4-b] -pyrrole -1 -yl) -ethyl] -2-methyl-amino-butyramide; (S) -N - [(S) -1-Cyclohexy-l-2-oxo-2 - ((3aS, 6a S) -6-oxo-5-f eneti I-hexahydro-pyrrolo- [3,4-b ] -pyrrol-1-yl) -ethyl] -2-methyl-amino-propionamide; (S) -N - [(R) -1-Cyclohexyl-2-oxo-2 - ((3aS, 6a S) -6-oxo-5-f eneti I-hexahydro-pyrrolo- [3,4-b] -pyrrol-1-yl) -ethyl] -2-methyl-ami? o-propionamide; (S) -N - [(S) -1- (R) -cyclohexy-2-oxo-2 - ((S) -7-phenethyl-octahydro-pyrrolo- [2,3-c] -azepin-1- il) -ethyl] -2-methyl-amino-propionamide; (S) -N - [(S) -1- (S) -cyclohexyl-2-oxo-2 - ((R) -8-oxo-7-phenethyl-octahydro-pyrrolo- [2,3-c] - azepin-1-yl) -ethyl] -2-methyl-amino-butyramide; and pharmaceutically acceptable salts thereof.

25. A compound selected from: N- [1-cyclohexyl-2-oxo-2- (6-f eneti-l-octah id ro-p i rrolo- [2, 3-c] -pyridin-1- il) -ethyl] -2-methyl-amino-propionamide; N-. { 1-cyclohexyl-2-oxo-2- (2- (3-phenoxy-phenyl) -pyridinidin-1-yl] -ethyl.} -2-methyl-amino-propionamide; N- [1 -cyclohexyl-2 -oxo-2- (7-f eneti l-octah id ro-p iro I o- [2, 3-c] -azepin-1-yl) -ethyl] -2-methyl-amino-propionamide; ) -N - ((S) -1-cyclohexyl-2-. {(2S, 3R) -2 - [(ethyl-phenethyl-amino) -methyl] -3-methyl-pyrrolidin-1-yl}. -2-oxo-ethyl) -2-methyl-amino-propionamide; N-. {2- 2- [2 (2-benzyl-2H-tetrazol-5-yl) -pyrrolidin-1-yl] -cyclohexyl-2 - oxo-ethyl.} -2-methyl-amino-butyramide; N-. {2- [2-benzyloxy-imino-methyl) -pyrrolidin-1-yl} -1-cyclohexyl-2-oxo-ethyl-2-methyl-amino-propionamide; and pharmaceutically acceptable salts thereof.

26. A compound selected from: (S) -N-. { (S) -1-cyclohexyl-2-oxo-2 - [(S) -2- (3-phenoxy-phenyl) -pyrrolidin-1-yl] -ethyl} -2-methyl-amine-propionamide; (S) -N-. { (S) -1-cyclohexyl-2-oxo-2 - [(S) -2- (3-phenyl-sulfanyl-phenyl) -pyrrolidin-1-yl] -ethyl} -2-methyl-amino-propionamide; (S) -N-. { (S) -2 - [(S) -2- (2-Benzyl-2H-tetrazol-5-yl) -pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-ethyl} -2-methyl-amino-propionamide; (S) -N-. { (S) -2 - [(S) -2- (2-Benzyl-2H-tetrazol-5-yl) -pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-ethyl} -2-methyl-amino-butyramide; (S) -N-. { (S) -2 - [(S) -2- (1-Benzyl-1 H-tetrazol-5-yl) -pyrrole id in-1-yl] -1-cyclohexyl-2-oxo-ethyl} -2-methyl-amino-propionamide; (S) -N-. { (S) -2 - [(S) -2- (1-Benzyl-1H-tetrazol-5-yl) -pyrrolidin-1-yl] -1-cyclohexyl-2-oxo-ethyl} -2-methyl-amino-butyramide; and pharmaceutically acceptable salts thereof.